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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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Mark Daniel, Todd P. Knutson, Jamie M. Sperger, Yingming Li, Anupama Singh, Charlotte N. Stahlfeld, Courtney Passow, Benjamin Auch, Joshua M. Lang, and Scott M. Dehm

Castration-resistant prostate cancer (CRPC) is driven by AR gene aberrations that arise during androgen receptor (AR)-targeted therapy. AR amplification and mutations have been profiled in circulating tumor cells (CTCs), but whether AR gene rearrangements can be assessed in CTCs is unknown. In this study, we leveraged CRPC cell lines with defined AR gene rearrangements to develop and validate a CTC DNA analysis approach that utilized whole genome amplification and targeted DNA-sequencing of AR and other genes important in CRPC. We tested the utility of this approach by analyzing matched CTC DNA and plasma cell-free DNA (cfDNA) from a case series of ten CRPC patients. One of ten CTC samples and two of ten cfDNA samples were positive for AR gene rearrangements. All AR gene rearrangements were discordant between matched liquid biopsy samples. One patient harbored separate AR gene rearrangements in CTC DNA and cfDNA, but concordant AR amplification and AR T878A mutation. This patient also displayed concordant loss of TP53 and PTEN, but loss of RB1 in cfDNA only. The overall frequency of discordant alterations in these genes between matched CTC DNA and cfDNA was high. This study establishes the technical feasibility of analyzing structural rearrangements, mutations, and copy number variants in AR and other CRPC genes using two different sources of DNA from a single blood sample. Paired CTC DNA and cfDNA analysis may have utility for capturing the heterogeneity of genetic alterations in CRPC patients.

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Alyaksandr V. Nikitski, Marina N Nikiforova, Linwah Yip, Esra Karslioglu-French, Sally E. Carty, and Yuri E Nikiforov

Mutations of the TP53 tumor suppressor gene are highly prevalent in thyroid anaplastic carcinomas (AC) but are also reported in some well-differentiated cancers and even benign adenomas. The natural history of TP53-mutant adenomas, and whether they may represent a precursor for well-differentiated cancer or AC is largely unknown. Similarly, the frequency of TP53 mutations in thyroid nodules found on routine molecular analysis of fine-needle aspiration (FNA) samples is not established. A database on 44,510 FNA samples from thyroid nodules with predominantly indeterminate cytology tested using ThyroSeq v3 was reviewed to identify TP53-mutant cases and analyze their genetic profile and available clinicopathological findings. Among 260 (0.6%) selected thyroid nodules, 36 had an isolated TP53 mutation, and 224 carried a combination of TP53with other genetic alterations. No significant difference was observed between these groups with respect to patient age, gender, nodule size, and spectrum of TP53mutations. Histopathologically, 86% of the resected nodules with isolated TP53mutations were benign (mostly adenomas), whereas 82% of nodules carrying TP53mutations co-occurring with other alterations were cancers (P=0.001), including de-differentiated AC. TP53-mutant benign tumors and well-differentiated cancers often had scattered single neoplastic cells with bizarre nuclei resembling those comprising AC. Our study demonstrates that a small but distinct proportion of thyroid nodules carry a TP53mutation, either as a single genetic event or in combination with other alterations. While the latter are mostly cancers prone to dedifferentiation, there is at least a theoretical possibility that TP53-mutated adenomas may represent a precursor for such cancers, including AC.

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Li Qin, Jianwei Chen, Dong Lu, Prashi Jain, Yang Yu, David Cardenas, Xiaohui Peng, Xiaobin Yu, Jianming Xu, Jin Wang, Bert W O'Malley, and David M. Lonard

Steroid receptor coactivators (SRCs) possess specific and distinct oncogenic roles in the initiation of cancer and in cancer progression to a more aggressive disease. These coactivators interact with nuclear receptors and other transcription factors to boost transcription of multiple genes which potentiate cancer cell proliferation, migration, invasion, tumor angiogenesis and epithelial mesenchymal transition (EMT). Targeting SRCs using small molecule inhibitors (SMIs) is a promising approach to control cancer progression and metastasis. By high throughput screening analysis, we recently identified SI-2 as a potent SRC SMI. To develop therapeutic agents, SI-10 and SI-12, the SI-2 analogs, are synthesized that incorporate the addition of fluorine atoms to the SI-2 chemical structure. As a result, these analogs exhibit a significantly prolonged plasma half-life, minimal toxicity and improved hERG activity. Biological functional analysis showed that SI-10 and SI-12 treatment (5-50 nM) can significantly inhibit viability, migration and invasion of breast cancer cells in vitro and repress the growth of breast cancer PDX organoids. Treatment of mice with 10 mg/kg/day of either SI-10 or SI-12 was sufficient to repress growth of xenograft tumors derived from MDA-MB-231 and LM2 cells. Furthermore, in spontaneous and experimental metastasis mouse models developed from MDA-MB-231 and LM2 cells respectively, SI-10 and SI-12 effectively inhibited progression of breast cancer lung metastasis. These results demonstrate that SI-10/SI-12 are promising therapeutic agents and are specifically effective in blocking tumor metastasis, a key point in tumor progression to a more lethal state that results in patient mortality in the majority of cases.

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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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Milena Simões Peixoto, Andressa de Vasconcelos e Souza, Iris Soares Andrade, Carolina de Carvalho el Giusbi, Caroline Coelho Faria, Fabio Hecht, Leandro Miranda-Alves, Andrea Claudia Freitas Ferreira, Denise Pires Carvalho, and Rodrigo S Fortunato

Breast cancer and thyroid dysfunctions have been associated for decades. Although many studies suggest a biological correlation, the mechanisms linking these two pathologies have not been elucidated. Reactive oxygen species (ROS) can oxidize lipids, proteins, and DNA molecules and may promote tumor initiation. Hence, we aimed at evaluating the mammary redox balance and genomic instability in a model of experimental hypothyroidism. Female Wistar rats were treated with 0.03% methimazole for 7 or 21 days to evaluate ROS generation, antioxidant enzyme activities, and oxidative stress biomarkers, as well as genomic instability. After 7 days, lower catalase, GPX, and DUOX activities were detected in the breast of hypothyroid group compared to the control while the levels of 4-hydroxynonenal (HNE) were higher. In addition, hypothyroid group showed an increase in γH2Ax/H2Ax ratio. Twenty-one days hypothyroid group had increased catalase and SOD activities, without significant differences between groups in the levels of oxidative stress biomarkers and DNA damage. TSH-treated MCF10A cells showed a higher extracellular, intracellular, and mitochondrial ROS production. Additionally, greater DNA damage was observed in these cells, demonstrated by a higher comet tail DNA percentage and increased 53BP1 foci. Finally, we found that TSH treatment was not able to alter cell viability. The Genome Cancer Atlas (TGCA) data showed that high TSHR expression is associated with more invasive breast cancer types. In conclusion, we demonstrate that oxidative stress and DNA damage in breast are early events of experimental hypothyroidism. Moreover, high TSH levels induce oxidative stress and genomic instability in mammary cells.

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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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Murali Kesavan, Piyush Grover, Wei-sen Lam, Phillip G Claringbold, and J Harvey Turner

Thirty-seven patients with advanced gastroenteropancreatic neuroendocrine tumors (GEPNETs) were treated on a prospective phase II single-center study with four cycles of 7.8 GBq 177Lu-octreotate combined with capecitabine and temozolomide chemotherapy (CAPTEM). Each 8-week cycle combined radiopeptide therapy with 14 days of capecitabine (1500 mg/m2) and 5 days of temozolomide (200 mg/m2). The incidence of grade ≥ 3 hematologic toxicity was analyzed. At a median follow-up of 7-years (range 1–10), six (16%) patients developed persistent hematologic toxicity (PHT) (defined as sustained grade ≥ 3 hematologic toxicity beyond 36-months follow-up) and three (8%) developed MDS/AL with a median time-to-event of 46 and 34 months, respectively. The estimated cumulative incidence of MDS/AL was 11% (95% CI: 3.45–24.01). Development of PHT was the only significant risk factor for secondary MDS/AL (RR, 16; 95% CI: 2.53 to 99.55; P < 0.001). The median PFS was 48 months (95% CI: 40.80–55.20), and the median OS was 86 months (95% CI: 56.90–115.13). Twenty-one deaths were recorded, including 13 (62%) due to progressive disease and all 3 (14%) patients with MDS/AL. 177Lu-octreotate CAPTEM therapy for GEPNETs is associated with a risk of long-term hematologic toxicity. The rising cumulative incidence of MDS/AL > 10% mandates the long-term monitoring of treated patients. However, time to onset is unpredictable, and incidence does not correlate with conventional baseline risk factors. Novel methods are required for the stratification of prospective patients based on genetic risk.

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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.