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Nitya Raj, Youyun Zheng, Haley Hauser, Joanne Chou, Johnathan Rafailov, Jad Bou-Ayache, Peter Sawan, Jamie Chaft, Jennifer Chan, Kimberly Perez, Charles Rudin, Laura Tang, and Diane Reidy-Lagunes

The mammalian target of rapamycin inhibitor everolimus is an established therapy for well-differentiated (WD) foregut neuroendocrine tumors (NETs). Pre-clinical data demonstrates a potential synergistic role for cyclin dependent kinase 4/6 inhibition and everolimus to treat this disease. In this phase II multicenter study, patients with advanced foregut WDNETs received combination ribociclib and everolimus until confirmed disease progression or unacceptable toxicity. The first 12 patients received ribociclib 300 mg three weeks in a row with a 1 week break and everolimus 2.5 mg daily (recommended phase II dose). Due to unexpected hematologic and infectious toxicities, the trial was put on hold, modified, and an additional 9 patients received ribociclib 200 mg and everolimus 2.5 mg daily. The primary end point was progression-free survival. Archived pre-treatment tumor was profiled by next-generation sequencing to evaluate for genomic markers of drug response. Twenty-one patients were treated (median age, 56; range, 24 to 77). The study did not meet the pre-specified criteria to advance to stage two. No patients experienced an objective response. Thirteen patients (62%) experienced stable disease. Median progression-free survival was 7.7 months (95% CI, 2.8 months to not reached). Eleven of the first 12 patients (92%) developed grade 2 or more myelosuppression. Ten patients (84%) experienced treatment interruption and 8 patients (67%) required dose reduction. Genetic testing in archival tumor tissue samples failed to identify a predictive biomarker of disease stabilization. The combination of ribociclib and everolimus had insufficient activity to warrant further investigation in foregut WDNETs.

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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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Jingyuan Ma, Xinyu Huang, Jungong Zhao, Jingyi Lu, Wei Lu, Yuqian Bao, Jian Zhou, and Junfeng Han

Insulin release index (IRI) based on 72-h fasting test has been used for the definitive diagnosis of insulinoma; however, hospitalization and subsequent costs contribute the disadvantage of IRI. Therefore, a simple and cost effective screening procedure on the diagnosis of the insulinoma for outpatients are urgent as needed. Continuous glucose monitoring (CGM) has been widely used for high level of glucose monitoring in diabetic patients. The aim of the study is to determine the potential contribution or implementation of CGM in the screening of the insulinoma. We performed a single center prospective study with the demographics and laboratory data including 28 patients with the pathological diagnosis of insulinoma and 25 patients with functional hypoglycemia as control group. The analysis showed that areas under the receiver operating characteristic (ROC) curve of coefficient of variation (CV) was 0.914. The CV cut-off point was 19% with the Youden 62.1%, the corresponding sensitivity and specificity were 82.1% and 80%, respectively. In patients with CV greater than the median, more than 60% of insulinomas were located in the head of the pancreas; most Ki-67 values were more than 2% and compared with the group with CV smaller than the median, the average tumor size was 2.7 times larger. In conclusion, CGM can be used as a valuable tool in not only monitoring high glucose levels in diabetic patients, but also identifying the etiology of insulinoma. CV greater than 19% can be highly effective for the screening of insulinoma in outpatients.

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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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Yu-Ling Lu, Yu-Tung Huang, Ming-Hsien Wu, Ting-Chao Chou, Richard J Wong, and Shu-Fu Lin

Wee1 is a kinase that regulates the G2/M progression by inhibition of CDK1, which is critical for ensuring DNA damage repair before initiation of mitotic entry. Targeting Wee1 may be a potential strategy in the treatment of anaplastic thyroid cancer, a rare but lethal disease. The therapeutic effects of adavosertib, a Wee1 inhibitor for anaplastic thyroid cancer was evaluated in this study. Adavosertib inhibited cell growth in three anaplastic thyroid cancer cell lines in a dose-dependent manner. Cell cycle analysis revealed cells were accumulated in the G2/M phase. Adavosertib induced caspase-3 activity and led to apoptosis. Adavosertib monotherapy showed significant retardation of the growth of two anaplastic thyroid cancer tumor models. The combination of adavosertib with dabrafenib and trametinib revealed strong synergism in vitro and demonstrated robust suppression of tumor growth in vivo in anaplastic thyroid cancer xenograft models with BRAFV600E mutation. The combination of adavosertib with either sorafenib or lenvatinib also demonstrated synergism in vitro and had strong inhibition of tumor growth in vivo in an anaplastic thyroid cancer xenograft model. No appreciable toxicity appeared in mice treated with either single agent or combination treatment. Our findings suggest adavosertib holds the promise for the treatment of patients with anaplastic thyroid cancer.

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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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Georgios Kostopoulos, Ioannis Doundoulakis, Christina Antza, Emmanouil Bouras, Krishnarajah Nirantharakumar, Dimitrios Tsiachris, G. Neil Thomas, Gregory Y. H. Lip, and Konstantinos A. Toulis

Differentiated thyroid cancer (DTC) represents the most common form of thyroid neoplasms and is becoming increasingly prevalent. Evidence suggests a possible relationship between DTC diagnosis and subsequent atrial fibrillation (AF). If confirmed, this may present an alarming health risk (AF) in an otherwise condition with a relatively good prognosis (DTC). The aim of this systematic review and meta-analysis is to provide for the first time a pooled estimate of AF incidence in DTC patients in comparison to healthy controls. A detailed search in electronic databases, clinical trial registries and grey literature was performed to identify studies reporting the incidence of AF in DTC patients. Newcastle-Ottawa quality assessment scale was used to assess study quality. We used a random effects (RE) generalized linear mixed model (GLMM) in pooling of individual studies and also calculated a prediction interval for the estimate of a new study. Six observational studies met the eligibility criteria, which included totally 187,754 patients with DTC and 199,770 healthy controls. The median follow-up period was 4.3 to 18.8 years; the incidence rate of AF was 4.86 (95% CI, 3.29 to 7.17, I2= 96%) cases per 1000 person-years, while the incidence rate ratio was 1.54(95%CI, 1.44 to 1.65, I2 = 0%, 95%PI, 1.33 to 1.78).This is the first meta-analysis to confirm that patients with DTC are at a high risk for developing AF, which may be attributed to a state of iatrogenic hyperthyroidism due to long-term thyrotropin suppression therapy.

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Raghavendra Tk Poluri, Virginie Paquette, Éric P Allain, Camille Lafront, Charles Joly-Beauparlant, Cindy Weidmann, Arnaud Droit, Chantal Guillemette, Martin Pelletier, and Etienne Audet-Walsh

Prostate cancer (PCa) cells rely on the androgen receptor (AR) signaling axis to reprogram metabolism to sustain aberrant proliferation. Whether additional transcription factors participate to this reprogramming remains mostly unknown. To identify such factors, DNA motif analyses were performed in the promoter and regulatory regions of genes sensitive to androgens in PCa cells. These analyses identified two transcription factors, KLF5 and NFYA, as possibly associated with PCa cell metabolism. In clinical datasets, KLF5 and NFYA expression levels were associated with disease aggressiveness, being significantly decreased and increased, respectively, during PCa progression. Their expression was next investigated by qPCR and Western blot in human PCa cell models, revealing a positive regulation of KLF5 by androgens and a correlation between NFYA and AR protein expression status. siRNA-mediated knockdown of KLF5 increased human PCa cell proliferation rates in an AR-positive cell models, suggesting a tumor suppressor function. Live-cell metabolic assays showed that knockdown of KLF5 promoted mitochondrial respiration, a key metabolic pathway associated with PCa progression. The opposite was observed for knockdown of NFYA regarding proliferation and respiration, indicative of oncogenic characteristics. RNA-seq analyses following knockdown of either KLF5 and NFYA confirmed that both factors regulated distinct metabolic gene signatures, as well as other gene signatures, explaining their differential impact on PCa cell proliferation and metabolism. Overall, our findings identify KLF5 and NFYA as novel regulators of PCa cell metabolism.

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Lisa K Philp, Anja Rockstroh, Martin C Sadowski, Atefeh Taherian Fard, Melanie Lehman, Gregor Tevz, Michelle S Libério, Charles L Bidgood, Jennifer H Gunter, Stephen McPherson, Nenad Bartonicek, John D Wade, Laszlo Otvos Jr, and Colleen C Nelson

Hyperleptinemia is a well-established therapeutic side-effect of drugs inhibiting the androgen axis in prostate cancer (PCa), including main stay androgen deprivation therapy (ADT) and androgen targeted therapies (ATT). Given significant crossover between the adipokine hormone signalling of leptin and multiple cancer-promoting hallmark pathways, including growth, proliferation, migration, angiogenesis, metabolism and inflammation, targeting the leptin axis is therapeutically appealing, especially in advanced PCa where current therapies fail to be curative. In this study we uncover leptin as a novel universal target in PCa, and are the first to highlight increased intratumoural leptin and leptin receptor (LEPR) expression in PCa cells and patient tumours exposed to androgen deprivation, as is observed in patient tumours of metastatic and castrate resistant (CRPC) PCa. We also reveal world-first preclinical evidence that demonstrates marked efficacy of targeted leptin signalling blockade, using Allo-aca, a potent, specific, and safe LEPR peptide antagonist. Allo-aca suppressed tumour growth and delayed progression to CRPC in mice bearing LNCaP xenografts, with reduced tumour vascularity and altered pathways of apoptosis, transcription/translation, and energetics in tumours determined as potential mechanisms underpinning anti-tumour efficacy. We highlight LEPR blockade in combination with androgen axis inhibition represents a promising new therapeutic strategy vital in advanced PCa treatment.