ResearchPad - cancer https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Retrospective observational cohort study on innovation in oncology and progress in survival: How far have we gotten in the two decades of treating patients with advanced non-small cell lung cancer as a single population?]]> https://www.researchpad.co/article/elastic_article_13816 We assessed the impact of new antineoplastic agents on the overall survival (OS) of advanced non-small cell lung cancer (aNSCLC) patients followed up until 2012. Multivariate regression models were run for OS (outcome) and four proxies for innovation (exposure): Index (InnovInd, for SEER-Research data 1973–2012) and three levels of aggregation of Mean Medication Vintage, i.e. Overall (MMVOverall), using data aggregated at the State Level (MMVState), and using patient-level data (MMVPatient) using data from the US captured in SEER-Medicare 1991–2012. We derived Hazard ratios (HR) from Royston-Parmar models and odds ratios (OR) from a logistic regression on 1-year OS. Including 164,704 patients (median age 72 years, 56.8% stage IV, 61.8% with no comorbidities, 37.8% with adenocarcinoma, 22.9% with squamous-cell, 6.1% were censored). One-year OS improved from 0.22 in 1973 to 0.39 in 2012, in correlation with InnovInd (r = 0.97). Ten new NSCLC drugs were approved and 28 more used off-label. Regression-models results indicate that therapeutic innovation only marginally reduced the risk of dying (HROverall = 0.98 [0.98–0.98], HRMMV-Patient = 0.98 [0.97–0.98], and HRMMV-State = 0.98 [0.98–0.98], and slightly improved 1-year survival (ORMMV-Overall = 1.05 95%CI [1.04–1.05]). These results were validated with data from the Swedish National Health Data registers. Until 2013, aNSCLC patients were treated undifferentiated and the introduction of innovative therapies had statistically significant, albeit modest, effects on survival. Most treatments used off-guidelines highlight the high unmet need; however new advancements in treatment may further improve survival.

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<![CDATA[Vitamin D, magnesium, calcium, and their interaction in relation to colorectal cancer recurrence and all-cause mortality]]> https://www.researchpad.co/article/elastic_article_12388 Higher concentrations of 25-hydroxyvitamin D3 [25(OH)D3] at diagnosis are associated with a lower mortality risk in colorectal cancer (CRC) patients. However, magnesium and calcium are important in vitamin D metabolism.ObjectivesWe aimed to investigate 25(OH)D3, magnesium, or calcium and their interaction among patients with CRC in relation to recurrence and all-cause mortality.MethodsThe study population included 1169 newly diagnosed stage I–III CRC patients from 2 prospective cohorts. Associations between 25(OH)D3 concentrations, magnesium or calcium intake through diet and/or supplements at diagnosis, and recurrence and all-cause mortality were evaluated using multivariable Cox proportional hazard models. The interaction between 25(OH)D3 and magnesium or calcium was assessed by investigating 1) joint compared with separate effects, using a single reference category; and 2) the effect estimates of 1 factor across strata of another.ResultsSerum 25(OH)D3, calcium, and magnesium, alone and their interactions, were not associated with recurrence. Serum 25(OH)D3 concentrations seemed to be associated with all-cause mortality. An inverse association between magnesium intake (HRQ3 vs. Q1: 0.55; 95% CI: 0.32, 0.95 and HRQ4 vs. Q1: 0.65; 95% CI: 0.35, 1.21), but not calcium intake, and all-cause mortality was observed. When investigating the interaction between 25(OH)D3 and magnesium, we observed the lowest risk of all-cause mortality in patients with sufficient vitamin D concentrations (≥50 nmol/L) and a high magnesium intake (median split) (HR: 0.53; 95% CI: 0.31, 0.89) compared with patients who were vitamin D deficient (<50 nmol/L) and had a low magnesium intake. No interactions between calcium and vitamin D in relation to all-cause mortality were observed.ConclusionsOur findings suggest that the presence of an adequate status of 25(OH)D3 in combination with an adequate magnesium intake is essential in lowering the risk of mortality in CRC patients, yet the underlying mechanism should be studied. In addition, diet and lifestyle intervention studies are needed to confirm our findings. The COLON study was registered at clinicaltrials.gov as NCT03191110. The EnCoRe study was registered at trialregister.nl as NTR7099. ]]> <![CDATA[Administration of lower doses of radium-224 to ankylosing spondylitis patients results in no evidence of significant overall detriment]]> https://www.researchpad.co/article/elastic_article_11232 The use of low doses of radium-224 (224Ra) chloride for the treatment of ankylosing spondylitis was stopped following the discovery that patients treated with it had a higher than control incidence of leukaemia and other cancers. This was so even though the treatment resulted in decreased pain and increased mobility–both of which are associated with decreased mortality. It was decided to re-analyze the epidemiological data looking at all causes of death. The risk of leukaemia, solid cancer, death from non-cancer causes and from all causes in a study populations of men that received either the typical dose of 5.6 to 11.1 MBq of 224Ra, any dose of 224Ra or no radium were compared using the Cox proportional hazard model. For patients that received the typical dose of 224Ra agreed with the excess cancer was similar to that reported in previous studies. In contrast, these patients were less likely to die from non-cancer diseases and from all causes of death than the control patients. No excess mortality was also found in the population of all males that received the radionuclide. It is concluded that 224Ra treatment administered at low doses to patients with ankylosing spondylitis did not impact mortality from all causes. The study demonstrates the need to consider all causes of death and longevity when assessing health impacts following irradiation.

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<![CDATA[A modified arginine-depleting enzyme NEI-01 inhibits growth of pancreatic cancer cells]]> https://www.researchpad.co/article/elastic_article_11227 Arginine deprivation cancer therapy targets certain types of malignancies with positive result in many studies and clinical trials. NEI-01 was designed as a novel arginine-depleting enzyme comprising an albumin binding domain capable of binding to human serum albumin to lengthen its half-life. In the present work, NEI-01 is shown to bind to serum albumin from various species, including mice, rat and human. Single intraperitoneal administration of NEI-01 to mice reduced plasma arginine to undetectable level for at least 9 days. Treatment of NEI-01 specifically inhibited cell viability of MIA PaCa-2 and PANC-1 cancer cell lines, which were ASS1 negative. Using a human pancreatic mouse xenograft model, NEI-01 treatment significantly reduced tumor volume and weight. Our data provides proof of principle for a cancer treatment strategy using NEI-01.

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<![CDATA[LINC00221 suppresses the malignancy of children acute lymphoblastic leukemia]]> https://www.researchpad.co/article/elastic_article_9231 As the most common malignant disease in childhood, children acute lymphoblastic leukemia (ALL) is a heterogeneous disease caused by the accumulated genetic alterations. Long non-coding RNAs (lncRNAs) are reported as critical regulators in diseases. GEPIA database indicated that long intergenic non-protein coding RNA 221 (LINC00221) was conspicuously down-regulated in acute myeloid leukemia. However, its expression pattern in ALL has not been revealed. This work was carried out to study the role of LINC00221 in ALL cells. Quantitative real-time PCR (qRT-PCR) quantified LINC00221 expression in ALL cells. The function of LINC00221 in ALL was determined by ki-67 immunofluorescence staining, EdU, TUNEL, JC-1, and caspase-3/8/9 activity assays. RNA pull down and Ago2-RNA immunoprecipitation (RIP) assays investigated the interaction between miR-152-3p and LINC00221 or ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2 (ATP2A2). Our study revealed the low expression of LINC00221 in ALL cells. Subsequently, LINC00221 was verified to bind with miR-152-3p. Moreover, functional assays pointed out that LINC00221 overexpression posed anti-proliferation and pro-apoptosis effects in ALL cells, and these effects could be separately reversed by miR-152-3p up-regulation. Afterward, LINC00221 was revealed to regulate ATP2A2 expression via sponging miR-152-3p. Additionally, ATP2A2 was verified to involve in regulating LINC00221-mediated ALL cell proliferation and apoptosis. In conclusion, LINC00221 suppressed ALL cell proliferation and boosted ALL cell apoptosis via sponging miR-152-3p to up-regulate ATP2A2.

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<![CDATA[Circular RNA hsa_circ_0072309 inhibits non-small cell lung cancer progression by sponging miR-580-3p]]> https://www.researchpad.co/article/elastic_article_9229 Objective: Non-small cell lung cancer (NSCLC) continues to top the list of cancer mortalities worldwide. Early diagnosis and therapeutic interventions targeting NSCLC is becoming the world’s significant challenge. Circular RNAs (circRNAs) are emerging as a group of potential cancer biomarkers.

Materials and methods: Quantitative real-time PCR (qRT-PCR) was employed to examine the expression of circ_0072309 in NSCLC tissues and cell lines. Cell counting kit 8 (CCK-8), wound healing and Transwell assays were used to analyze cell proliferation, migration and invasion in A549 and H1299 cells. The relationship between circ_0072309 and miR-580-3 was analyzed by Luciferase reporter and RNA pull down assays.

Results: We screened circ_0072309 from Gene Expression Omnibus and found that circ_0072309 was lowly expressed in NSCLC tissues and cell lines. The transfection of circ_0072309-overexpressing vector significantly suppressed the cell proliferation, migration and invasion in A549 and H1299 cells. We predicted that miR-580-3p is a target of circ_0072309 by using publicly available bioinformatic algorithms Circinteractome tool and confirmed that circ_0072309 directly bound to miR-580-3p. Furthermore, the addition of miR-580-3p mitigated the blockage of cell proliferation, migration and invasion induced by circ_0072309.

Conclusions: These data showed that circ_0072309 inhibits the progression of NSCLC progression via blocking the expression of miR-580-3p. These findings revealed the anti-tumor role of circ_0072309 during the development of NSCLC and provided a novel diagnostic biomarker and potential therapy for NSCLC.

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<![CDATA[MiR-139-5p influences hepatocellular carcinoma cell invasion and proliferation capacities via decreasing SLITRK4 expression]]> https://www.researchpad.co/article/elastic_article_9224 The microRNA, miR-139-5p, has been proved to play important roles in regulating tumor progression, including prostate cancer, osteosarcoma, esophageal cancer, and so on, but its correlation of hepatocellular carcinoma (HCC) still remains unclear. Here we found that hsa-miR-139-5p (miR-139-5p) was decreased in HCC samples compared with normal liver tissues, and a lower expression of miR-139-5p was connected to a poorer prognosis. Mechanism study indicated that a decreased/increased miR-139-5p could increase/decrease HCC cells invasion and proliferation capacities via increasing SLITRK4 expression, what’s more, the reverse assays also confirmed the conclusion when we knocked down SLITRK4 in the miR-139-5p low-expression cells. Luciferase assay confirmed that miR-139-5p could directly bind to the 3′UTR of SLITRK4 mRNA to regulate its expression. Together, these findings show the importance of miR-139-5p/SLITRK4 pathway in HCC growth and progression and may provide new targets for us to better arrange the progression of HCC.

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<![CDATA[MON-513 Suppressing the Growth of Human Medullary Thyroid Cancer Cells Using FDA-Approved Drug]]> https://www.researchpad.co/article/elastic_article_8789 Medullary thyroid carcinoma (MTC) is a solid tumor of the parafollicular cells in the thyroid gland. MTC has worse prognosis, when compared with other differentiated thyroid cancers, and MTC patients with distant metastases have a low survival rate unless thyroidectomy is performed at an early stage. Furthermore, conventional treatments have only marginal benefits. Therefore, there is a need to develop novel therapeutics for MTC. Several drugs that are developed and tested in preclinical trials fail in clinical trials. Therefore, repurposing the already US Food and Drug Administration (FDA)-approved drugs towards the treatment of cancers may have potential benefits, like saving the lives of cancer patients and lowering the investment cost of drug development. Here, we explored a novel precision treatment for thyroid cancers by repurposing the FDA-approved small molecule anti-parasitic drug Nitazoxanide (NTZ). In our study, we examined the anticancer effects of NTZ on human MTC cells using the TT cell line. We treated the TT cells with different concentrations of NTZ and assessed the cell proliferation by water-soluble tetrazolium salt (WST-1) assay and oxygen consumption rate (OCR) by Seahorse extracellular flux analysis (Seahorse XFe24 Analyzer). Additionally, we determined the effects of NTZ on the protein expression of key signaling molecules that regulate MTC cell growth by western blot analysis. Our results indicated that NTZ significantly suppressed the growth of TT cells at 24 h treatment. Very importantly, NTZ reduced the basal OCR demonstrating the inhibition of mitochondrial respiration. Moreover, protein expression studies revealed that NTZ markedly reduced the key Hippo signaling pathway effector molecule TAZ and the oncogene c-myc. Interestingly, NTZ decreased the expression of epidermal growth factor receptor (EGFR) that plays an important role for RET activation in MTC. Importantly, NTZ increased the expression of p53 upregulated modulator of apoptosis (Puma). Taken together, our findings demonstrate for the first time that NTZ inhibits the growth of MTC cells and decreases the cancer cell metabolism. The mechanisms by which NTZ targets the MTC cells involve the suppression of key oncogenic proteins and upregulation of tumor suppressor molecule. Thus, our study highlights that repurposing this FDA-approved currently used drug may have a greater advantage of being tested in preclinical models of MTC, and therefore, for the rapid consideration of NTZ as a potential therapeutic drug to treat MTC patients in the near future.

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<![CDATA[MON-508 Clinicopathological Features of Papillary Thyroid Cancer After Fukushima and Chernobyl Accidents]]> https://www.researchpad.co/article/elastic_article_8783 The phenomenon of a sharp increase in the incidence of thyroid cancer worldwide is now under debate. Screening activity, diagnostic improvements or real rise in incidence as a result of unknown carcinogens are discussed. Studies in Belarus after Chernobyl showed that the synergistic influence of radiation and nitrates might lead to an increased thyroid cancer (TC) risk in children. For better understanding of the etiology, we compared the published clinical data of pediatric TC patients after the nuclear emergency of Fukushima with the observations we made after the Chernobyl accident.

In a large-scale survey after the Fukushima accident, 300,476 subjects were screened and by September 2018, 191 subjects were diagnosed with thyroid malignancy or suspected malignancy by fine needle aspiration. Mean age of TC patients was 17.8 years at presentation. Mean tumor size was 14.9 mm. Postoperative lymph node metastasis, extra-thyroidal invasion, and pulmonary metastasis were detected in 79%, 45%, and 2.1% of all cases, respectively. Only 4.8% TC cases were staged as low risk pT1aN0M0 (Suzuki et al. 2018). For comparison, in Belarus patients mean age was 13.0 years at presentation (1078 cases), mean tumor size 14.4 mm. Lymph node metastases were observed in 74%, pulmonary metastasis in 11% and extra-thyroidal extension in 48.5 - 64.1% (with respect to latency period). The low risk (pT1aN0M0) TC patients were diagnosed in 19.2% cases.

The most of TC cases from Japan and Belarus were clinically significant, not “overdiagnosed” and screened on time. Given that the accidental thyroid doses were very low in Japanese cases, it would be very important to evaluate and compare the exposure to endocrine disruptors as e.g. nitrates and low radiation doses from diagnostic procedures (dental X-ray examination and computed tomography).

Referece:

Suzuki S, Matsumoto Y, Ookouchi C, Nakano K, Iwadate M, Suzuki S, Nakamura I, Fukushima T, Mizunuma H, Yamashita S, Takenoshita S. The clinicopathological features of childhood and adolescent thyroid cancer in Fukushima after the Fukushima Daiichi nuclear power plant accident. Thyroid. 2018; Supplement 1, (Poster 136).

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<![CDATA[MON-490 Calcitonin-Based Thyroidectomy Is a Safe Approach in Patients with Germline RET Mutation and Permits to Delay Surgery in Children]]> https://www.researchpad.co/article/elastic_article_8776 Introduction: Medullary thyroid cancer (MTC) arises from C cells secreting calcitonin. In familial MTC cases, a germline RET mutation is discovered in 98% of cases. Nowadays, an early diagnosis and radical surgery are the only curative approach. However, thyroidectomy in children is associated with a higher rate of surgical adverse events, compared to surgery in adults. The best clinical approach in patient harboring germline RET mutation (gene carriers, GC) is still undefined. Methods and materials: since 1994 to 2018 we identified 174 GC by RET screening. 56 GC underwent total thyroidectomy and lymph node dissection for the evidence of high calcitonin levels at the first clinical evaluation, whereas 27 GC underwent surgery for high stimulated calcitonin levels during the active surveillance (median 16 months, range 13-118). 90 GC are still in follow up. Results: In the group of 27 GC patients who underwent surgery during the active surveillance, 15 GC had only C cells hyperplasia (CCH) foci and 12 were affected by MTC. These carcinomas were all confined to the thyroid, without any lymph node and distant metastasis. All these patients are still in clinical remission, after a median follow-up of 4 years (range 1-11). At time of the surgery, the patients affected by MTC were significantly older than patients harboring only CCH (median 49 vs 30 years old, respectively). Among these 27 GC, 7 were diagnosed as GC when they were younger than 18 years (median 7 years old, range 2-18) and they underwent surgery after a median period of 3 years (range 1-10 years), when they were all older than 7 years. In this group, 6 of 7 were affected by CCH and only one case by a microMTC. There were not any persistent surgical adverse events and all of them are still in clinical remission. 41 of 90 GC, who are still in active surveillance, were younger than 18 years at time of RET screening: nowadays, 10/41 are older than 18 years and 15/41 are older than 14 years, all with calcitonin still in the normal range. Conclusions: we demonstrated that the calcitonin-based thyroidectomy is a safe approach in GC. Intriguingly, this approach seems to be interesting especially in children in order to perform still an early and safe surgery but when they are older, possibly adults.

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<![CDATA[MON-532 Characterization of the Angiogenic Factor SFRP2 in Papillary Thyroid Carcinoma]]> https://www.researchpad.co/article/elastic_article_8774 Over the last decade, there has been an average annual increase of 3.1% in thyroid cancer diagnosis in the U.S. Papillary thyroid carcinoma (PTC) accounts for 80% of all thyroid cancer diagnoses. However, few molecular markers exist to identify clinically aggressive phenotypes. The angiogenic factor, secreted frizzled-related protein 2 (SFRP2), is associated with a poor prognosis in several malignancies including breast cancer and melanoma. The role of SFRP2 in PTC has yet to be investigated. The aims of this study were to determine the differential expression of SFRP2 in PTC, benign thyroid adenomas, normal thyroid tissue (from patients without cancer), and normal adjacent tissue (NAT) (non-cancerous tissue from patients with PTC) and investigate the role of SFRP2 in tumor development in two PTC cell lines, PTC classical variant (PTC-CV) and PTC follicular variant (PTC-FV), upon treatment with a humanized anti-SFRP2 monoclonal antibody (hSFRP2 mAb). Immunohistochemistry (IHC) was performed using human tissue protein microarrays including 226 PTC, 79 benign adenomas, 112 NAT, and 30 normal thyroid tissue samples. In-vitro proliferation and apoptosis experiments were performed on MDA-T41 (PTC-CV) and MDA-T68 (PTC-FV) cell lines by treating with hSFRP2 mAb, Xolair IgG control, and a vehicle control. SFRP2 expression was significantly higher in PTC compared with benign adenomas and normal thyroid (mean expression scores 9, 6, and 1, respectively; p<0.05). SFRP2 expression was significantly higher in NAT than normal thyroid (mean expression score 4 and 0, respectively, p<0.05). Apoptotic rates were increased by 40% and 62% in the PTC-CV hSFRP2 mAb treatment group compared with the Xolair and vehicle treatment groups, respectively (p<0.05). Apoptotic rates were increased by 126% and 59% in the PTC-FV hSFRP2 mAb treatment group compared with the Xolair and vehicle treatment groups, respectively (p<0.05). Treatment with hSFRP2 mAb had no significant effect on proliferation in either cell line. In conclusion, SFRP2 expression is significantly higher in PTC than in benign adenomas and normal thyroid tissue. SFRP2 expression in NAT is significantly higher than in normal thyroid tissue and not significantly different from benign adenomas. SFRP2 expression in nonmalignant tissue adjacent to PTC could be due to expression in the tumor microenvironment. Treatment with a novel hSFPR2 mAb increases apoptotic rates in two different PTC cell lines. These data suggest that SFPR2 is involved in tumorigenesis of PTC.

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<![CDATA[SUN-483 A Retrospective Diagnosis of Malignant Struma Ovarii After Discovery of Pulmonary Metastases]]> https://www.researchpad.co/article/elastic_article_8771 Background: Malignant struma ovarii is a rare ovarian tumor that is histologically identical to differentiated thyroid carcinoma.1 We present a case of a struma ovarii that was recognized as being malignant only after the discovery of pulmonary metastases.

Clinical Case: A 29 year old female presented to the hospital with acute right lower abdominal pain, suspicious for ovarian torsion. She underwent urgent right salpingoopherectomy and pathology demonstrated a mature cystic teratoma with benign struma ovarii. Two years later, a CT of the abdomen incidentally revealed bilateral pulmonary nodules. Review of the imaging showed that these pulmonary nodules were also present two years prior, and had since become larger. Video-assisted thoracoscopic surgery was performed and lung biopsy was positive for well-differentiated thyroid carcinoma. The patient then underwent total thyroidectomy which revealed a 0.3 x 0.3 cm infiltrative papillary thyroid cancer, follicular variant, without lymphovascular invasion. Thyroglobulin level decreased from 169 ng/mL pre-operatively to 80 ng/mL post-operatively, but then continued to be variable ranging from 56 to 252 ng/mL (1.6-50 ng/mL). Thyroglobulin antibodies remained negative.

Pathology from right ovary was re-reviewed at a second institution and found to be consistent with highly differentiated thyroid carcinoma with characteristic nuclear features of papillary thyroid carcinoma.

A diagnostic whole body I-131 scan showed uptake within the thyroid bed, bilateral lung nodules, left distal thigh and right mid thigh. These thigh lesions were not visualized on lower extremity ultrasound. After dosimetry was performed, the patient received radioactive iodine-131 200 mCI. Post-therapy scan six days later demonstrated uptake in the thyroid bed, bilateral lungs and bilateral thighs. About five months later, thyroglobulin level had decreased to 0.4 ng/mL with a suppressed TSH. A repeat CT chest demonstrated that the lung nodules had all decreased in size, largest from 0.5 cm to 0.3 cm.

Conclusion: Careful examination of struma ovarii pathology should be performed to evaluate for malignant features since benign appearing histology can present diagnostic difficulty.2 In this case, thyroglobulin level was lower than reported in previous cases; however, sites of metastases were responsive to radioactive iodine therapy indicating well differentiated disease and a favorable prognosis.

References: 1. Goffredo P, Sawka AM, Pura J, Adam MA, Roman SA, Sosa JA. Malignant Struma Ovarii: A Population-Level Analysis of a Large Series of 68 Patients. Thyroid. 2015:25(2): 211-216.

2. Roth LM, Miller AW, Talerman A. Typical Thyroid-Type Carcinoma Arising in Struma Ovarii: A Report of 4 Cases and Review of Literature. Int J Gynecol Pathol. 2008:27(4): 496-506.

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<![CDATA[MON-103 Pattern and Predictors of Thyroid Dysfunction Among Paediatric Endocrine Referrals at Tertiary Care Centre: A Longitudinal Study]]> https://www.researchpad.co/article/elastic_article_8735 Background Post iodisation era has experienced gradual change in pattern of thyroid disorders among paediatric population with autoimmunity taking precedence over iodine deficiency disorders and subclinical hypothyroidism (SCH) now more frequently diagnosed but inappropriately managed. Aims This study was conducted to evaluate pattern of abnormal thyroid function among children referred to our tertiary care centre, to ascertain characteristics that influence treatment decisions and to follow them for various outcome measures. Design It was an observational longitudinal follow up study where all children less than 18 years, referred to our outpatient clinic for suspected thyroid disorder were recruited. Demographic data, personal and family history, clinical features were noted and laboratory tests including TT4, TT3, TSH, anti-thyroid peroxidase(antiTPO) and anti-thyroglobulin(antiTG) antibody were conducted in study subjects. Management was based on the clinical judgment of the attending endocrinologist. Patients were followed at 6 week, 3 months, 6 months and one year with clinical and laboratory work up at each visit. Results A total of 241 subjects aged 18 days to 17 years were included out of which 62.25% were females. Initial evaluation revealed SCH in 40% of refereed subjects, overt hypothyroidism (OH) in 33%, congenital hypothyroidism (CH) in 18% and overt thyrotoxicosis in 5%. Autoimmune thyroiditis constituted the major cause of hypothyroidism in the OH group with significantly higher prevalence of anti-TPO and antiTG antibody in comparison of SCH group (61% vs 31%; 45% vs 21.9%, p<0.05) respectively. All subjects in OH group were treated whereas 76% subjects in SCH group were treated and the mean dose of L thyroxine required to treat OH was significantly higher (2.31+1.1ug/kg/day vs 1.76+1.07ug/kg/day; p<0.001) in comparison of SCH group. A major independent predictor of treatment in SCH was initial TSH which was significantly higher in the treated group (11.65 + 3.80 uIU/ml vs 9.24 + 1.31 uIU/ml; p<0.001). Subjects with congenital hypothyroid presented at a mean age of 6 months (18 days to 2 years) with most common aetiology being thyroid hypoplasia and dyshormonogenesis

(20% each). Graves’ disease was diagnosed in 11 out of 12 subjects with thyrotoxicosis and were treated with antithyroid drugs. Overall 85.5% of refereed subjects were treated and after one-year follow up management was found to be adequate in 81% subjects. Conclusions The evolving trend of diagnosing children having nonspecific symptoms with SCH is a matter of concern as many are subjected to the burden of unwanted prolonged treatment and frequent testing as highlighted in our study. Delayed presentation of CH in our study warrants active surveillance of children at birth for thyroid disorders to avoid long term adverse effects on mental development.

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<![CDATA[MON-499 Nivolumab-Induced Hypothyroidism Is Irreversible in Most Patients]]> https://www.researchpad.co/article/elastic_article_8665 Background Thyroid dysfunction caused by the immune checkpoint inhibitor (ICPI) is common, however mild dysthyroidism could occur easily in cancer patients due to other causes. The aim of this study was to investigate the incidence and clinical course of ICPI-induced hypothyroidism requiring thyroid hormone replacement. Patients and methods We analyzed baseline and follow up thyroid function tests of cancer patients treated with nivolumab between March 2016 and March 2019 at Chonnam University Hwasun Hospital retrospectively. Results Among 265 cancer patients treated with nivolumab therapy, six patients were excluded from the study because they were on thyroid hormone replacement therapy before starting nivolumab therapy. Twenty-one patients (8.1%) newly developed thyroid dysfunction during nivolumab therapy and sixteen patients (6.2%) required thyroid hormone replacement therapy due to drug-induced hypothyroidism. Cancer diagnoses included lung cancer (n=7), renal cell carcinoma (n=4), malignant melanoma (n=2), hepatocellular carcinoma (n=2), and esophageal cancer (n=1). Six patients (37.5%) showed thyrotoxic phase prior to overt hypothyroidism and the others (n=10, 62.5%) revealed hypothyroidism without thyrotoxic phase. Most ICPI-induced hypothyroidism was irreversible, only one patient was able to discontinue thyroid hormone replacement after quitting nivolumab therapy. Conclusion A significant number of patients treated with nivolumab developed ICPI-induced hypothyroidism requiring thyroid hormone replacement and its clinical course was irreversible in most patients.

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<![CDATA[MON-450 Prophylactic Thyroidectomy in a Patient with Codon 891 Mutation of the RET Proto-Oncogene]]> https://www.researchpad.co/article/elastic_article_8650 Background: Medullary thyroid cancer (MTC) is a neuroendocrine tumor of the parafollicular or C cells of the thyroid gland, accounting for 1-2% of thyroid cancers in the United States. About 25% MTCs are familial as a part of the MEN2 syndrome or familial MTC (FMTC). Germline mutations in codon 891 are predominantly associated with FMTC. Case: 65-year-old Caucasian male was referred to the Endocrinology clinic after bilateral thyroid nodules were found on thyroid US. The patient had requested an ultrasound of his thyroid after his brother was diagnosed with MTC following fine-needle aspiration for an incidental thyroid nodule prompting total thyroidectomy and genetic testing. The patient’s brother was found to be heterozygous for RET mutation (c.2617T>G;pSer891Ala). This resulted in screening of the other siblings including this patient, also found to be heterozygous for this mutation. Both parents were deceased, and their clinical history is not known. Only one of the remaining two siblings had genetic testing; one brother refused testing for the mutation and one sister was positive for the mutation but had no thyroid nodules on ultrasound. She underwent prophylactic thyroidectomy. Neither the patient, nor his siblings, have any progeny. The patient screened negative for primary hyperparathyroidism and pheochromocytoma. Calcitonin (739, normal </=14.3 pg/mL)and CEA levels (31.7, 0-3.0 ng/mL) were elevated. Thyroid ultrasound (US) showed two solid hypoechoic nodules with lobulated margins and internal coarse calcifications in the right and two in the left thyroid lobe; 1.5 cm and 1.2 cm in maximum diameter, and 1.2 cm and 3 mm in maximum diameter, respectively. Based on elevated calcitonin and CEA levels, known RET mutation and evidence for thyroid nodules, we recommended a total thyroidectomy and central neck dissection. Pathology revealed multifocal, bilateral medullary carcinoma (largest focus of 1.5 cm), with 4/4 lymph nodes positive for metastasis. This was classified as mpT1bN1aM0 (Stage III). Patient was started on levothyroxine with plans to repeat calcitonin and CEA levels and neck ultrasound, 3 months following surgery. CT chest, abdomen and pelvis did not reveal any distant metastasis. Conclusion: Inherited MTCs are rare. Early diagnoses by screening of at-risk family members in MEN2 kindreds is important because MTC can be life-threatening and can be cured and prevented by early thyroidectomy. While our suspicion for FMTC in this patient and his siblings is high, FMTC is now considered a variant of MEN2A and ongoing screening for pheochromocytoma and primary hyperparathyroidism is recommended.

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<![CDATA[MON-LB86 The Sensitivity and Specificity of Various Thyroid Nodule Ultrasound Characteristics and the Diagnostic Accuracy of the ATA Guidelines and ACR TI-RADS for Predicting Thyroid Cancer at an Urban Endocrinology Clinic]]> https://www.researchpad.co/article/elastic_article_8610 Introduction: Several current guidelines assess sonographic features to guide management of thyroid nodules. The ACR uses an additive point system to assign the level of risk to various sonographic features, whereas the ATA groups sonographic features together to determine the level of risk. The purpose of this study is to compare the performance of the ATA guidelines and ACR TI-RADS at an urban endocrinology clinic in risk stratifying thyroid nodules by their specific sonographic features.

Methods: This retrospective, chart-review study includes adult patients who met sonographic criteria for fine needle aspiration (FNA) biopsy based on ATA or ACR TI-RADS at an outpatient endocrinology practice in San Francisco, CA between December 2011 and August 2019. Patients with a prior history of thyroid malignancy (anaplastic and medullary thyroid carcinoma or thyroid lymphoma) were excluded. The reference standard for the diagnosis of malignancy was surgical pathology or FNA cytology Bethesda category V or VI when surgical pathology was unavailable. Analysis of guideline performances and specific sonographic features included: sensitivities (Sn), specificities (Sp), positive predictive values (PPV), negative predictive values (NPV), and area-under-the-curve (AUC) using Fisher’s exact test.

Results: Two hundred seventy-five nodules among 195 adults (86.2% were women) were included in the analysis. Twelve nodules were malignant, with an associated malignancy rate of 4.4%. TI-RADS had higher accuracy based on AUC of 0.710 compared to 0.623 using ATA guidelines. TI-RADS also had a higher PPV of 21.4% among nodules with 9 points, versus 5.8% among nodules in the ATA “high suspicion” category. Ultrasound characteristics with the highest Sp, relative PPV and NPV were: microcalcifications (84.5%, 4.3%, 96.0%, respectively), taller-than-wide (81.7%, 7.1%, 96.7%), irregular margins (77.7%, 6.0%, 96.5%); the characteristic with the highest Sn was hypoechogenicity (83.3%), however this had relatively low Sp (25.4%) and PPV (4.5%).

Conclusions: TI-RADS performed better with higher overall accuracy and PPV when applied to nodules classified as having the highest malignancy risk. Taller-than-wide shape, irregular margins, and microcalcifications were the characteristics most useful for malignancy risk stratification. Limitations of this study include: interobserver bias, small sample size, referred patient population (which may differ from other institutions), and inability in some cases to confirm malignant FNA cytology with surgical pathology.

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<![CDATA[MON-537 Primary Adrenal Insufficiency During Tyrosine Kinase Inhibitors Treatment in Advanced Thyroid Cancer Patients]]> https://www.researchpad.co/article/elastic_article_8597 Objective: Tyrosine kinase inhibitors (TKIs) are used for the treatment of metastatic differentiated (DTC), poorly differentiated (PDTC) and medullary (MTC) thyroid cancer. Several adverse events (AEs) have been reported in almost all patients (pts) treated with TKIs. One of the less known AE related to the use of these drugs is the primary adrenal insufficiency (PAI).

Methods: We analyzed the basal and stimulated adrenal function, ACTH levels, adrenal antibodies and electrolytes levels in 82 thyroid cancer pts treated with TKIs (vandetanib and cabozantinib in MTC pts, lenvatinib and sorafenib in DTC and PDTC pts) and we correlated these results with the clinical-pathological features of our pts.

Results: In our series, 25/82 (30.5%) pts showed a PAI after stimulation test with a progressive ACTH increase in 14/25 (56%) pts. Thirteen/25 (52%) pts with PAI were DTC, 8/25 (32%) pts were MTC and 4/25 (16%) pts were PDTC. Sixteen/25 (64%) pts were treated with lenvatinib, 8/25 (32%) were treated with vandetanib and 1/25 (4%) was treated with cabozantinib at the time of stimulation test. In 5/25 (20%) pts PAI occurred within 12 months from the TKIs treatment initiation, in 9/25 (36%) within 36 months and in 11/25 (44%) after 36 months of treatment. Eighteen/25 pts with PAI were older than 55 years. Twenty/25 (80%) of these pts were treated with cortisone acetate replacement therapy with the improvement of fatigue in a small part of these while other 5 pts were untreated due to the mild degree of PAI and the absence of specific symptoms (i.e fatigue). Moreover, in our pts the evaluation of adrenal antibodies was negative and the electrolytes levels were in the normal range. We also correlated the presence of PAI with the clinical-pathological features of our pts but we didn’t observe any significant correlation.

Conclusions: We observed that PAI, mainly subclinical, can occur during TKIs treatment in thyroid cancer pts. The appearance of fatigue, the typical symptom of PAI, could be multifactorial in these pts due also to the direct effect of TKIs treatment. Thus, in these cases is very difficult to recognize the cause of fatigue and to decide the appropriate treatment (cortisone acetate replacement therapy vs TKIs dose reduction). Moreover, the time of PAI appearance is variable since it can be early (<12 months) or late (>36 months) after TKIs treatment initiation and the adrenal function must be monitored during all TKIs treatment period. More studies are needed to know the pathophysiology of this “adverse event” during TKIs treatment and to improve the acknowledgments regarding the differential diagnosis and treatment of these pts, regardless of symptoms.

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<![CDATA[OR22-04 Relationship of TSH Levels with the Components of Metabolic Syndrome in a Nationally Representative Population of Youth in the United States]]> https://www.researchpad.co/article/elastic_article_8587 Introduction: Subclinical hypothyroidism (SH) is defined as elevated TSH with normal thyroid levels, and is often associated with obesity. SH has been linked to cardiometabolic risk factors such as abnormal lipids, elevated blood pressure, atherosclerosis and fatty liver. This study sought to elucidate the association of TSH level with the components of metabolic syndrome independent of BMI in children from the National Health and Nutrition Examination Survey (NHANES).

Methods: NHANES surveys 1999-01 and 2007-12 that measured thyroid function tests were included in the study. Youth aged 2-18 years with TSH levels < 10 uU/mL and normal Total T4 (TT4) levels were included in the analysis. The components of metabolic syndrome were defined as abdominal obesity (waist circumference > 95th %tile), hypertriglyceridemia (TG >=100 for 0-9 years and >=130 mg/dL for > 10 years), low HDL cholesterol < 40 mg/dL), elevated blood pressure (> 95th %tile for age/sex/height) and hyperglycemia (FBG > 100 mg/dL, or diagnosis of diabetes). The association of these components with quartiles of TSH were examined by logistic and linear regression controlling for age, sex, race/ethnicity and BMI. All analyses were performed in R v3.5.1.

Results: After excluding youth with TSH >10 uU/mL and TT4 levels < 12.4 mcg/dL, 2377 subjects (50% female) were included in the study. The mean age of the cohort was 15 ± 1.7 years; 28.2 % were non-hispanic whites and 38.5 % hispanic/latino. Obesity (BMI >95 %tile) was seen in 21.7% individuals. There were 44 subjects with TSH levels >4.5 uU/mL that was not different by BMI (2.5% in BMI >95%tile and 1.7% BMI < 95%tile, p = 0.29). Based on the distribution in the population, TSH levels were divided into 4 quartiles: Q1= 0.01-0.97, Q2= 0.98-1.42, Q3=1.43-2.0, Q4 = > 2.01 uU/mL. A statistically significant association of the Q4 TSH was seen with abdominal obesity, OR 2.44 (1.38-4.39), p=0.002 and elevated BP, OR 1.6 (1.06-2.44), p = 0.02 but not with high TG, OR 1.58 (0.93-2.75), p=0.09, low HDL, OR 0.84 (0.6-1.17), p = 0.31 or those with hyperglycemia and/or diabetes, OR = 1.25 (0.78-2.05), p = 0.36. Linear regression models showed statistically significant association of abdominal obesity, hypertriglyceridemia, elevated BP and hyperglycemia (and/or diabetes) with increase in TSH level.

Conclusions: In children from a representative US population, the prevalence of SH defined as TSH level >4.5 uU/mL is low, even with BMI >95th %tile. The association of measures of metabolic syndrome with linear increase in TSH suggests that the current reference range may require modification.

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<![CDATA[MON-435 Hashimoto Thyroiditis and Goiter: Never Cease Follow-Up]]> https://www.researchpad.co/article/elastic_article_8555 Background

Hashimoto thyroiditis (HT) is the most common cause of hypothyroidism in iodine-sufficient areas. Its incidence is estimated to be 3.5 per 1000 per year in women and 0.8 per 1000 per year in men (3). Primary thyroid lymphoma (PTL) is a rare complication of HT, but often forgotten. Regular follow-up and high clinical suspicion is needed to diagnose this complication early. We present a patient who developed PTL as a complication of HT after 10 years of diagnosis of HT and goiter.

Clinical case

A 70-year-old male with history of hypertension and obstructive sleep apnea followed up in the endocrine clinic for the last 10 years for Hashimoto thyroiditis and stable goiter presented with a sudden enlargement of right neck mass. In 2008 he was incidentally diagnosed with HT. In 2010 the patient returned with a neck swelling and further investigation revealed a cold nodule in the right lobe. The patient underwent aspiration biopsy with repeat finding of HT, and was followed up yearly with thyroid ultrasound and TSH. In 2014 due to concern in the echotexture of thyroid on ultrasound, he had a biopsy of the right thyroid nodule with findings again consistent with HT. No significant changes were noted on yearly follow-up ultrasound until March 2019. He presented 5 months later with a large mass on the right side of his neck. Ultrasound showed enlarged and confluent lymph nodes anterior to the enlarged right thyroid gland. Further CT evaluation showed a large right neck mass measuring 5.2 x 7.5 x 12 cm extending from the right thyroid lobe to the level of C1. The mass crossed the midline posteriorly. Fine needle aspiration was positive for malignant cells. A core biopsy confirmed diffuse large B-cell lymphoma. The patient had tests for staging, including bone marrow biopsy, and was found to be stage II E diffuse large B-cell lymphoma involving the thyroid. Subsequently, the patient was started on chemotherapy with RCHOP(Rituximab, Cyclophosphamide,Doxorubicin,Vincristine,Prednisolone).

Conclusion

Although Primary thyroid lymphoma (PTL) is a rare condition, it should always be considered in the differential diagnosis of a rapidly growing goiter or thyroid nodule. Its incidence is 2 per million, with nearly all cases the non-Hodgkin’s type. PTL accounts for only 0.5–5% of all thyroid malignancies and 1% to 7% of all extranodal lymphomas. The prevalence of Hashimoto thyroiditis in patients with PTL is highly variable, but patients with HT have a 40- to 80-fold increased risk of developing PTL. A rapidly enlarging neck mass with or without compressive symptoms is the common presentation of PTL. Most common histotype is diffuse large B cell lymphoma which accounts for 50% to 70% of cases. High clinical suspicion and awareness among physicians is needed to diagnose PTL early. The main treatment is chemotherapy. Surgical interventions are needed to relieve pressure symptoms. The prognosis of PTL is generally excellent.

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<![CDATA[Regulation of cell growth and migration by miR-96 and miR-183 in a breast cancer model of epithelial-mesenchymal transition]]> https://www.researchpad.co/article/elastic_article_7836 Breast cancer is the most commonly diagnosed malignancy in women, and has the second highest mortality rate. Over 90% of all cancer-related deaths are due to metastasis, which is the spread of malignant cells from the primary tumor to a secondary site in the body. It is hypothesized that one cause of metastasis involves epithelial-mesenchymal transition (EMT). When epithelial cells undergo EMT and transition into mesenchymal cells, they display increased levels of cell proliferation and invasion, resulting in a more aggressive phenotype. While many factors regulate EMT, microRNAs have been implicated in driving this process. MicroRNAs are short noncoding RNAs that suppress protein production, therefore loss of microRNAs may promote the overexpression of specific target proteins important for EMT. The goal of this study was to investigate the role of miR-96 and miR-183 in EMT in breast cancer. Both miR-96 and miR-183 were found to be downregulated in post-EMT breast cancer cells. When microRNA mimics were transfected into these cells, there was a significant decrease in cell viability and migration, and a shift from a mesenchymal to an epithelial morphology (mesenchymal-epithelial transition or MET). These MET-related changes may be facilitated in part by the regulation of ZEB1 and vimentin, as both of these proteins were downregulated when miR-96 and miR-183 were overexpressed in post-EMT cells. These findings indicate that the loss of miR-96 and miR-183 may help facilitate EMT and contribute to the maintenance of a mesenchymal phenotype. Understanding the role of microRNAs in regulating EMT is significant in order to not only further elucidate the pathways that facilitate metastasis, but also identify potential therapeutic options for preventing or reversing this process.

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