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Guoliang Wang, Na Ren, Shengcai Wang, Xuexi Zhang, Yanzhen Li, Nian Sun, Qiaoyin Liu, Jie Zhang, Wenqi Song, and Xin Ni

It is uncertain whether serum TSH concentration is an independent risk factor for the malignancy of pediatric thyroid nodules. We sought the association of serum TSH concentration with the malignancy of pediatric thyroid nodules and with the characteristics of pediatric thyroid cancer. A total of 219 pediatric thyroid nodule patients were collected retrospectively for 5 consecutive years. The medical records collected included sex, age, serum TSH concentration, thyroid autoantibody status, thyroid ultra-sonography parameters, histological type, and pathological TNM stages. The serum TSH concentrations were compared between benign and malignant nodules or corresponding subgroups. Binary logistic regression analysis was used to evaluate the correlation of TSH concentration with the malignancy of thyroid nodules and with the characteristics of pediatric thyroid cancer. There was no significant difference in TSH concentration between benign nodule and thyroid cancer in total subjects and various subgroups. The serum TSH level was not correlated with the malignancy of thyroid nodules in univariate analysis, but negatively correlated with the malignancy of thyroid nodules (odds ratio = 0.856, P  = 0.013) after adjusting for the patients’ sex, age, thyroid autoantibody status, and nodule size. The serum TSH level was not correlated with the tumor characteristics in pediatric thyroid cancer patients. In conclusion, the serum TSH concentration seems not to be a carcinogenic factor in pediatric thyroid nodule patients, nor to be an independent risk factor for characteristics of pre-existing pediatric thyroid cancers.

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Avaniyapuram Kannan Murugan, Abeer Al-Amr, Mysoon M Al-Ansari, Pulicat S Manogaran, Hindi Al-Hindi, and Ali S Alzahrani

Thyroid cancer is a common endocrine neoplasm. Despite its good prognosis, it can lead to significant morbidity and mortality due to metastasis and recurrence. However, the factors involved in metastasis are not well studied. Therefore, we selected matrix metalloproteinases 2 (MMP2) and determined whether it has any role in thyroid cancer. We sequenced the exons of MMP2 in 211 samples including 16 multi-nodular goiters and 195 differentiated thyroid cancers. We identified four non-synonymous single nucleotide polymorphisms (SNPs) of the MMP2 gene in 3.06% (6/195) thyroid cancers. Of the four tumors harboring MMP2 SNPs, three (75%) concomitantly had BRAF V600E. Hence, we speculated that the MMP2 SNPs may cooperate with BRAF V600E in promoting tumor aggressiveness. Overexpression of two MMP2 SNPs (P38L and T458I) exhibited markedly enhanced gelatinase activity with an intact dimerization and induced strong cortactin foci formation in HEK293T cells. Stable expression of the two MMP2 SNPs in BRAF V600E positive BCPAP cells dramatically enhanced cell proliferation, colony formation, and focus formation. Analysis of the morphology of MMP2 SNP bearing BCPAPV600E cells exhibited highly invasive phenotypes characterized by a high rate of wound healing and enhanced cell invasion compared with parental BCPAPV600E cells bearing vector. We also determined that BCPAPV600E cells stably transfected with MMP2 SNPs were highly sensitive to the treatment of BRAF inhibitor, PLX4720. Our study demonstrates that MMP2 SNPs could cooperate with BRAF V600E to promote oncogenicity, migration, and invasiveness of PTC cells. These results suggest that a subset of papillary thyroid cancer with this genetic makeup may benefit from BRAF-mediated therapeutic interventions.

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Carla Colombo, Marina Muzza, Gabriele Pogliaghi, Sonia Palazzo, Guia Vannucchi, Leonardo Vicentini, Luca Persani, Giacomo Gazzano, and Laura Fugazzola

Cytology is the gold standard method for the differential diagnosis of thyroid nodules, though 25–30% of them are classified as indeterminate. We aimed to set up a ‘thyroid risk score’ (TRS) to increase the diagnostic accuracy in these cases. We prospectively tested 135 indeterminate thyroid nodules. The pre-surgical TRS derived from the sum of the scores assigned at cytology, EU-TIRADS classification, nodule measurement, and molecular characterization, which was done by our PTC-MA assay, a customized array able to cost-effectively evaluate 24 different genetic alterations including point mutations and gene fusions. The risk of malignancy (ROM) increased paralleling the score: in the category >4 and ≤ 6 (low suspicion), >6 ≤ 8 (intermediate suspicion), and >8 (high suspicion); ROM was 10, 47 and 100%, respectively. ROC curves selected the score >6.5 as the best threshold to differentiate between malignant and benign nodules (P < 0.001). The TRS > 6.5 had a better performance than the single parameters evaluated separately, with an accuracy of 77 and 82% upon inclusion of noninvasive follicular thyroid neoplasm with papillary-like nuclear features among malignant or benign cases, respectively. In conclusion, for the first time, we generated a score combining a cost-effective molecular assay with already validated tools, harboring different specificities and sensitivities, for the differential diagnosis of indeterminate nodules. The combination of different parameters reduced the number of false negatives inherent to each classification system. The TRS > 6.5 was highly suggestive for malignancy and retained a high accuracy in the identification of patients to be submitted to surgery.

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Satya Das, Liping Du, Aimee Schad, Shikha Jain, Aaron Jessop, Chirayu Shah, David Eisner, Dana Cardin, Kristen Ciombor, Laura Goff, Marques Bradshaw, Dominique Delbeke, Martin Sandler, and Jordan Berlin

We developed a clinical score (CS) at Vanderbilt Ingram Cancer Center (VICC) that we hoped would predict outcomes for patients with progressive well-differentiated neuroendocrine tumors (NETs) receiving therapy with Lutetium-177 (177Lu)-DOTATATE. Patients under consideration for 177Lu-DOTATATE between March 1, 2016 and March 17, 2020 at VICC were assigned a CS prospectively. The CS included 5 categories: available treatments for tumor type outside of 177Lu-DOTATATE, prior systemic treatments, patient symptoms, tumor burden in critical organs and presence of peritoneal carcinomatosis. The primary outcome of the analysis was progression-free survival (PFS). To evaluate the effect of the CS on PFS, a multivariable Cox regression analysis was performed adjusting for tumor grade, primary tumor location, and the interaction between 177Lu-DOTATATE doses received (zero, 1–2, 3–4) and CS. A total of 91 patients and 31 patients received 3–4 doses and zero doses of 177Lu-DOTATATE, respectively. On multivariable analysis, in patients treated with 3–4 doses of 177Lu-DOTATATE, for each 1-point increase in CS, the estimated hazard ratio (HR) for PFS was 2.0 (95% CI 1.61–2.48). On multivariable analysis, in patients who received zero doses of 177Lu-DOTATATE, for each 1-point increase in CS, the estimated HR for PFS was 1.22 (95% CI 0.91–1.65). Among patients treated with 3–4 doses of 177Lu-DOTATATE, those with lower CS experienced improved PFS with the treatment compared to patients with higher CS. This PFS difference, based upon CS, was not observed in patients who did not receive 177Lu-DOTATATE, suggesting the predictive utility of the score.

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Saya Ahmad, Myrthe R Naber, Rachel H Giles, Gerlof D Valk, and Rachel S van Leeuwaarde

Pancreatic neuroendocrine tumors (pNETs) in Von Hippel–Lindau (VHL) disease have a relatively good prognosis. However, a subset of pNETs metastasize and significantly contribute to VHL-related mortality. Evidence-based guidelines are needed for timely detection, management and intervention of these tumors. However, the value of several diagnostic tools is controversial, and evidence-based management strategies are lacking. This systematic review aims to update current literature on diagnostic and management strategies of pNETs in VHL and proposes evidence-based recommendations. The databases of PubMed/Medline, Embase and Web of Science were systematically searched to identify relevant studies. Studies were screened independently and cross-checked by two authors to assess eligibility for inclusion. Eighty-four articles were eligible for full text reading, and thirteen were critically appraised using the modified Quality Assessment of Diagnostic Accuracy Studies or modified Quality in Prognostic Studies tool. Six studies assessed the diagnostic value of imaging modalities, five focused on the optimal timing for surgical intervention, and one article studied the growth rate of pNETs. Quality of the available evidence was determined using the Grading of Recommendations, Assessment, Development and Evaluations tool. Studies recommended CT or MRI as the primary screening modalities for pNETs. For detection of metastases, 68Gallium-DOTATATE/TOC PET/CT is advised. For pNETs <2 cm a watch-and-wait approach is recommended, while for pNETs ≥2.5 cm surgical resection is advised. Due to limited data, no strong recommendations on surveillance could be proposed.

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Tim Schauer, Anne-Sophie Mazzoni, Anna Henriksson, Ingrid Demmelmaier, Sveinung Berntsen, Truls Raastad, Karin Nordin, Bente K Pedersen, and Jesper F Christensen

Exercise training has been hypothesized to lower the inflammatory burden for patients with cancer, but the role of exercise intensity is unknown. To this end, we compared the effects of high-intensity (HI) and low-to-moderate intensity (LMI) exercise on markers of inflammation in patients with curable breast, prostate and colorectal cancer undergoing primary adjuvant cancer treatment in a secondary analysis of the Phys-Can randomized trial (NCT02473003). Sub-group analyses focused on patients with breast cancer undergoing chemotherapy. Patients performed 6 months of combined aerobic and resistance exercise on either HI or LMI during and after primary adjuvant cancer treatment. Plasma taken at baseline, immediately post-treatment and post-intervention was analyzed for levels of interleukin 1 beta (IL1B), IL6, IL8, IL10, tumor-necrosis factor alpha (TNFA) and C-reactive protein (CRP). Intention-to-treat analyses of 394 participants revealed no significant between-group differences. Regardless of exercise intensity, significant increases of IL6, IL8, IL10 and TNFA post-treatment followed by significant declines, except for IL8, until post-intervention were observed with no difference for CRP or IL1B. Subgroup analyses of 154 patients with breast cancer undergoing chemotherapy revealed that CRP (estimated mean difference (95% CI): 0.59 (0.33; 1.06); P  = 0.101) and TNFA (EMD (95% CI): 0.88 (0.77; 1); P  = 0.053) increased less with HI exercise post-treatment compared to LMI. Exploratory cytokine co-regulation analysis revealed no difference between the groups. In patients with breast cancer undergoing chemotherapy, HI exercise resulted in a lesser increase of CRP and TNFA immediately post-treatment compared to LMI, potentially protecting against chemotherapy-related inflammation.

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Zhi-yuan Pang, Yun-tao Wei, Mu-yan Shang, Shuang Li, Yang Li, Quan-xiu Jin, Zhi-xuan Liao, Ming-ke Cui, Xiao-yan Liu, and Qiang Zhang

Aberrant leptin signaling and overexpression of fibroblast growth factor receptor 1 (FGFR1) are both implicated in the pathogenesis of letrozole resistance in breast cancer (BCa), but it remains unknown whether these two pathways are involved in letrozole resistance in a coordinated manner. Here, we demonstrate that expression levels of the pre-B-cell leukemia homeobox transcription factor 3 (PBX3), a pioneer factor that governs divergent biological processes, were significantly upregulated in letrozole-resistant BCa cells and tissues, and this upregulation correlated to a poorer progression-free survival in patients. By leveraging a patient-derived xenograft model with pharmacological approaches, we demonstrated that leptin activated PBX3 expression in a STAT3 (signal transducer and activator of transcription 3)-dependent manner. Our loss- and gain-of-function study further showed that PBX3 attenuated response to letrozole by potentiating BCa cell survival and anchorage-independent growth in BCa cells. By profiling BCa cells with ectopic PBX3 expression, we revealed that PBX3 conferred letrozole resistance via transactivation of the FGFR1 signaling, and this molecular event must coordinate a synergistic transcription activation programs through interacting with MTA1-HDAC2 (metastasis-associated 1-histone deacetylase 2) complex. Overall, the available data reveal a novel role of leptin/PBX3 cascade linking energy homeostasis (i.e. hyperleptinemia) and endocrine therapy failure (i.e. letrozole resistance) in BCa.

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Livia Lamartina, Nadège Anizan, Corinne Dupuy, Sophie Leboulleux, and Martin Schlumberger

Based on experimental data, the inhibition of the MAPkinase pathway in patients with radioiodine refractory thyroid cancer was capable to induce a redifferentiation. Preliminary data obtained on small series of patients are encouraging and this strategy might become an alternative treatment in those patients with a druggable mutation that induces a stimulation of the MAP kinase pathway. This is an active field of research to answer many still unresolved questions.

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Mintallah Haider, Satya Das, Taymeyah Al-Toubah, Eleonora Pelle, Ghassan El-Haddad, and Jonathan Strosberg

Peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTATATE has been approved for the treatment of gastroenteropancreatic NETs. An understanding of benefits and risks is important for the appropriate implementation of this therapy. This review summarizes study data supporting the use of radiolabeled somatostatin analogs for the treatment of advanced NETs and highlights risks, including potential toxicities in specific populations. Key ongoing clinical trials, including randomized studies, are designed to better define the position of PRRT within the broader therapeutic landscape. Preclinical and early-phase human studies are focused on the development of novel somatostatin-receptor agonists and antagonists, new radionuclides, and radiosensitizing combination therapies.