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Thi-Van-Trinh Tran, Cari Meinhold Kitahara, Laurence Leenhardt, Florent de Vathaire, Marie-Christine Boutron-Ruault, and Neige Journy

In a previous systematic review and meta-analysis of studies reporting associations between hyper-/hypothyroidism and breast cancer incidence published through 29 January 2019, we identified a higher risk with diagnosed hyperthyroidism compared to euthyroidism, but no association with diagnosed hypothyroidism. This 2-year updated meta-analysis aims to investigate the role of menopause in this association and the dose–response relationship with blood levels of thyroid-stimulating hormone (TSH) and thyroid hormones. After the exclusion of studies with only mortality follow-up, with thyroid dysfunction evaluated as a cancer biomarker or after prior breast cancer diagnosis, we reviewed 25 studies that were published up to 01 December 2021 and identified in MEDLINE, the COCHRANE library, Embase, or Web of Science; of these, 9 were included in the previous meta-analysis. Risk estimates from 22 of the 25 studies were included in the meta-analysis and pooled using random-effects models. Compared to euthyroidism, hyperthyroidism and hypothyroidism diagnoses were associated with higher (pooled risk ratio (RR): 1.12, 95% CI: 1.06–1.18, 3829 exposed cases) and lower risks (RR = 0.93, 95% CI: 0.86–1.00, 5632 exposed cases) of breast cancer, respectively. The increased risk after hyperthyroidism was greater among postmenopausal women (RR = 1.19, 95% CI 1.09–1.30) and the decreased risk after hypothyroidism was more pronounced among premenopausal women (RR = 0.69, 95% CI 0.53–0.89). Among women with no prior history of thyroid disease, every 1 mIU/L increase in TSH level was associated with a 0.8% (95% CI > 0–1.5%) lower risk of breast cancer. In conclusion, this meta-analysis supports an association between thyroid hormone levels and breast cancer risk, which could be modified by menopausal status.

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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 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 4,689 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 4 fasting glucose–associated SNPs in PCSK1, SPC25, ADCY5, and MTNR1B and 3 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 increased risk of BC, particularly ER/PR+ BC, in a gene–lifestyle dose-dependent manner. The joint effect of smoking was more substantial in women with a prolonged exposure to cigarette smoking and female hormones. The top GWA-SNPs associated with metabolic biomarkers in combination with lifestyles synergistically increase the predictability of invasive ER/PR positive BC risk among AA women. Our findings highlight generically targeted preventive interventions for women who carry particular risk genotypes and lifestyles.

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Reut Halperin, Liat Arnon, Sapir Nasirov, Limor Friedensohn, Michal Gershinsky, Alona Telerman, Eitan Friedman, Rinat Bernstein-Molho, and Amit Tirosh

Multiple endocrine neoplasia 4 (MEN4) is a rare multiglandular endocrine neoplasia syndrome clinically hallmarked by primary hyperparathyroidism (PHPT), pituitary adenoma (PitAd), and neuroendocrine tumors (NET), clinically overlapping MEN1. The underlying mutated gene – CDKN1B, encodes for the cell-cycle regulator p27. Possible genotype–phenotype correlations in MEN4 have not been thoroughly assessed. Prompted by the findings in three Israeli MEN4 kindreds, we performed a literature review on published and unpublished data from previously reported MEN4/CDKN1B cases. Univariate analysis analyzed time-dependent risks for developing PHPT, PitAd, or NET by variant type and position along the gene. Overall, 74 MEN4 cases were analyzed. PHPT risk was 53.4% by age 60 years (mean age at diagnosis age 50.6 ± 13.9 years), risk for PitAd was 23.2% and risk for NET was 16.2% (34.4 ± 21.4 and 52.9 ± 13.9 years, respectively). The frameshift variant p.Q107fs was the most common variant identified (4/41 (9.7%) kindreds). Patients with indels had higher risk for PHPT vs point mutations (log-rank, P = 0.029). Variants in codons 94–96 were associated with higher risk for PHPT (P < 0.001) and PitAd (P = 0.031). To conclude, MEN4 is clinically distinct from MEN1, with lower risk and older age for PHPT diagnosis. We report recurrent CDKN1B frameshift variants and possible genotype–phenotype correlations.

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.

Free access

Kaylee B Punter, Charles Chu, and Edmond Y W Chan

It has long been recognised that cancer cells critically depend on reprogrammed patterns of metabolism that can enable robust and abnormally high levels of cell proliferation. As mitochondria form hubs of cellular metabolic activity, it is reasonable to propose that pathways within these organelles can form targets that can be manipulated to compromise the ability of cancer cells to cause disease. However, mitochondria are highly multi-functional, and the full range of mechanistic inter-connections are still being unravelled to enable the full potential of targeting mitochondria in cancer therapeutics. Here, we aim to highlight the potential of modulating mitochondrial dynamics to target key metabolic or apoptotic pathways in cancer cells. Distinct roles have been demonstrated for mitochondrial fission and fusion in different cancer contexts. Targeting of factors mediating mitochondrial dynamics may be directly related to impairment of oxidative phosphorylation, which is essential to sustain cancer cell growth and can also alter sensitivity to chemotherapeutic compounds. This area is still lacking a unified model, although further investigation will more comprehensively map the underlying molecular mechanisms to enable better rational therapeutic strategies based on these pathways.

Free access

Mouna Tabebi, Peter Söderkvist, and Oliver Gimm

Mitochondrial DNA (mtDNA) alterations have been reported in different types of cancers and are suggested to play important roles in cancer development and metastasis. However, there is little information about its involvement in pheochromocytomas and paragangliomas (PCCs/PGLs) formation. PCCs and PGLs are rare endocrine tumors of the chromaffin cells in the adrenal medulla and extra-adrenal paraganglia that can synthesize and secrete catecholamines. Over the last 3 decades, the genetic background of about 60% of PCCs/PGLs involving nuclear DNA alterations has been determined. Recently, a study showed that mitochondrial alterations can be found in around 17% of the remaining PCCs/PGLs. In this review, we summarize recent knowledge regarding both nuclear and mitochondrial alterations and their involvement in PCCs/PGLs. We also provide brief insights into the genetics and the molecular pathways associated with PCCs/PGLs and potential therapeutical targets.

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

Precision medicine (PM) aims at maximizing risk-benefit balance of medical decisions by integrating individual patient and disease characteristics. This approach is gaining increasing recognition by 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. This article is the summary of plenary lecture presented at 6th International Symposium on Pheochromocytoma/paraganglioma held on October 20, 2022 at Prague, Czech Republic exploring the current and future roles of diagnostic and therapeutic nuclear medicine in the era of PM taking into account the digital revolution in health care which is speeding up. It is anticipated that technological breakthroughs and new tracers will continue to position nuclear medicine among the large players of PM.

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R Michael Tuttle, Duan Li, and Fourat Ridouani

Minimalistic management options such as active surveillance and thyroid lobectomy are increasingly being accepted as reasonable management options for properly selected patient with low-risk papillary thyroid cancer. Leveraging technologies developed for the treatment of benign thyroid nodules, ultrasound guided percutaneous thermal ablation is now being evaluated as a potential additional minimalistic management option for small, intrathyroidal, low-risk papillary thyroid cancer. Published retrospective data on more than 5,000 low risk papillary thyroid cancer patients treated with thermal ablation indicate that with appropriate training and proper patient selection these technologies can be safely and effectively applied to papillary microcarcinomas. When compared to immediate surgery, thermal ablation appears to have lower complication rates with similar short-term rates of recurrence. Proper patient selection is facilitated by use of a clinical framework which integrates imaging characteristics, patient characteristics, and medical team characteristics to classify a patient as ideal, appropriate, or inappropriate for minimalistic management options (active surveillance, thyroid lobectomy, or thermal ablation). While retrospective in nature and lacking randomized prospective clinical trial data, currently available data does support the proposition that thermal ablation technologies reliably destroy papillary thyroid microcarcinoma lesions and are associated with clinically acceptable oncologic outcomes when done by experienced teams in properly selected patients.

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Julie Abildgaard, Hein Vincent Stroomberg, A Kirstine Bang, Jakob Albrethsen, Laura Smedegaard Kruuse, Anders Juul, Klaus Brasso, Andreas Røder, and Niels Jørgensen

Men with high-risk, non-metastatic prostate cancer receive adjuvant androgen deprivation therapy (ADT) for at least 2 years according to Danish guidelines. It remains unclarified if patients regain the function of the pituitary–testis axis after cessation of ADT. Thus, we aimed to investigate the function of the pituitary–testis axis following adjuvant ADT. In this study, we included men who underwent external beam radiation therapy and ADT for high-risk prostate cancer. All patients underwent assessment of testosterone deficiency (TD) symptoms, full biochemical assessment of the pituitary–testis axis, and dynamic stimulatory tests of gonadotropin (gonadotropin-releasing hormone (GnRH) test) and testosterone production (human chorionic gonadotrophin (hCG) test). Patients were diagnosed with TD based on a combination of TD symptoms and testosterone below age-specific reference ranges. TD was characterized as primary, secondary, or mixed based on serum gonadotropins and stimulatory tests. We found that among the 51 patients included in the study, the median time on ADT was 3.2 years and median time since ADT cessation was 3.8 years. Twenty-eight patients were diagnosed with TD; 10 had primary TD (testicular dysfunction), 11 secondary TD (pituitary dysfunction), and 7 mixed TD (combined pituitary and testicular dysfunction). An inadequate testosterone response to hCG stimulation was shown in 42 patients, whereas only 11 patients had a subnormal gonadotropin response to GnRH. We conclude that persistent TD is a common long-term consequence of adjuvant ADT in prostate cancer survivors, equally distributed between pituitary and testicular dysfunction. The study emphasizes the necessity for systematic follow-up of full pituitary–testis axis function in patients receiving adjuvant ADT.