Incomplete Biochemical Response Research Articles

8584 Quite High Thyroglobulin Levels in Thyroid Cancer in the Absence of Structural Lesion: Lab Interference or Microscopic Disease with Elevated Thyroglobulin?

Abstract Disclosure: M. Ahmad: None. A.P. Calimag: None. B. Arshad: None. J.T. Chaiban: None. Introduction: Thyroglobulin (Tg) is standard practice for follow-up of differentiated thyroid cancer (TC). Due to existence of thyroglobulin antibodies (Tg Ab) and Heterophile antibodies, Tg immunometric assays may be subject to interference. We present 2 challenging cases of TC with elevated Tg with absence of structural disease. Both tested positive for Epstein-Barr virus antibodies to viral capsid antigen (EBV anti VCA ab). DESCRIPTION: Case 1: 70 y.o Pt found to have calcified thyroid nodule on CT cervical spine. Thyroid ultrasound (U/S) revealed a left thyroid nodule- FNA being papillary thyroid cancer (PTC) with Bethesda 6. She had total thyroidectomy and central left lateral neck dissection. Pathology revealed PTC with 3/14 l.nodes +ve for cancer. Her Tg was 40.5 (1.2 - 35.0 ng/mL) 6 days after surgery, she received 100 mCi of radioactive Iodine (RAI). Subsequent WBS showed uptake in thyroid bed only. On follow ups, Tg started to rise persistently. PET CT unremarkable and her commensurate unstimulated Tg was 12. PET CT with interval development of a hypermetabolic focus in the postsurgical bed of thyroid and hypermetabolic cervical l.nodes. She received 100 mCi RAI + WBS that was negative for recurrence. Her Tg transiently improved but then was persistently elevated in the range 8.1-11.6 ng/ml on multiple checks. Repeat thyroid U/S did not show residual disease. Her Tg antibodies (Tg Ab) as well as Heterophile Antibody and HAMA were negative. Tg by LC-MS, was elevated in the range of 7.5 to 10.8 ng/ml. EBV anti VCA ab, IgG were positive. Case 2: 76 y.o lady initially diagnosed with toxic compressive goiter, found to have follicular thyroid cancer (FTC) after total thyroidectomy: a 5.5 cm FTC with minimal capsular/lymphatic invasion, no extrathyroidal extension, and negative margins. She received 103.7 mCi RAI after surgery. Subsequent WBS showed uptake only in the thyroid bed. Postoperatively Tg levels decreased to the range 1.6 to 5.1 ng/ml. Follow-up WBS a year later was unremarkable, and the Tg started to rise. CT scan of the chest and neck were negative. Tg by LC-MS was elevated in the range 1.6-9.2 ng/ml. PET CT was negative. Tg Ab as well as Heterophile Antibody and HAMA were negative. She tested positive for EBV anti VCA ab, IgG as well. Conclusion: Both case were elderly females- almost similar age, one with PTC and one with FTC- that had excellent structural response, but incomplete biochemical response. Measurement of Tg by LC-MS is recognized as an accurate method for Tg quantification. LC-MS assays are based on peptide quantitation after tryptic digestion which itself can have limitations due to existence of abnormal polymorphic tumor thyroglobulin (for which not much literature is available). The elevated Tg could be related to assay interference from EBV anti VCA ab (a cause or coincidence!?) or a possibility of persistent microscopic disease, hence longitudinal follow up of patients is important. Presentation: 6/2/2024

7911 High Dose Serial Radioactive Iodine Therapies Facilitated byAutologous Stem Cell Cryopreservation in a Patient with Exceptionally Avid Metastatic FTC

Abstract Disclosure: S. Paknikar: None. D. Toro Tobon: None. J. Durski: None. H. Alkhateeb: None. M.M. Ryder: None. Introduction: Radioactive iodine (RAI) therapy-induced myelosuppression is a dose-limiting toxicity for RAI avid metastatic differentiated thyroid cancers. We describe a patient with exceptionally RAI avid metastatic follicular thyroid cancer (FTC) who underwent autologous stem cell cryopreservation (ASCC) to enable high dose I-131 treatments. Case: A 60-year-old woman with T1bN0M0 FTC underwent two-stage thyroidectomy and three doses of I-131 between 2002-2007 (434 mCi cumulative activity) due to incomplete biochemical response. She presented to our institution in 2015 with rising thyroglobulin (Tg) levels and lung nodules that were intensely RAI avid. She enrolled in a clinical trial of selumetinib versus placebo (for 1 month) followed by 150 mci I-131. She had a profound response with an 80% reduction in Tg and 50% tumor shrinkage. The following year her Tg rose to 8381 ng/mL and she developed biopsy proven, well differentiated metastatic FTC in the hip and liver. Lenvatinib treatment resulted in partial tumor and Tg response but was halted due to grade 3/4 toxicities. Tumor genomic interrogation revealed NRAS, PIK3CA, and TSH-R activating mutations, providing a causal explanation of her intensely RAI avid and responsive disease. Repeat I-131 therapy was facilitated by GM-CSF stimulated ASCC (8.57 x10(6) CD34+ cells/kg for two cycles) as a tool to help mitigate future potential RAI-induced myelosuppression. The patient received 295 mci I-131 followed by a 98% decrease in Tg and 20-25% shrinkage of liver metastases. Transient pancytopenia ensued but did not require autologous stem cell transplantation (ASCT). Due to insurance issues, the patient was lost to follow-up for two years. She returned with cachexia from severe, untreated thyrotoxicosis due to widespread functional, thyroxine producing metastatic disease. Anti-thyroid drug therapy (ATD) restored euthyroid status with significant clinical improvement. A non-stimulated I-123 whole body scan showed diffuse RAI avid disease with 88% whole body radioiodine retention at 48h. She received 125 mci I-131 with initial tumor response but with progression of bone marrow, calvaria, and retinal metastases. Six months later, a final dose of 253 mCi I-131 (cumulative activity 1,370 mCi) resulted in mixed tumor responses. Unfortunately, resection of a RAI refractory calvaria lesion postoperatively resulted in serious complications. ASCT and salvage treatments could not be pursued due to her impaired functional status. The patient pursued hospice care and passed away 20 years after her diagnosis. Conclusion: We characterize a patient with NRAS, PIK3CA and TSH-R mutant metastatic, thyroxine-producing FTC whose recurrences over 20 years retained intense RAI avidity and response to I-131 therapy. In cases with potential benefit from multiple high dose RAI therapies, ASCT may be a tool to mitigate I-131-induced myelosuppression. Presentation: 6/1/2024

Tacrolimus versus mycophenolate for AutoImmune hepatitis patients with incompLete response On first-line therapy (TAILOR study): a study protocol for a phase III, open-label, multicentre, randomised controlled trial

BackgroundAutoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemical response is the most important risk factor for liver transplantation or liver-related mortality. First-line treatment consists of a combination of azathioprine and prednisolone. If CR is not reached, tacrolimus (TAC) or mycophenolate mofetil (MMF) can be used as second-line therapy. Both products are registered for the prevention of graft rejection in solid organ transplant recipients. The aim of this study is to compare the effectiveness and safety of TAC and MMF as second-line treatment for AIH.MethodsThe TAILOR study is a phase IIIB, multicentre, open-label, parallel-group, randomised (1:1) controlled trial performed in large teaching and university hospitals in the Netherlands. We will enrol 86 patients with AIH who have not reached CR after at least 6 months of treatment with first-line therapy. Patients are randomised to TAC (0.07 mg/kg/day initially and adjusted by trough levels) or MMF (max 2000 mg/day), stratified by the presence of cirrhosis at inclusion. The primary endpoint is the difference in the proportion of patients reaching CR after 12 months. Secondary endpoints include the difference in the proportion of patients reaching CR after 6 months, adverse effects, difference in fibrogenesis, quality of life and cost-effectiveness.DiscussionThis is the first randomised controlled trial comparing two second-line therapies for AIH. Currently, second-line treatment is based on retrospective cohort studies. The rarity of AIH is the main issue in clinical research for alternative treatment options. The results of this trial can be implemented in existing international clinical guidelines.Trial registrationClinicalTrials.gov NCT05221411. Retrospectively registered on 3 February 2022; EudraCT number 2021–003420-33. Prospectively registered on 16 June 2021.

BRAF V600E mutation in papillary thyroid microcarcinoma: is it a predictor for the prognosis of patients with intermediate to high recurrence risk?

The BRAFV600E mutation is the universal genetic mutation in papillary thyroid microcarcinoma (PTMC). The present study is to estimate the role of the BRAFV600E mutation in the clinical outcome of PTMC with intermediate to high recurrence risk after radioactive iodine (RAI) therapy, which is considered to be an indolent tumor. We conducted a single-center retrospective study. Between May 2016 and March 2019, PTMC patients with known BRAFV600E status who received RAI therapy were reviewed at the Second Hospital of Shandong University. Treatment and follow-up were defined according to criteria used in the 2015 ATA guidelines. The association between the BRAFV600E mutation and clinicopathological characteristics, response to RAI therapy, and recurrence after a period of follow-up were analyzed. Propensity score matching (PSM) and logistic regression were used to control confounding variables. Of the 322 patients with intermediate to high recurrence risk in PTMC, the mean age of the patients were 43.7 ± 12.2 years, and 72.1% were women. BRAFV600E mutation was found in 64.9% (209/322). After PSM, 112 pairs of patients were matched, and except for multifocality (P = 0.001), extrathyroidal invasion (P = 0.003) and tumor size (P = 0.03), there was no significant difference in all baseline characteristics between the two groups. An excellent response (ER) to RAI therapy was observed in 273 patients (84.7%). At the end of the study, 17(5.2%) and 6(1.8%) patients showed structural incomplete response (SIR) and biochemical incomplete response (BIR) status. The proportion of patients who achieved ER status in the BRAFV600E mutation positive and negative groups was 86.6% and 81.4%, respectively. Kaplan-Meier analyses showed that the BRAFV600E mutation was not related to lower ER reached time. The median follow-up was 51 months. We found the BRAFV600E mutation was associated with multifocality, extrathyroidal invasion, and tumor size in papillary thyroid microcarcinoma. However, the BRAFV600E mutation had no significant association with clinical outcomes in patients with intermediate to high recurrence risk after RAI therapy. Furthermore, the extra-thyroid uptake results and distant metastasis had been proven to be independent factor predicting the clinical response. ChiCTR2200062911.

SAT546 Papillary Thyroid Cancer Surveillance: Thyroglobulin Levels Affected by HAMA

Abstract Disclosure: J. Sanchez Perez: None. M. Obeid: None. M. Fariduddin: None. D.J. Toft: None. Introduction: Thyroglobulin (TG) measurement is a major means of detecting recurrence of previously treated differentiated thyroid cancers. Human-Anti Mouse Antibodies (HAMA) can interfere with lab measurements of TG levels and affect clinical decisions and treatment for these cancers.Clinical Case: A 65-year-old female was diagnosed with papillary thyroid cancer (PTC). Surgical pathology following total thyroidectomy demonstrated a tumor of 3.5 cm in its greatest dimension, unifocal, without invasion of locoregional tissue classified as Stage I (pT2N0M0) per AJCC 8th edition. Radioiodine whole body scan (WBS) demonstrated iodine uptake in the neck and 126.5 mCi of I-131 was given. In surveillance 5 years later, TSH was found to be 0.17 mcIU/ml (ref range: 0.35 - 4.00) TG 64.7 ng/ml (ref range: 1.3 - 31.8 ng/mL), and anti-Tg antibodies were undetectable. Neck US consistently showed nonspecific findings of stable small nodes with normal morphology in both supraclavicular regions. Given elevated TG levels, 250 mCi of I-131 was given. Follow-up TG levels ranged from 27.8 to 36.4 ng/ml. A repeat WBS did not reveal any uptake, but as TG remained elevated, I-131 (238 mCi) was again given. Subsequent TG throughout the following 15 years ranged from 2.8 - 58.6 ng/ml. Repeat Neck US only showed benign-appearing lymph nodes. WBS did not have any focal activity to suggest recurrent disease and PET/CT did not show any abnormal FDG uptake. The persistently high TG levels without clinical evidence of tumor recurrence raised the suspicion of lab interference. The serum sample was treated with a blocking reagent that contained mouse immunoglobulin after which the TG level decreased to 2.7 ng/ml compared to untreated value of 20.5 ng/ml.Conclusion: HAMA are human antibodies against mouse antibodies which are believed to develop in humans from direct contact with rodents, including mice, and from the recent increase in the use of mouse monoclonal antibodies for diagnostic and therapeutic purposes. These antibodies implicate an unexpected source of interference in immunoassays, as seen in our patient, which can confound laboratory results and create a clinical dilemma. This patient with PTC had a complete radiological response after surgery, but an incomplete biochemical response which caused the patient to be given a total of 614 mCi of I-131. This case highlights the importance of recognizing the possible presence of HAMA when analyzing TG levels, particularly when the TG levels are used for treatment decisions. Presentation Date: Saturday, June 17, 2023

131 A MORE UNIQUE THAN RARE MYOPERICARDITIS - A CASE REPORT

Abstract A 33yo man, ex-convict, with a history of IV substance abuse, without previous cardiological history, was admitted at our emergency department in the clinical context of an acute pericarditis, intermittent fever in the last 10 days and non-itchy maculo-papular erythema of palms and thorax. EKG documented a diffuse ST-segment elevation, chest X-rays revealed a bilateral pleural effusion and echocardiography documented a normal biventricular morphology and function, normal valvular function, and a circumferential pericardial effusion (14mm). The patient was admitted at our Cardiology Unit after a negative PCR SARS-CoV-2 test. Blood chemistry showed elevated WBC count with an important neutrophilia (24.000/mm3; 90% neutrophils), elevated TnI-HS (236 ng/L; n.v. <18 ng/L), elevated C-reactive protein (340 mg/L; n.v. < 5mg/L). A classic anti-inflammatory therapy was set up with indomethacin + colchicine with little clinical benefit. Blood cultures, bacterial serology (i.e., Tubercolosis, T.gondii, Syphilis, Leptospirosis) and viral serology (i.e., HIV, HCV, HBV, EBV, HSV) resulted negative. However, an empirical antibiotic coverage was set up: sequentially with Piperacillin/Tazobactam, Vancomycin, Linezolid and Ceftriaxone. None of the antibiotics improved patient's clinical status. On the contrary, the patient developed an allergic reaction to Vancomycin and Linezolid. All autoantibodies tested resulted negative. After 10 days of hospitalization, the patient's clinical status continued to deteriorate. The intermittent fever (max 41°C) was not responsive to any treatment. The evanescent skin rash had spread to the whole body and was concomitant with the fever peaks. The indexes of inflammation were rising (C-reactive protein 400 mg/L) and so were the WBC count (36.000/mm3). The patient lost weight (-8kg), developed hand and feet arthralgia, diffuse myalgia, painful retronucal lymph nodes, pharyngodynia and abdominal pain. An abdominal echography and CT were performed with evidence of mild abdominal effusion and splenomegaly. Hepatic cytolysis indices began to rise (AST 100 U/L; ALT 150 U/L; LDH 385 U/L). At that point, on the basis of Yamaguchi's Criteria, we suspected our patient could be affected by Adult-onset Still's disease (AOSD) with an initial stage of hemophagocytic lymphohistiocytosis (HLH). Prednisone (IV 2 mg/kg/die) was administered for 72h with an incomplete clinical and biochemical response (C-reactive Protein 180 mg/L). Subsequently, Anakinra (SC 100 mg/die) was administered with a complete clinical response in less than 72h. AOSD is very uncommon. The annual incidence is 0.16/100.000 with an equal distribution between sexes. HLH have been observed in 15% of patients, meanwhile myopericarditis is a rare complication. Although rare, it is fair to know and consider AOSD in the complicated and tricky diagnostic process of myopericarditis. A noteworthy point of this case report is the extreme efficacy of Anakinra in contexts of systemic inflammation and myopericarditis. A point still to be clarified concerns the duration of the treatment and the down-titration of Anakinra in these complicated contexts.

Fenofibrate Downregulates NF-κB Signaling to Inhibit Pro-inflammatory Cytokine Secretion in Human THP-1 Macrophages and During Primary Biliary Cholangitis.

Chronic liver diseases, e.g., cholestasis, are negatively impacted by inflammation, which further aggravates liver injury. Pharmacotherapy targeting the peroxisome proliferator-activated receptor alpha (PPARα), e.g., fenofibrate, has recently become an off-label therapeutic option for patients with refractory cholestasis. Clinical studies show that fibrates can reduce some pro-inflammatory cytokines in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC); however, its anti-inflammatory mechanisms have not been established. Numerous cytokines are regulated by the transcription factor nuclear receptor kappa B (NF-κB), and PPARα has been shown to interfere with NF-κB signaling. This study investigates the anti-inflammatory mechanism of fenofibrate by inhibiting NF-κB signaling in human macrophages and clinical outcomes in patients with PBC. For adult patients with PBC and an incomplete biochemical response to ursodiol (13-15mg/kg/day), the addition of fenofibrate (145-160mg/day) reduced serum levels of TNF-α, IL-17A, IL-1β, IL-6, IL-8, and MCP-1 and increased IL-10. In THP-1 cells, pretreatment with fenofibrate (125μM) reduced LPS-stimulated peak concentrations of IL-1β (- 63%), TNF-α (- 88%), and IL-8 (- 54%), in a PPARα-dependent manner. Treatment with fenofibrate prior to LPS significantly decreased nuclear NF-κB p50 and p65 subunit binding by 49% and 31%, respectively. Additionally, fenofibrate decreased nuclear NF-κB p50 and p65 protein expression by 66% and 55% and increased cytoplasmic levels by 53% and 54% versus LPS alone, respectively. Lastly, fenofibrate increased IκBα levels by 2.7-fold (p < 0.001) vs. LPS. These data demonstrate that fenofibrate reduces pro-inflammatory cytokines section by inhibiting in NF-κB signaling, which likely contribute to its anti-inflammatory effects during chronic liver diseases.

Hürthle Cell Carcinoma: Single Center Analysis and Considerations for Surgical Management Based on the Recent Literature

BackgroundHürthle cell carcinoma (HCC) of the thyroid is rare. There are contrasting data on its clinical behavior. The aim of this study was to describe clinic-pathological features and outcomes of HCC patients at our institution, in order to adapt our surgical management.MethodsWe retrospectively studied 51 cases of HCC treated at the interdisciplinary endocrine center of the University Hospital of Cologne, Germany between 2005 and 2020.ResultsPatients median age was 63 years (range 29-78) with 64.7% of cases being female. Primary treatment included surgery and postoperative radioiodine therapy with 3.7 GBq in all patients. Surgery consisted of total thyroidectomy in all cases and additional central lymphadenectomy in 90.2% of cases. The median number of harvested lymph nodes was 11 (range 2-31). Lymph node involvement was found in two (4.3%) pT4a tumors. In all other cases (95.7%), central lymphadenectomy was prophylactic and lymph nodes were free of metastasis in final histopathology. Twelve (23.5%) patients with incomplete biochemical response to primary treatment were diagnosed with structural relapse during the course of disease, for which seven (58.4%) underwent resection of isolated cervical metastasis. Histopathology revealed soft tissue implants in all cases and cervical surgery led to biochemical and radiologic cure in only two (28.5%) cases. Five (41.6%) patients developed metastatic disease, followed by systemic therapy in two patients. Vascular invasion of the primary tumor was significantly associated with relapse (p<0.01).ConclusionsRecurrence of HCC was common in this study. Given the low rate of lymph node metastases both in this study and in recent literature and the nature of relapse (soft tissue instead of nodal metastasis), the benefit of routine prophylactic central lymph node dissection for HCC remains unclear, especially in the absence of vascular invasion from the primary tumor.

The Role of American Thyroid Association Pediatric Thyroid Cancer Risk Stratification and BRAFV600E Mutation in Predicting the Response to Treatment in Papillary Thyroid Cancer Patients ≤18 Years Old

Objective:This study aimed to evaluate the role of risk stratification by the American Thyroid Association (ATA) pediatric thyroid cancer risk levels and BRAFV600E mutation to predict the response to treatment in papillary thyroid cancer (PTC) patients ≤18 years old.Methods:Clinical outcomes during a median period of 6 (2-21.8) years were assessed in 70 patients, according to ATA pediatric risk stratification, BRAFV600E mutation status, and dynamic risk stratification (DRS) at final follow-up.Results:Of 70 patients, 44 (63%), 14 (20%), and 12 (17%) were classified initially as low-, intermediate-, and high-risk, respectively. BRAFV600E mutation analysis data was available in 55 (78.6%) patients, of whom 18 (32.7%) had the BRAFV600E mutation. According to the final DRS, 61 (87%), two (3%), six (9%), and one (1%) patients were classified as an excellent, incomplete biochemical, incomplete structural, and indeterminate response, respectively. All ATA low-risk patients showed excellent response to treatment, whereas the rate of excellent response was 65.4% in intermediate- and high-risk levels (p<0.001). The rates of excellent response in BRAFV600E positive and negative patients were 83% and 92%, respectively (p=0.339). The rate of locoregional recurrence was significantly higher in BRAFV600E positive vs negative patients (33.3% vs 2.7% respectively, p=0.001).Conclusion:ATA pediatric risk stratification is effective in predicting response to treatment in PTC patients ≤18 years old. The presence of BRAFV600E mutation was highly predictive for recurrence but had no significant impact on the rate of excellent response to treatment at final follow-up.

Antithyroglobulin Antibody Variation During Follow-Up Has a Good Prognostic Value for Preoperative Antithyroglobulin Antibody-Positive Differentiated Thyroid Cancer Patients: A Retrospective Study in Southwest China.

ObjectiveAntithyroglobulin antibody (TgAb) is a potential tumour marker for detecting differentiated thyroid cancer (DTC) recurrence, but insufficient data have supported its clinical applications. Our study aimed to describe the changing trend of TgAb after surgery and identify the relationship between this trend and clinical outcomes.Patients and MethodsWe reviewed the electronic records of 1,686 DTC patients who had undergone total thyroidectomy (TT) and radioactive iodine (131I) therapy at West China Hospital of Sichuan University from January 2015 to December 2017. Finally, 289 preoperative TgAb-positive DTC patients were included and divided into four subgroups depending on the clinical outcome: Group A (tumour free), Group B (uncertain), Group C (incomplete biochemical response), and Group D (structural disease). The patient demographics, tumour characteristics, operations, pathology reports, and all serological biomarkers were reviewed and compared, and the prognostic efficacy of TgAb was evaluated.ResultsAmong all 1,686 patients, 393 (23.65%) were TgAb positive (>40 IU/ml) preoperatively. The TgAb level in Group A decreased significantly after surgery and 131I therapy and stabilised at a low level after 1–2 years of 131I therapy. However, in the other three groups, the decrease in TgAb was not significant after treatment. Conversely, TgAb declined slowly and remained stable or increased. The variations in TgAb relative to the preoperative level of Group A were significantly larger than those of Groups B, C, and D at most time points of follow-up (p < 0.001). By receiver operating characteristic (ROC) analyses, the variations of TgAb > −77.9% at 6 months after 131I therapy (area under the curve (AUC) = 0.862; p < 0.001) and TgAb > −88.6% at 2 years after 131I therapy (AUC = 0.901; p < 0.001) had good prognostic efficacy in tumour-free survival. When the variation in TgAb > −88.6% at 2 years after 131I therapy was incorporated as a variable in the American Thyroid Association (ATA) categories, both intermediate- and high-risk patients also had a significantly increased chance of being tumour free (from 75.68% to 93.88% and 42.0% to 82.61%, respectively).ConclusionsFor preoperative TgAb-positive DTC patients, variations in TgAb > −77.9% at 6 months after 131I therapy and TgAb > −88.6% at 2 years after 131I therapy had good prognostic efficacy. Their incorporation as variables in the ATA risk stratification system could more accurately predict disease-free survival.

Factors predicting the risk of biochemical incomplete response in well-differentiated thyroid cancer after total thyroidectomy.

Differentiated thyroid cancer (DTC) is the most common endocrine carcinoma with an overall good prognosis. However, persistent or recurrent disease (P/R disease) and incomplete biochemical response (BIR) are causes of morbidity. Histopathology and TNM stage may not predict P/R disease and BIR in all patients. Various clinical parameters, histopathological features and preablative-stimulated thyroglobulin (presTg) have been proposed to predicts P/R disease. However, there is uncertainty for presTg cutoff and diagnostic accuracy. The study's objective was to predict the BIR before radioiodine ablation from available clinical, histopathological and biochemical parameters. A retrospective, single-center study, including DTC patients, was done. Demography and factors predicting BIR evaluated. In comparison to the patients in remission, patients with BIR were older (P = 0.042), had higher presTg (P < 0.001), and lymph nodes (LN) metastases [central or lateral compartment (P < 0.001)]. Visualization of LN on whole-body scan (P = 0.014), higher TNM stage (P = 0.001) and distance metastasis (P < 0.001) were also associated with BIR. On multivariate analysis, high presTg (P < 0.001) and LN metastases (LNscan and histopathologically proven LN involvement, P < 0.001) were associated with BIR. A presTg level ≥12.30 ng/ml has high sensitivity (90.6%) and specificity (80.6%) to predict the BIR (odds ratio 39.90). The presTg and LN involvement are robust markers that predict BIR. A raised presTg level with LN metastases and nonvisualization of the LN on the whole-body scan is a worrying feature for the future BIR. We propose the inclusion of high presTg as a high-risk factor in DTC.

Predictors for incomplete response to ursodeoxycholic acid in primary biliary cholangitis. Data from a national registry of liver disease.

BackgroundThe current standard of treatment in primary biliary cholangitis (PBC) is ursodeoxycholic acid (UDCA), although a considerable proportion of patients show incomplete response resulting in disease progression.ObjectiveThis study aimed to assess the prevalence of incomplete response to UDCA and determine associated patients' characteristics.MethodsPatients with PBC as main diagnosis were included from a national multicentric patient registry—Liver.pt. Main endpoints included incomplete response to UDCA treatment according to Barcelona, Paris I and Paris II criteria, Globe and UK PBC scores and the association between baseline characteristics and incomplete response according to Paris II criteria.ResultsA total of 434 PBC patients were identified, with a mean age of 55 years and 89.2% females. Nearly half of patients were asymptomatic at diagnosis and 93.2% had positive anti‐mitochondrial antibodies. Almost all patients (95.6%) had been prescribed at least one drug for PBC treatment. At the last follow‐up visit, 93.3% were under treatment of which 99.8% received UDCA. Incomplete response to UDCA was observed in 30.7%, 35.3%, 53.7% and 36.4% of patients according to Barcelona, Paris I, Paris II criteria and Globe score, respectively. After adjusting for age and sex, and accordingly to Paris II criteria, the risk for incomplete biochemical response was 25% higher for patients with cirrhosis at diagnosis (odds ratio [OR] = 1.25; 95% confidence interval [95%CI]: 1.02–1.54; p = 0.033) and 35% (95%CI:1.06–1.72; p = 0.016) and 5% (OR = 1.05; 95%CI:1.01–1.10; p = 0.013) for those with elevated gamma‐glutamyl transferase (GGT) and alkaline phosphatase (ALP).ConclusionA considerable proportion of patients showed incomplete biochemical response to UDCA treatment according to Paris II criteria. Cirrhosis, elevated GGT and ALP at diagnosis were identified as associated risk factors for incomplete response. Early identification of patients at risk of incomplete response could improve treatment care and guide clinical decision to a more careful patient monitorization.

Thyroid Stimulating Hormone Receptor Transcripts in Correlation with Clinical Parameters in Thyroid Carcinoma Patients

BACKGROUND: Differentiated thyroid carcinomas (DTC) preserve expression of thyroid stimulating hormone receptor (TSHR).&#x0D; AIM: The aim of our study was to evaluate the expression of mRNA-TSHR in peripheral blood of DTC patients, then to correlate the expression with clinical features: Serum thyroglobulin (sTg) value, initial staging and findings from the whole body scan (WBS), neck ultrasound (US), and total received dose of radioiodine therapy.&#x0D; MATERIALS AND METHODS: Forty patients were divided into three groups according to the treatment response: Patients with incomplete structural response (TCs), incomplete biochemical response (TCb), and excellent responders (TCr). Total RNA was isolated from peripheral blood and used for two-step reverse transcriptase-PCR with appropriate primers. Relative quantification using the ΔCt and 2–ΔΔCt and method was applied. sTg levels were evaluated with chemiluminescent assay. The statistical analysis was performed with Spearman Rank Order Correlation.&#x0D; RESULTS: We found that TCs patients expressed mRNA-TSHR by a 5.37-fold higher level than TCr patients, TCb patients expressed TSHR by an 8.88-fold higher level than TCr patients. A significant negative correlation was detected between sTg and ΔCt (CtTSHR - CtGAPDH) value (R = −0.475; p &lt; 0.05), and between WBS/US findings and ΔCt (R= −0.321; p &lt; 0.05).&#x0D; CONCLUSION: Our data revealed higher expression of mRNA-TSHR in peripheral blood of TCs and TCb compared to TCr patients and analysis revealed a significant correlation between mRNA-TSHR and sTg and US/WBS findings. Further studies with larger number of subjects and absolute quantification are needed for understanding the real meaning of mRNA-TSHR as a biomarker in DTC.

Thyroid remnant ablation with radioiodine activity of 30, 60, and 100 mCi in patients with differentiated thyroid cancer - a prospective comparison of long-term outcomes.

IntroductionThe aim of this prospective study was to evaluate long-term outcomes in differentiated thyroid cancer (DTC) patients postoperatively treated with distinct RAI activities of 30 mCi, 60 mCi, and 100 mCi.Material and methodsThe analysis involved 277 low-risk and 46 intermediate-risk patients, who underwent radioiodine (RAI) ablation with 30 mCi, 60 mCi or 100 mCi under prospective, randomized clinical trials. Seventy-eight patients from the low-risk group received 30 mCi, whereas 125 and 74 patients received 60 mCi and 100 mCi, respectively. Regarding the intermediate-risk group, 20 patients were given 60 mCi, and 26 subjects were given 100 mCi. The mean time of follow-up was 11 years.ResultsAn excellent treatment response was obtained in 88%, 89% and 90% of low-risk patients treated with 30 mCi, 60 mCi, and 100 mCi, respectively, and in 85% of intermediate-risk patients, who were administered 60 or 100 mCi. An indeterminate response was achieved in 9.4% and 6.5%, whereas an incomplete structural response was obtained in 1.4% and 6.5% of low-risk and intermediate-risk patients, respectively. An incomplete biochemical response was observed only in 2.2% of intermediate-risk patients. The differences in treatment response regarding RAI activity were not significant.ConclusionsRAI activity of 30 mCi demonstrates a comparable efficacy as 60 mCi and 100 mCi in low-risk DTC. RAI activity of 60 mCi seems to be effective in intermediate-risk DTC.

Radioiodine Ablation of Remaining Thyroid Lobe in Patients with Differentiated Thyroid Cancer Treated by Lobectomy: A Systematic Review and Metaanalysis.

We aimed to conduct a systematic review and metaanalysis of studies reporting the performance of radioactive iodine (131I) therapy in differentiated thyroid cancer (DTC) patients requiring a completion treatment after lobectomy. We also evaluated the response to 131I therapy according to 2015 American Thyroid Association guidelines and the adverse events. Methods: A specific search strategy was designed to find articles evaluating the use of 131I in patients with evidence of DTC after lobectomy. PubMed, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science were searched. The search was updated until January 2020, without language restriction. Data were cross-checked and any discrepancy discussed. A proportion metaanalysis (with 95% confidence interval) was performed using the random-effects model. Metaregressions on 131I success were attempted. Results: The pooled success ablation rate was 69%, with better results in patients receiving a single administration of about 3.7 GBq; high heterogeneity was found (I2 test, 85%), and publication bias was absent (Egger test, P = 0.57). Incomplete structural responses were recorded in only 14 of 695 (2%) patients enrolled in our analysis. Incomplete biochemical responses were observed in 8%-24% of patients, with higher rates (24%) in patients receiving low radioiodine activities (∼1.1 GBq) and lower rates (8%-18%) in patients receiving higher activities of radioiodine (∼3.7 GBq). Neck pain due to thyroiditis was reported in up to 18% of patients, but in most cases, symptoms resolved after oral paracetamol or a short course of prednisone. Conclusion: Lobar ablation with 131I is effective, especially when high 131I activities are used. However, the rate of incomplete biochemical response to initial treatment appears to be slightly higher than in the classic scheme of initial treatment of DTC. Radioisotopic lobectomy should be considered for patients with low- to intermediate-risk DTC requiring completion treatment after lobectomy due to specific individual risk factors or patient preferences.

Microscopic extrathyroid extension in papillary thyroid carcinoma: impact on response to therapy.

Objectives Evaluate the impact of microscopic extrathyroid extension (MEE) on outcome and therapy response in patients with cT1 and cT2 papillary thyroid carcinoma (PTC). Subjects and methods Retrospective study of 970 consecutive patients, who underwent surgery for PTC between 2000 and 2016. All patients had: tumours ≤ 4 cm, apparent complete tumour resection, without clinically apparent lymph node or distant metastasis at diagnosis and nonaggressive histologic variant. Results Based on the finding of MEE, 175 (18.0%) patients were upstaged to T3. They were older (53.9 versus 50.6 years; P = 0.004) and were more prone to have multifocal tumours (38.2% versus 24.8%; P = 0.001). Radioiodine ablation therapy (RAI) was administered more often to MEE patients (92% versus 40.5%; P < 0.001), as well as prophylactic lymph node resection (35.4% versus 28.6%, P = 0.048). They were more likely to have biochemical incomplete response (4% versus 0.3%; P = 0.03) at the end of the follow-up period. There was no significant association between MEE and recurrence rate, persistence of disease or disease-specific mortality. Conclusion These results support the changes made to the latest edition of the TNM staging system, regarding MEE. Although incomplete biochemical response is more common in these patients, it does not seem to affect their prognosis.

Biochemical and plasma lipid responses to pemafibrate in patients with primary biliary cholangitis.

Fibrate addition to ursodeoxycholic acid (UDCA) therapy has been shown to improve both liver biochemistry and long-term prognosis in primary biliary cholangitis (PBC) patients showing an incomplete biochemical response to UDCA alone. We herein describe the clinical outcome of seven cases of PBC that received the new selective peroxisome proliferator-activated receptor α modulator, pemafibrate, in combination with UDCA therapy to investigate the biochemical and plasma lipid responses to the drug. Of 124 initially enrolled PBC patients, 12 treated with UDCA alone and seven receiving UDCA plus bezafibrate showed alkaline phosphatase (ALP) levels above the upper limit of normal (330U/L). Ultimately, seven patients with PBC and dyslipidemia who had agreed to biweekly visits at our hospital for UDCA plus pemafibrate combination therapy were retrospectively analyzed. In the four cases that switched from bezafibrate to pemafibrate, ALP became significantly decreased (0.031) and γ-glutamyltransferase tended to decrease (0.063) over the 3months following pemafibrate addition. Two patients showed a greater than 50% reduction in ALP. No remarkable differences were observed for plasma lipid levels, alanine aminotransferase, aspartate aminotransferase, or the liver fibrosis marker Mac-2 binding protein glycosylation isomer between these time points. No adverse drug reactions were recorded. Pemafibrate might be another option for PBC patients with an incomplete response to UDCA therapy.

Shifting paradigms in the management of pediatric differentiated thyroid cancer from static to dynamic risk stratification: a step forward toward precision medicine.

This study aimed to assess the usefulness of a risk-adopted management system known as dynamic risk stratification (DRS) in comparison with the American (ATA) and European Thyroid Associations' (ETA) risk classifications in the management of pediatric patients with differentiated thyroid cancer (DTC). The current study included 50 pediatric patients with DTC who were treated with total or near total thyroidectomy and radioiodine ablation whose risk assessment was initially defined according to the ATA and ETA guidelines. During the two years after initial treatment, patients were reclassified according to their DRS. The study showed that the ability of the DRS system to predict the final outcome was superior to that of the ATA and ETA guidelines. The observed variance in predicting final outcome was 2.3 % for ETA, 14.8 % for ATA, and 83.4 % for DRS. In intermediate/high-risk patients, according to the ATA/ETA guidelines, an excellent response to initial therapy resulted in a noteworthy reduction (about 40 %) for detection of structural disease at the time of final follow-up. The risk of structural disease at the time of final follow-up was significantly higher in the structural incomplete response group (HR = 23.34, P = 0.00) and biochemical incomplete response group (HR = 13.83, P = 0.03) than in the excellent response group. The data documented the significance of re-stratifying pediatric patients with DTC on the basis of the findings obtained at the time of or after their initial therapy (total thyroidectomy and radioiodine ablation), predominantly in the intermediate/high-risk patients. In addition, DRS helped to better modulate the later follow-up, excluding a large number of intermediate/high risk patients from needless intensive workups, allowing personalization of follow-up management.

Radiologic Nonalcoholic Fatty Liver Disease Increases the Risk of Hepatocellular Carcinoma in Patients With Suppressed Chronic Hepatitis B.

Although nonalcoholic fatty liver disease (NAFLD) is a risk factor of hepatocellular carcinoma (HCC), it is unclear whether NAFLD additionally increases the risk of HCC among chronic hepatitis B (CHB) patients. This study evaluated the association between NAFLD and the risk of HCC in patients whose hepatitis B virus (HBV) was well controlled. This study included consecutive CHB patients whose serum HBV DNA levels were continuously suppressed <2000 IU/mL with antiviral treatment. Fatty liver was radiologically diagnosed. Patients with concomitant hepatitis C infection, autoimmune hepatitis, or excessive alcohol use were excluded. Among 826 patients, 86 patients (10.4%) developed HCC during the study period (median, 43.1 mo). The patients with NAFLD (N=260) had a significantly higher risk for HCC compared with patients without NAFLD (N=566) (adjusted hazard ratio, 1.67; 95% confidence interval, 1.05-2.63; P=0.03) after adjustment for age, the presence of cirrhosis, hepatitis B envelop antigen positivity, low-level viremia and hypertension. There was significant association between incomplete biochemical response (IBR) (alanine aminotransferase levels ≥40 IU/L) and the presence of NAFLD (P<0.001 by χ test). IBR at the time of virological response was associated with a significantly higher risk of HCC development (adjusted hazard ratio, 1.63; 95% confidence interval, 1.06-2.54; P=0.03). NAFLD increases the risk of HCC in patients with CHB in whom HBV is effectively suppressed by antivirals. Patients with IBR should be suspected of concurrent NAFLD. Further study is warranted to evaluate whether improvement of NAFLD might decrease the risk of HCC development.

New molecular biomarkers in differentiated thyroid carcinoma: Impact of miR-146, miR-221 and miR-222 levels in the evolution of the disease.

MircroRNAs (miR) are small, noncoding RNA molecules of 18-25 nucleotides. Their dysregulation has been widely studied in many human tumours including differentiated thyroid cancer (DTC). miRs more frequently associated with these kinds of tumours are miR-146, miR-221 and miR-222. Our objective was to assess the relationship among circulating miR levels and the evolution and outcomes of disease. We analysed a sample of 60 patients with DTC assigning them to one of three groups according to the dynamic scale of risk (excellent response, incomplete biochemical response and incomplete structural response). At study inclusion, we determined thyroid-stimulating hormone, thyroxine, thyroglobulin, antithyroglobulin antibodies and plasma levels of miR-146, miR-221 and miR-222. Male sex and advanced age at diagnosis were associated with the worst disease progression. miR-222 was twofold to threefold higher in tall cell papillary carcinomas (P=0.038). miR-146 (P=0.016) and miR-221 (P=0.050) had a positive correlation with thyroglobulin at the time of sampling. In regression analysis, miR-146 (P=0.006), miR-221 (P=0.004) and miR-222 (P=0.007) predicted more than 70% of the variation in thyroglobulin levels at the time of sampling. Elevated miR-222 and miR-146 levels are associated with poorer outcomes of the disease and may have a prognostic value in the management and follow-up of DTC.