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Ophélie De Rycke, Thomas Walter, Marine Perrier, Olivia Hentic, Catherine Lombard-Bohas, Romain Coriat, Guillaume Cadiot, Anne Couvelard, Philippe Ruszniewski, Jérôme Cros, and Louis de Mestier

A rechallenge is common after the initial efficacy of alkylating-based chemotherapy (ALK) in pancreatic neuroendocrine tumors (PanNET). High MGMT expression seems associated with a lower response to ALK. We aimed to evaluate the efficacy and toxicity of ALK rechallenge in PanNET, and to assess the evolution of MGMT expression under ALK. All consecutive patients with advanced PanNETs who received initial ALK (achieving tumor control) followed by a pause of > 3 months, then an ALK rechallenge (ALK2) upon progression were retrospectively studied (cohort A). The primary endpoint was progression-free survival under ALK2 (PFS2). The MGMT expression was retrospectively assessed by immunohistochemistry (H-score) in consecutive PanNET surgically resected following ALK (cohort B). We found that Cohort A included 62 patients (median Ki67 8%), for whom ALK1 followed by a pause achieved an objective response rate of 55% and a PFS1 of 23.7 months (95% IC, 19.8–27.6). ALK2 achieved no objective response and stability in 62% of patients. The median PFS2 was 9.2 months (IC 95% 7.1–11.3). At multivariable analysis, a hormonal syndrome (P = 0.032) and a pause longer than 12 months (P = 0.041) were associated with a longer PFS2. In cohort B (17 patients), the median MGMT H-score increased from 45 (IQR 18–105) before ALK to 100 (IQR 56–180) after ALK (P = 0.003). We conclude that after the initial efficacy of ALK treatment, a pause followed by ALK rechallenge might be appropriate to prolong tumor control, improve quality of life and limit long-term adverse events. Increased MGMT expression under ALK might explain the low efficacy of ALK rechallenge.

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Tung Hoang, Quy Nguyen Ngoc, Jeonghee Lee, Eun Kyung Lee, Yul Hwangbo, and Jeongseon Kim

The cumulative effect of single-nucleotide polymorphisms (SNPs) on thyroid cancer has been adequately defined in individuals of European ancestry; however, similar evidence in the Korean population is limited. This study aimed to investigate the influence of modifiable factors and the polygenic risk score (PRS) and their interactive and combined effects on thyroid cancer. Using data from the cancer screenee cohort, this study included 759 thyroid cancer cases and 759 age- and sex-matched controls. We examined the effects of tobacco smoking, alcohol consumption, and regular exercise habits, BMI, and the PRS of six SNPs on thyroid cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) for the associations were obtained using a conditional logistic regression model. The results indicated that family history, obesity, and the unweighted and weighted PRS were independently associated with susceptibility to thyroid cancer, with ORs (95% CIs) of 2.96 (1.63–5.36), 1.72 (1.20–2.48), 1.46 (1.10–1.93), and 1.56 (1.19–2.03), respectively, whereas the effect of smoking, drinking, and regular exercise was not significant. The contribution of the PRS remained after stratifying participants with healthy behaviors, such as nonsmokers/nondrinkers, and regular exercise. Although the PRS did not significantly contribute to the risk for thyroid cancer when participants were stratified according to BMI, BMI and the PRS had a cumulative effect on thyroid cancer risk. The combined effect of genetic polymorphisms on predisposition to thyroid cancer may differ based on tobacco smoking, alcohol consumption, regular exercise behaviors and cumulative BMI. Larger population-based studies are needed to validate these findings.

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Ha Nguyen, Komal Shah, Steven G Waguespack, Mimi I Hu, Mouhammed Amir Habra, Maria E Cabanillas, Naifa L Busaidy, Roland Bassett, Shouhao Zhou, Priyanka C Iyer, Garrett Simmons, Diana Kaya, Marie Pitteloud, Sumit K Subudhi, Adi Diab, and Ramona Dadu

Data on the diagnosis, natural course and management of immune checkpoint inhibitor (ICI)-related hypophysitis (irH) are limited. We propose this study to validate the diagnostic criteria, describe characteristics and hormonal recovery and investigate factors associated with the occurrence and recovery of irH. A retrospective study including patients with suspected irH at the University of Texas MD Anderson Cancer Center from 5/2003 to 8/2017 was conducted. IrH was defined as: (1) ACTH or TSH deficiency plus MRI changes or (2) ACTH and TSH deficiencies plus headache/fatigue in the absence of MRI findings. We found that of 83 patients followed for a median of 1.75 years (range 0.6–3), the proposed criteria used at initial evaluation accurately identified 61/62 (98%) irH cases. In the irH group (n = 62), the most common presentation was headache (60%), fatigue (66%), central hypothyroidism (94%), central adrenal insufficiency (69%) and MRI changes (77%). Compared with non-ipilimumab (ipi) regimens, ipi has a stronger association with irH occurrence (P = 0.004) and a shorter time to irH development (P < 0.01). Thyroid, gonadal and adrenal axis recovery occurred in 24, 58 and 0% patients, respectively. High-dose steroids (HDS) or ICI discontinuation was not associated with hormonal recovery. In the non-irH group (n = 19), one patient had isolated central hypothyroidism and six had isolated central adrenal insufficiency. All remained on hormone therapy at the last follow-up. We propose a strict definition of irH that identifies the vast majority of patients. HDS and ICI discontinuation is not always beneficial. Long-term follow-up to assess recovery is needed.

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Huy Gia Vuong, Truong P X Nguyen, Hanh T T Ngo, Lewis Hassell, and Kennichi Kakudo

Malignant thyroid teratoma (MTT) is a very rare thyroid malignancy. These neoplasms have been reported only in case reports and small-sized case series so far. In this study, we searched for MTTs in the Surveillance, Epidemiology, and End Result (SEER) program during 1975–2016. Subsequently, we incorporated the SEER data with published MTT cases in the literature to analyze the characteristics and prognostic factors of MTTs. Integrated data were analyzed using chi-square or Fisher’s exact test for categorical covariates, and t-test or Mann-Whitney test for continuous variables. We included 28 studies with 36 MTT cases and found additional 8 cases from the SEER program for final analyses. Our results showed that MTT is typically seen in adult females. These neoplasms were associated with an aggressive clinical course with high rates of extrathyroidal extension (80%) and nodal involvement (62%). During follow-up, the development of recurrence and metastases were common (42% and 46%, respectively), and one-third of patients died at the last follow-up. Large tumor size (P  = 0.022) and the presence of metastases during follow-up (P  = 0.008) were associated with a higher mortality rate. In conclusion, our study demonstrated the characteristic features of MTT patients and outlined some parameters associated with a negative outcome which could help clinicians better predict the clinical course of these neoplasms.

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Xiong Wang, Li Ma, Qiao-yan Ding, Wen-yu Zhang, Yong-gang Chen, Jin-hu Wu, Hong-feng Zhang, and Xiu-li Guo

Prolactinomas have harmful effects on human health, and the pathogenesis is still unknown. Furthermore, 25% of prolactinoma patients do not respond to the therapy of dopamine receptor agonist in the clinic. Thus, it is important to reveal the pathogenesis and develop new therapeutic methods for prolactinomas. Herein, two animal models of prolactinomas, namely oestrogen-treated rats and transgenic D2 dopamine receptor-deficient mice, were used. PET/CT imaging detection showed that translocator protein-mediated microglia activation and inflammation significantly increased in the pituitary glands of prolactinomas rats. Messenger RNA microarrays were used to analyze and compare the differential gene and signal pathways of the pituitary glands between control and prolactinomas rats. Statistical results pertaining to gene enrichment showed that the innate immune response genes were upregulated in the pituitary glands of prolactinoma rats. This suggested that the innate immune response was activated. We analyzed the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome that is one of the most important members of the innate immune system in mammals and found that the expressions of NLRP3, Caspase-1, apoptosis-associated speck-like, interleukin 1B (IL1B) and IL18 proteins of pituitary glands in prolactinomas rats were increased considerably compared with those in control rats. This suggested the activation of the NLRP3 inflammasome during the emergence and evolution of prolactinomas. Immunohistochemistry results also confirmed that the NLRP3 expression was elevated in human prolactinoma tissues, and the microglia marker-ionised calcium binding adaptor molecule-1 was co-located with the NLRP3 protein in prolactinomas by immunofluorescence assay. Finally, compared with the WT mice, NLRP3−/− mice had smaller pituitary glands (weight/body weight) and diminished prolactin (PRL) expressions and secretions. These findings were associated with a reduction in the caspase-1 activation and maturation of IL1B. Furthermore, MCC950 decreased the PRL expression and secretion following the inhibition of NLRP3 inflammasome activation in GH3 cells stimulated with lipopolysaccharide and nigericin. And MCC950 inhibited the pituitary tumor overgrowth and PRL expression and secretion in prolactinoma rats. These data confirm that the microglial NLRP3 inflammasome activation upregulates the inflammatory cytokines IL1/IL18 in the pituitary glands and induces prolactinomas. Our findings showed that microglial NLRP3 inflammasome activation-mediated IL1B-related inflammation promoted the development of prolactinomas and identified the inflammasome as a new therapeutic target for prolactinomas.

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Chiara Borga, Carlo Alberto Dal Pozzo, Elisabetta Trevellin, Francesca Bergamo, Sabina Murgioni, Anna Caterina Milanetto, Claudio Pasquali, Umberto Cillo, Giada Munari, Chiara Martini, Eugenio De Carlo, Vittorina Zagonel, Vincenza Guzzardo, Gianmaria Pennelli, Angelo Paolo Dei Tos, Roberto Vettor, and Matteo Fassan

The knowledge of the molecular landscape of ileal neuroendocrine tumors (NETs) is affected by the lack of systematic studies investigating intra-tumoral heterogeneity. In this study, intra-tumoral heterogeneity was investigated in 27 primary ileal G1-NETs and their matched nodal and liver metastases in order to assess the tumor grading, the expression status of two somatostatin receptor isoforms (i.e. SSTR2A and SSTR5) and mTOR signaling dysregulation (ph-mTOR, ph-p70S6K, ph-4EBP1, PTEN and miR-21). Among the 27 G1 primary tumors, 4 shifted to G2 in the matched liver metastasis. Although mTOR activation was pretty consistent between primary and secondary malignancies, mTOR effectors (ph-p70S6K and ph-4EBP1) were overexpressed in matched liver metastases, whereas PTEN expression profile changed in only two cases. MiR-21 was significantly up-regulated in the metastatic setting. Although SSTRs expression was present in most of the primary tumors and matched metastasis, we found SSTR5 expression to be significantly increased in liver metastases. Notably, SSTRs expression was heterogeneous within the same lesions in most of the lesions. Overall, despite primary and metastatic ileal NETs show a similar molecular landscape, tumor grading and mTOR signaling pathway may diverge in the metastatic setting, thus affecting prognosis and treatment.

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Fabio Turco, Marcello Tucci, Rosario Francesco Di Stefano, Alessandro Samuelly, Maristella Bungaro, Marco Audisio, Chiara Pisano, Massimo Di Maio, Giorgio Vittorio Scagliotti, and Consuelo Buttigliero

Obesity represents a well-known risk factor for renal cell carcinoma development. Several studies evaluated the relationship between obesity and outcome in patients with non-metastatic and metastatic renal cell carcinoma using different parameters such as BMI, visceral fat area and s.c. fat area. These studies suggest that obesity is associated with a better prognosis in renal cell carcinoma patients. This phenomenon is called obesity paradox and it was found in other diseases in which obesity represents an established risk factor such as heart failure, diabetes, atrial fibrillation, hypertension and coronary heart disease. The purpose of this review is to analyze the mechanisms by which obesity increases the risk of renal cell carcinoma development, to describe the evidence available to date about the link obesity-outcome and to evaluate the mechanisms to explain this apparently paradoxical relationship.

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Sara Pusceddu, Antonio Facciorusso, Luca Giacomelli, Natalie Prinzi, Francesca Corti, Monica Niger, Massimo Milione, Jorgelina Coppa, Tommaso Cascella, Iolanda Pulice, Lavinia Biamonte, Simonetta Papa, Maria Di Bartolomeo, Aashni Shah, Rodolfo Sacco, and Filippo de Braud

Although combination therapy is not recommended in patients with gastro–entero–pancreatic (GEP) neuroendocrine tumors (NETs), this strategy is widely used in clinical practice. This network meta-analysis of randomized trials evaluates targeted therapies and somatostatin analogues in GEP-advanced NETs, either alone or in combination, comparing the efficacy of different, single or combined treatment strategies in terms of progression-free survival (PFS). Interventions were grouped as analogs, everolimus, everolimus plus SSAs, sunitinib and placebo. In a secondary analysis, we also assessed the efficacy of individual-specific pharmacological treatments vs placebo or each other. From 83 studies identified, 8 randomized controlled trials were selected, with a total of 1849 patients with either functioning or non-functioning NETs. The analysis confirmed the superiority of all treatments over placebo (HR ranging from 0.34, 95% CI: 0.24–0.37 with the combination of everolimus plus SSAs to 0.42, 0.31–0.57 with the analogs; moderate quality of evidence). On ranking analysis, the combination of everolimus plus SSA (P score = 0.86) and then everolimus alone (P score = 0.65) ranked highest in increasing PFS. On comparative evaluation of different interventions, pasireotide (P score = 0.96) and everolimus + octreotide (P score = 0.82) ranked as the best pharmacological treatment options. Our findings support the use of combination therapy in the treatment of functioning and non-functioning GEP NETs. The role of pasireotide should be explored in selected subgroups of patients. Lastly, the combination of everolimus and octreotide appears promising and should be more widely considered in clinical practice.

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Helena Andrea Sterle, Ximena Hildebrandt, Matías Valenzuela Álvarez, María Alejandra Paulazo, Luciana Mariel Gutierrez, Alicia Juana Klecha, Florencia Cayrol, María Celeste Díaz Flaqué, Cinthia Rosemblit, María Laura Barreiro Arcos, Lucas Colombo, Marcela Fabiana Bolontrade, Vanina Araceli Medina, and Graciela Alicia Cremaschi

The patient’s hormonal context plays a crucial role in the outcome of cancer. However, the association between thyroid disease and breast cancer risk remains unclear. We evaluated the effect of thyroid status on breast cancer growth and dissemination in an immunocompetent mouse model. For this, hyperthyroid and hypothyroid Balb/c mice were orthotopically inoculated with triple-negative breast cancer 4T1 cells. Tumors from hyperthyroid mice showed an increased growth rate and an immunosuppressive tumor microenvironment, characterized by increased IL-10 levels and decreased percentage of activated cytotoxic T cells. On the other hand, delayed tumor growth in hypothyroid animals was associated with increased tumor infiltration of activated CD8+ cells and a high IFNγ/IL-10 ratio. Paradoxically, hypothyroid mice developed a higher number of lung metastasis than hyperthyroid animals. This was related to an increased secretion of tumor CCL2 and an immunosuppressive systemic environment, with increased proportion of regulatory T cells and IL-10 levels in spleens. A lower number of lung metastasis in hyperthyroid mice was related to the reduced presence of mesenchymal stem cells in tumors and metastatic sites. These animals also exhibited decreased percentages of regulatory T lymphocytes and myeloid-derived suppressor cells in spleens but increased activated CD8+ cells and the IFNγ/IL-10 ratio. Therefore, thyroid hormones modulate the cellular and cytokine content of the breast tumor microenvironment. A better understanding of the mechanisms involved in these effects could be a starting point for the discovery of new therapeutic targets for breast cancer.

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Andrew E. Greenstein, Mouhammed Amir Habra, Subhagya A. Wadekar, and Andreas Grauer

Elevated glucocorticoid (GC) activity may limit tumor immune response and immune checkpoint inhibitor (ICI) efficacy. Adrenocortical carcinoma (ACC) provides a unique test case to assess correlates of GC activity, as approximately half of ACC patients exhibit excess GC production (GC+). ACC multi-omics were analyzed to identify molecular consequences of GC+ and assess the rationale for combining the glucocorticoid receptor (GR) antagonist relacorilant with an ICI. GC status, mRNA expression, and DNA mutation and methylation data from 71 adrenal tumors were accessed via The Cancer Genome Atlas. Expression of 858 genes differed significantly between GC- and GC+ ACC cases. KEGG pathway analysis showed higher gene expression of 3 pathways involved in steroid synthesis and secretion in GC+ cases. Fifteen pathways, most related to NK cells and other immune activity, showed lower expression. Hypomethylation was primarily observed in the steroid synthesis pathways. Tumor-infiltrating CD4+ memory (P=.003), CD8+ memory (P=.001), and NKT-cells (P=.014) were depleted in GC+ cases; tumor-associated neutrophils were enriched (P=.001). Given the pronounced differences between GC+ and GC- ACC, the effects of cortisol on NK cells were assessed in vitro (NK cells from human PBMCs stimulated with IL-2 or IL-12/15). Cortisol suppressed, and relacorilant restored, NK cell activation, proliferation, and direct tumor cell killing. Thus, GR antagonism may increase the abundance and function of NK and other immune cells in the tumor microenvironment, promoting immune response in GC+ ACC and other malignancies with GC+. This hypothesis will be tested in a phase 1 trial of relacorilant + ICI.