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Background Patients with chronic limb‐threatening ischemia (CLTI) face a high long‐term mortality risk. Identifying novel mortality predictors and risk profiles would enable individual health care plan design and improved survival. We aimed to leverage a random survival forest machine‐learning algorithm to identify long‐term all‐cause mortality predictors in patients with CLTI undergoing peripheral vascular intervention. Methods and Results Patients with CLTI undergoing peripheral vascular intervention from 2017 to 2018 were derived from the Medicare‐linked VQI (Vascular Quality Initiative) registry. We constructed a random survival forest to rank 66 preprocedural variables according to their relative importance and mean minimal depth for 3‐year all‐cause mortality. A random survival forest of 2000 trees was built using a training sample (80% of the cohort). Accuracy was assessed in a testing sample (20%) using continuous ranked probability score, Harrell C‐index, and out‐of‐bag error rate. A total of 10 114 patients were included (mean±SD age, 72.0±11.0 years; 59% men). The 3‐year mortality rate was 39.1%, with a median survival of 1.4 years (interquartile range, 0.7–2.0 years). The most predictive variables were chronic kidney disease, age, congestive heart failure, dementia, arrhythmias, requiring assisted care, living at home, and body mass index. A total of 41 variables spanning all domains of the biopsychosocial model were ranked as mortality predictors. The accuracy of the model was excellent (continuous ranked probability score, 0.172; Harrell C‐index, 0.70; out‐of‐bag error rate, 29.7%). Conclusions Our random survival forest accurately predicts long‐term CLTI mortality, which is driven by demographic, functional, behavioral, and medical comorbidities. Broadening frameworks of risk and refining health care plans to include multidimensional risk factors could improve individualized care for CLTI.

Background Peripheral artery disease (PAD) and microvascular disease (MVD) are highly prevalent conditions that share common risk factors. This observational study aimed to characterize patients with both conditions and determine the impact of comorbid PAD/MVD on outcomes. Methods and Results Patients admitted across 31 states January 2011 through December 2018 with a primary or secondary diagnosis of PAD or MVD were included from the National Readmissions Database and weighted to approximate a national sample. Those age 500 000 in 2018. Major and minor amputations increased ≈50% for PAD/MVD between 2011 and 2018. Compared with PAD‐only, PAD/MVD was associated with a higher risk for major amputation (odds ratio [OR], 1.30 [95% CI, 1.28–1.32]), minor amputation (OR, 2.15 [95% CI, 2.12–2.18]), major adverse cardiac events (OR, 1.04 [95% CI, 1.03–1.04]), in‐hospital mortality (OR, 1.07 [95% CI, 1.05–1.09]), and readmission (hazard ratio, 1.02 [95% CI, 1.02–1.02]) after adjustment for baseline factors. Conclusions Comorbid MVD is present in a large and growing number of patients with PAD and is associated with augmented risk for adverse outcomes. Further prospective research is merited to understand this vulnerable population.

Digital health technologies (DHTs) are a broad and rapidly innovating class of interventions with distinctive pathways for development, regulatory approval, uptake and reimbursement. Given the unique nature of DHTs, existing value assessment frameworks and evidence standards for health technologies such as drugs and devices are not directly applicable. The value assessment framework presented here describes a conceptual model and associated methods to guide assessments of DHTs. The framework seeks to accomplish two goals: to set evidence standards that guide technology developers to generate robust evidence on their products; and to provide reviews that help organizations adopt high-impact DHTs with the strongest evidence for delivering improved clinical outcomes and cost savings. This assessment framework will serve as the roadmap for future evaluations of DHTs by the Institute for Clinical and Economic Review (ICER) and the Peterson Health Technology Institute (PHTI). We believe that all stakeholders will benefit from comprehensive and explicit standards of evidence on the different dimensions necessary to understand the value of DHTs.

New Institute for Clinical and Economic Review (ICER) analysis evaluates potential risks and advantages of reforms to current policies related to white bagging, brown bagging, and site of service policies that aim to address provider markup in the commercial insurance market.

While nutritional interventions are first-line therapy for many chronic diseases, most medical trainees receive minimal nutrition education, leaving them unprepared to address nutritional issues with patients. An interactive, single-session, virtual nutrition curriculum was taught online to 80 physician assistant (PA) students. Topics included plant-based nutrition, dietary history-taking and counseling, and culinary medicine. Students were surveyed before, immediately after, and four weeks after the curriculum to assess changes to nutrition-related knowledge, attitudes, confidence, and personal dietary behaviors. Seventy-three PA students (91%) completed the pre-survey, 76 (95%) completed the post-survey, and 42 (52.5%) completed the delayed post-survey. Knowledge scores increased immediately post-intervention (48.9% to 78.9%; p < 0.001) and persisted four weeks later (78.9% to 75.8%; p = 0.54). Post-intervention, students felt more confident in dietary history-taking (55% vs. 95%; p = 0.001) and nutrition counseling (53% vs. 84%; p = 0.003) and agreed that dietary changes alone could reverse type 2 diabetes (74% vs. 97%; p = 0.027) and coronary artery disease (66% vs. 92%; p = 0.039). Curricula using virtual teaching kitchens may be a scalable approach to nutrition education for medical trainees.

Category: Ankle; Ankle Arthritis; Basic Sciences/Biologics; Other Introduction/Purpose: Total ankle arthroplasty through the anterior approach (TAR-AA) is an increasingly popular treatment for ankle arthritis. This approach carries significant risk for wound complications. Several products have been investigated to mitigate this risk, but these are either costly or invasive. Noninvasive skin expansion strips (NSESs) have two nonelastic adhesive strips, one on either side of the incision, with an elastic band connecting them. These were designed to induce new skin growth at the edges of the strips for plastic surgery applications. In the postoperative setting, the NSES functions to transfer tension away from the site of the incision to the edge of the strips. We hypothesize that postoperative application of NSESs will decrease unplanned clinic visits and wound complications after TAR-AA. Methods: This is a prospective cohort study with retrospectively identified historical controls designed to evaluate the effectiveness of NSESs. Prospectively enrolled patients undergoing TAR-AA at a single institution (3 surgeons) received application of NSESs in the operating room after routine wound closure. At their two-week postoperative visit, each wound was assessed and new NSESs were applied. No other changes were made to the surgeons' wound closure technique, immobilization, follow-up cadence, or rehabilitation protocols. Patients following up with providers outside the institution were excluded. Thirty five consecutive historical controls were identified for comparison. Primary outcomes included (1) Additional clinic visit required for wound assessment or suture removal, (2) superficial wound complication before 8 weeks, and (3) deep infection before 8 weeks. Z-score test was used to calculate statistically significant (p

As a result of globalization, the number of people living outside of their countries of origin is on the rise. Among them are children of primary and secondary school age of varying socio-economic backgrounds. This article addresses the education-related challenges that children in such circumstances face. I first identify two principles – an educational adequacy principle and a presumption of responsibility on the part of a host country for meeting children’s educational needs – which are widely employed to guide national policy decisions on educational content and the distribution of educational resources. I then discuss a number of problems that students living abroad face which, I argue, policies devised on the basis of these principles either systematically overlook or, in some cases, exacerbate. Finally, I offer two alternative principles – a cosmopolitan revision of the first and a replacement for the second with a focus on collective responsibility – designed to promote education policies better suited to a globalized world which might help to alleviate the barriers to success commonly encountered by children learning abroad.

Mycosis fungoides (MF) is a rare cutaneous T-cell lymphoma (CTCL) which can cause significant morbidity. ​During​ ​the​ ​disease course, ​​ ​it​ ​classically​​ ​will​ ​progress​ ​through​ ​three​ ​clinical​ ​stages​ ​in​ ​the​ ​skin​: ​ ​patch-,​ ​plaque-,​ ​and tumor-stage.​ The early stages exhibit​ ​various​ ​histopathological​ ​mimics​ ​that​ ​often​ ​lead​ ​to misdiagnosis.​ It rarely affects the oral cavity. Oral MF is historically associated with poor prognosis. We present a rare case of MF afflicting the dorsal tongue and extremities of a 72-year-old male.

Genetic testing for germline RET pathogenic variants, which cause the Multiple Endocrine Neoplasia Type 2 (MEN2) syndrome, has become crucial in managing patients with medullary thyroid carcinoma (MTC). Classically, RET heterozygous missense pathogenic variants are transmitted in a Mendelian autosomal dominant pattern, of which germline/gonadal mosaicism has never been reported. We report the novel occurrence of a MEN2A patient's family in which the siblings inherited three different RET 634 genotypes: wild type (p.Cys634), p.Cys634Gly or p.Cys634Arg heterozygous pathogenic variants. We hypothesized that germline/gonadal mosaicism, derived from an inherited + early somatic mutation in the mother or a double de novo mutation during maternal embryogenesis, led to this rare event in the RET gene. Exome analysis of the proband's deceased mother's paraffin-embedded thyroid tissue confirmed the three nucleotides in the same 634 codon position. For the first time, we describe germline/gonadal mosaicism in RET, generating a second pathogenic amino acid change in the same codon causing MEN2A. Our finding shows that RET parental mosaicism, confirmed by somatic exome sequencing, might explain discrepant genotype cases in siblings with inherited cancers., (© 2024 Wiley Periodicals LLC.)

Purpose: This article aims to describe the presentation of Plummer disease and its evolution after radioiodine treatment and determine factors that may influence treatment efficacy., Patients and Methods: The sample included retrospective medical records of 165 adult patients with toxic nodular goiter treated with radioiodine between 1997 and 2017, followed up at a single thyroid center., Results: The efficacy of treatment with a single dose of radioiodine was higher than 90%. The mean radioiodine activity was 28.9 ± 3.4 mCi. The mean time between radioiodine performance and hyperthyroidism resolution was 3.6 ± 3.0 months, ranging from 1-12 months. After the first year, 33.9% of the patients were under hypothyroidism, 59.4% under euthyroidism, and 6.7% under hyperthyroidism. Among the nonresponders, the variables that showed statistical difference were the presence of multinodular goiter and the radioiodine activity (mean, 25.5 ± 6.5 mCi; median, 30 [15-30 mCi]). The cumulative rate of hypothyroidism was 48.9% over 20 years of follow-up., Conclusions: Radioiodine therapy is an effective and safe treatment. In Plummer disease, high rates of euthyroidism are expected after the radioiodine treatment. Therapeutic failure was observed mainly in patients with larger multinodular goiters treated with lower doses of radioiodine. The evolution to hypothyroidism was mostly observed in younger patients with larger and uninodular goiters., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The risk of malignancy and diagnostic accuracy of fine-needle aspiration biopsy (FNAB) of thyroid nodules (TN) with diameters ≥ 3-4 cm remains controversial. However, some groups have indicated surgical treatment in these patients regardless of the FNAB results. We aimed to evaluate the diagnostic accuracy of the FNAB in systematically resected ≥4 cm TN and if the risk of malignancy is higher in these patients., Subjects and Methods: We retrospectively evaluated 138 patients (142 nodules) with TN with diameters ≥4 cm who underwent thyroidectomy., Results: The FNAB results were nondiagnostic/unsatisfactory (ND/UNS) in 2.1% of the cases and benign in 51.4%. They indicated atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) in 23.9% of cases, follicular neoplasia/suspicious for a follicular neoplasm (FN/SFN) in 9.2%, suspicion of malignancy (SUS) in 8.5%, and malignant in 4.9%. The histopathological analysis after thyroidectomy revealed a thyroid cancer rate of 100% in the FNABs classified as malignant, 33.3% in SUS cases, 7.7% in FN/SFN, 17.6% in AUS/FLUS, and 4.1% in benign FNABs. None of the ND/UNS FNABs were malignant. The global malignancy diagnosis was 14.8% (n = 21). However, the rate of false negatives for FNAB was low (4.1%)., Conclusion: We showed that the risk of malignancy in nodules with diameters ≥4 cm was higher compared to the risk of thyroid cancer in TN in general. However, we found a low rate of false-negative cytological results; therefore, our data do not justify the orientation of routine resection for these larger nodules.

Pheochromocytoma and paragangliomas (PPGLs) are rare neuroendocrine tumors carrying 25-40% pathogenic germline gene variants (PGVs). We evaluated clinical, laboratory, and germline molecular profile of 115 patients with pathologic (14 patients were relatives from 8 different families recruited for genetic survey) confirmed PPGL followed in our institution. Patients with classic MEN2A/MEN2B phenotypes and at-risk relatives underwent direct analysis of RET proto-oncogene, and the remaining had samples submitted to complete next-generation sequencing aiming 23 PPGL-related genes: ATM, ATR, CDKN2A, EGLN1, FH, HRAS, KIF1B, KMT2D, MAX, MDH2, MERTK, MET, NF1, PIK3CA, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53, and VHL . We also developed a clinical judgment score (CJS) to determine the probability of patients having a potentially hereditary disease. The resulting genetic landscape showed that 67 patients (58.3%) had variants in at least one gene: 34 (50.7%) had exclusively pathogenic or likely pathogenic variants, 13 (19.4%) had pathogenic or likely pathogenic variants and variant of undetermined significance (VUS), and 20 (29.8%) carried only VUS. PGVs were found in RET ( n  = 18; 38.3%), VHL ( n  = 10; 21.3%), SDHB and NF1 ( n  = 8; 17% each), and MAX , SDHD , TMEM127, and TP53 ( n  = 1; 2.1% each). Direct genetic testing disclosed 91.3% sensitivity, 81.2% specificity, and 76.4% and 93.3% positive predictive value (PPV) and negative predictive values (NPV), respectively. The CJS to identify patients who would not benefit from genetic testing had 75% sensitivity, 96.4% specificity, and 60% and 98.2% PPV and NPV, respectively. In summary, the landscape of PPGL germline gene variants from 115 Brazilian patients resulted in slightly higher prevalent pathogenic and likely pathogenic variants, especially in the RET gene. We suggest a CJS to identify PPGL patients who would not require initial genetic evaluation, improving test specificity and reducing costs., Competing Interests: There is no conflict of interest that could be perceived as prejudicing the impartiality of this research., (© the author(s).)

Background and Aims: Biliary tract cancer (BTC) is a rare, lethal, heterogeneous group of cancers often diagnosed at an advanced stage. While gemcitabine plus cisplatin is the standard of care for first-line treatment of locally advanced or metastatic BTC, no globally accepted standard of care currently exists for second-line treatment of BTC following chemotherapy. However, the treatment landscape is evolving with approvals for therapies targeting actionable mutations. This study aimed to characterize treatment patterns and survival in patients with locally advanced or metastatic BTC., Methods: Patients with advanced or metastatic BTC in the Surveillance, Epidemiology, and End Results Medicare database between 2010 and 2015 (N = 2063) were included; patients with nonprimary BTC were excluded. Patient and clinical characteristics, line and type of therapy, and overall survival of patients were analyzed., Results: Only 45.5% (n = 938) of patients initiated systemic therapy within 90 days of diagnosis. The most common event following diagnosis was initiation of first-line therapy, and the most common event following first-line treatment was death. Median survival ranged from 5.0 months for patients receiving second-line fluoropyrimidine to 9.7 months for patients receiving second-line gemcitabine. Duration of therapy ranged from 0.7 months for patients receiving second-line fluoropyrimidine to 3.7 months for patients receiving first-line gemcitabine plus cisplatin therapy., Conclusion: Overall survival from diagnosis was poor and influenced by age, sex, stage, mobility limitations, comorbidity burden, poverty, and previous cancer. Treatment patterns varied for patients who progressed following first-line therapy, as there was no consensus second-line treatment for locally advanced or metastatic BTC without clinically targetable mutations., (© 2023 The Authors.)

This report presents the American Society of Clinical Oncology's (ASCO's) evaluation of the adaptations in care delivery, research operations, and regulatory oversight made in response to the coronavirus pandemic and presents recommendations for moving forward as the pandemic recedes. ASCO organized its recommendations for clinical research around five goals to ensure lessons learned from the COVID-19 experience are used to craft a more equitable, accessible, and efficient clinical research system that protects patient safety, ensures scientific integrity, and maintains data quality. The specific goals are: (1) ensure that clinical research is accessible, affordable, and equitable; (2) design more pragmatic and efficient clinical trials; (3) minimize administrative and regulatory burdens on research sites; (4) recruit, retain, and support a well-trained clinical research workforce; and (5) promote appropriate oversight and review of clinical trial conduct and results. Similarly, ASCO also organized its recommendations regarding cancer care delivery around five goals: (1) promote and protect equitable access to high-quality cancer care; (2) support safe delivery of high-quality cancer care; (3) advance policies to ensure oncology providers have sufficient resources to provide high-quality patient care; (4) recognize and address threats to clinician, provider, and patient well-being; and (5) improve patient access to high-quality cancer care via telemedicine. ASCO will work at all levels to advance the recommendations made in this report.

Medullary thyroid carcinoma (MTC) is a malignant tumor originating from thyroid C-cells that can occur either in sporadic (70-80%) or hereditary (20-30%) form. In this study we aimed to identify recurrent copy number alterations (CNA) that might be related to the pathogenesis or progression of MTC. We used Affymetrix SNP array 6.0 on MTC and paired-blood samples to identify CNA using PennCNV and Genotyping Console software. The algorithms identified recurrent copy number gains in chromosomes 15q, 10q, 14q and 22q in MTC, whereas 4q cumulated losses. Coding genes were identified within CNA regions. The quantitative PCR analysis performed in an independent series of MTCs ( n = 51) confirmed focal recurrent copy number gains encompassing the DLK1 (14q32.2) and AIFM3 (22q11.21) genes. Immunohistochemistry confirmed AIFM3 and DLK1 expression in MTC cases, while no expression was found in normal thyroid tissues and few MTC samples were found with normal copy numbers. The functional relevance of CNA was also assessed by in silico analysis. CNA status correlated with protein expression ( DLK1 , p = 0.01), tumor size ( DLK1 , p = 0.04) and AJCC staging ( AIFM3 p = 0.01 and DLK1 p = 0.05). These data provide a novel insight into MTC biology, and suggest a common CNA landscape, regardless of if it is sporadic or hereditary MTC.

The recent reclassification of a follicular variant of papillary thyroid carcinoma (FVPTC), subset as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), aims to avoid overtreatment of patients with an indolent lesion. The diagnosis of NIFTP has recently been revisited using more rigid criteria. This study presents histological and molecular findings and a long clinical follow-up of 94 FVPTC, 40 cases of follicular adenoma (FTA) and 22 cases of follicular carcinoma (FTC) that were classified before the advent of the NIFTP reclassification. All slides were reviewed using these rigid criteria and analysis of numerous sections of paraffin blocks and reclassified as 7 NIFTPs, 2 EFVPTCs, 29 infiltrative FVPTC (IFVPTCs), 57 invasive EFVPTC (I-EFVPTCs), 39 FTAs and 22 FTCs. Remarkably, EFVPTC and NIFTP patients were all free of disease at the end of follow-up and showed no BRAF mutation. Only one NIFTP sample harbored mutations, an NRAS Q61R. PAX8/PPARG fusion was found in I-EFVPTCs and FTC. Although additional studies are needed to identify a specific molecular profile to aid in the diagnosis of lesions with borderline morphological characteristics, we confirmed that the BRAF V600E mutation is an important tool to exclude the diagnosis of NIFTP. We also show that rigorous histopathological criteria should be strongly followed to avoid missing lesions in which more aggressive behavior is present, mainly via the analysis of capsule or vascular invasion and the presence of papillary structures.

Objective: To verify the presence of variants in HNF1B in a sample of the Brazilian population selected according to the presence of renal cysts associated with hyperglycemia., Subjects and Methods: We evaluated 28 unrelated patients with clinical suspicion of HNF1B mutation because of the concomitant presence of diabetes mellitus (DM) or prediabetes and renal cysts. Genotyping was accomplished using Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA). In positive cases, available relatives were recruited., Results: We found two patients with HNF1B mutations. The first presented the variant p.Pro328Leufs*48(c.983delC) and had DM, renal cysts, and hypomagnesemia. The second presented a heterozygous whole gene deletion in HNF1B, DM, renal cysts, body and tail pancreatic agenesis, and hypomagnesemia; this alteration was also found in his two siblings and his father., Conclusion: The recruitment of suspected cases of HNF1B gene mutations in Brazilians due to hyperglycemia and renal cysts presents two positive cases. Our cases contribute to the annotation of clinical and biochemical phenotypes of this rare form of maturity-onset diabetes of the young (MODY).

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazilian centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome.

We previously described that LIM domain containing 2 (LIMD2) overexpression was closely correlated with metastatic process in papillary thyroid carcinoma (PTC). We here evaluated the expression of LIMD2 in a series of non-metastatic and metastatic PTC and their matched lymph node metastases via immunohistochemistry. LIMD2 was expressed in 74 (81%) of primary PTC and 35 (95%) of lymph node metastases. Sub-analysis performed in 37 matched samples demonstrated that in four cases, LIMD2 is expressed in lymph node metastases, while it is not expressed in primary tumors. Moreover, in eight cases, the staining intensity of LIMD2 was stronger in the patient-matched lymph node metastases than in the primary tumors. Next, the expression of LIMD2 was correlated with clinical pathological parameters and BRAF V600E and RET/PTC mutational status. The expression of LIMD2 in primary tumors was correlated with the presence of BRAF V600E mutation (P = 0.0338). Western blot analysis in thyroid cell lines demonstrated that LIMD2 is expressed in two PTC cell lines, while it is not expressed in normal thyroid and follicular thyroid carcinoma cell lines. Importantly, its expression was higher in a PTC cell line that harbors BRAF V600E mutation than in a PTC cell line that harbors RET/PTC1. The available genomic profiling data generated by The Cancer Genome Atlas Research Network confirmed that LIMD2 expression is higher in BRAF-like PTC samples. Our data suggest that LIMD2 may play an important role in the metastatic process of PTC, predominantly in BRAF V600E-positive tumors.

Objective: Initial diagnosis of medullary thyroid carcinoma (MTC) is frequently associated with advanced stages and a poor prognosis. Thus, the need for earlier diagnoses and detection in relatives at risk for the disease has led to increased use of RET genetic screening., Subjects and Methods: We performed RET screening in 247 subjects who were referred to the Brazilian Research Consortium for Multiple Endocrine Neoplasia (BRASMEN) Center in the State of Ceará. Direct genetic sequencing was used to analyze exons 8, 10, 11, and 13-16 in MTC index cases and specific exons in at risk relatives. Afterward, clinical follow-up was offered to all the patients with MTC and their affected relatives., Results: RET screening was performed in 60 MTC index patients and 187 at-risk family members. At the initial clinical assessment of the index patients, 54 (90%) were diagnosed with apparently sporadic disease and 6 (10%) diagnosed with hereditary disease. After RET screening, we found that 31 (52%) index patients had sporadic disease, and 29 (48%) had hereditary disease. Regarding at-risk relatives, 73/187 were mutation carriers. Mutations in RET codon 804 and the rare p.M918V mutation were the most prevalent., Conclusions: Performing RET screening in Ceará allowed us to identify a different mutation profile in this region compared with other areas. RET screening also enabled the diagnosis of a significant number of hereditary MTC patients who were initially classified as sporadic disease patients and benefited their relatives, who were unaware of the risks and the consequences of bearing a RET mutation.

Objective: Calcitonin and carcinoembryonic antigen (CEA) doubling times are established prognostic markers in medullary thyroid cancer (MTC). On the other hand, 18 F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) shows an increased rate of detection with high blood tumor marker levels in several cancers. This study aimed to analyze the ability of 18 F-FDG PET/CT to determine prognosis in the follow-up of patients with MTC., Methods: Medical records of 17 patients with MTC who underwent 18 F-FDG PET/CT were analyzed retrospectively. All patients were classified into two groups: stable disease or progressive disease., Results: Eight patients presented with progressive disease, and all of them showed 18 F-FDG uptake (100%), compared to only 3 of 9 patients who presented in stable condition (33%). 18 F-FDG PET/CT results were able to distinguish progressive from stable disease (P = .009). Calcitonin levels >4,020 pg/mL (P = .0004), CEA levels >26.8 ng/mL (P = .04), and a calcitonin doubling time <24.1 months (P = .015) were associated with progressive disease in our cohort. The proportion of variance explained that predicted progressive disease was 32% for 18 F-FDG uptake, 27.1% for a calcitonin doubling time of 24.1 months, and 41.2% for doubling time plus 18 F-FDG PET/CT., Conclusion: 18 F-FDG uptake was able to distinguish progressive from stable disease. However, this tool should not replace the validated calcitonin doubling time, but rather the combination of information could improve the clinical re-assessment and better identify high-risk patients who require more careful surveillance., Abbreviations: CEA = carcinoembryonic antigen CT = computed tomography 18 F-FDG = 18 F-fluorodeoxyglucose MTC = medullary thyroid cancer PET = positron emission tomography PVE = proportion of variance explained sCT = serum calcitonin SUV = standard uptake value US = ultrasound.

Objectives: About one-quarter of patients with medullary thyroid cancer (MTC) have inherited disease due to mutations in the RET gene. A rare mutation in exon 8 (G533C) of RET , previously described in a large Brazilian family with MEN2A, also appeared to be clustering in Greece, whereas it was rarely reported in other ethnic groups. The aim of this study was to identify a possible common ancestry between these carriers., Patients and Methods: Twelve RET G533C mutation carriers, four randomly selected from the Brazilian cohort and eight from apparently unrelated Greek families, were studied for a possible common ancestral origin. RET flanking microsatellite markers at chromosome 10q (D10S197, D10S196, D10S1652 and D10S537) were used., Results: Genomic DNA analysis using these markers showed that many of these apparently unrelated individuals shared a common haplotype indicating a common ancestral origin., Conclusion: Our data suggest that Brazilian and Greek patients with MTC carrying the G533C mutation in exon 8 of RET gene originate from a common ancestor. Due to historical reasons, we speculate that the more plausible explanation for the origin of this mutation is in Greece., (© 2017 European Society of Endocrinology.)

Inward rectifying potassium - Kir - channels drive the resting potential to potassium reversal potential and, when disrupted, might be related to muscular diseases. Recently, Thyrotoxic Periodic Paralysis (TPP) has emerged as a channelopathy related to mutations in KCNJ18 gene, which encodes Kir2.6 channel. TPP is a neuromuscular disorder characterized by a triad of muscle weakness, hypokalemia, and thyrotoxicosis, the latter being essential for the crisis. Direct sequencing revealed two heterozygous mutations - D252N and R386C - in two TPP patients. KCNJ18 cDNAs were cloned into mammalian expression plasmids and transiently expressed in HEK 293T cells to investigate the functional effects of Kir2.6 mutations. Patch-clamp and confocal laser scanning microscopy experiments were carried out, comparing the WT channel to its mutants. D252N mutation down-regulates the Kir2.6 activity, decreasing the K + current density (∼34%) when compared to the WT channel; whereas the mutation R386C shows no significant changes from WT. The mutant D252N Kir2.6 channel also showed a substantial reduction of ∼51% in membrane abundance relative to WT channel. Our study describes the functional consequences of a single amino acid change in Kir2.6 channel. Further analysis regarding hormonal conditions and Kir channel expression are required to provide new clues about the TPP pathophysiology., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Germline mutations in codon 918 of exon 16 of the RET gene (M918T) are classically associated with multiple endocrine neoplasia type 2B (MEN 2B) with highly aggressive medullary thyroid cancer (MTC), pheochromocytoma and a unique phenotype. The objectives of this study are to describe the rare M918V RET mutation discovered in 8 MTC kindreds from Brazil lacking the MEN 2B phenotype classically observed in M918T patients and to investigate the presence of a founder effect for this germline mutation. Eight apparently sporadic MTC cases were diagnosed with the germline M918V RET mutation. Subsequently, their relatives underwent clinical and genetic assessment (n = 113), and M918V was found in 42 of them. Until today, 20/50 M918V carriers underwent thyroidectomy and all presented MTC/C-cell hyperplasia; the remainder carriers are on clinical follow-up. None of the M918V carriers presented clinical features of MEN 2B. Their clinical presentation was heterogeneous, and the age at tumor diagnosis ranged from 24 to 59 years. Lymph node metastases were present in 12/20 patients, and presumable distant metastases in 2/20; in contrast, we observed a carrier of up to 87 years of age without evidence of MTC. Ethnographic fieldwork and haplotype analyses suggested that the founder mutation first settled in that area fifteen generations ago and originated from Portugal. Our study is the first to demonstrate the RET M918V mutation co-segregating in 8 familial MTC kindreds with validated evidence of a founder effect. We suggest that M918V MTC should be clinically considered an American Thyroid Association (ATA) moderate-risk category., (© 2016 Society for Endocrinology.)

Background: Current surgical standard of care in sporadic medullary thyroid carcinoma (sMTC) consists of a minimum of total thyroidectomy with central neck dissection. Some have suggested thyroid lobectomy with isthmusectomy and central neck dissection for patients with sMTC, given their lower frequency of bilateral disease, although this topic has not been thoroughly studied. This study assessed the prevalence of multifocality in sMTC via a large international multi-institutional retrospective review to quantify this prevalence, including the impact of geography, to assess more accurately the risks associated with alternative surgical approaches., Methods: A retrospective chart review of sMTC patients from 11 institutions over 29 years (1983-2011) was undertaken. Data regarding focality, extent of disease, RET germline analysis plus family and clinical history for multiple endocrine neoplasia type 2 (MEN2), and demographic data were collected and analyzed., Results: Patients from four continents and seven countries were included in the sample. Data for 313 patients with documented sMTC were collected. Of these, 81.2% were confirmed with negative RET germline testing, while the remaining 18.8% demonstrated a negative family history and no manifestations of MEN2 syndromes other than MTC. Bilateral disease was identified in 17/306 (5.6%) patients, while multifocal disease was noted in 50/312 (16.0%) sMTC patients. When only accounting for germline negative patients, these rates were not significantly different (5.6% and 17%, respectively). Among them, when disease was unifocal in the ipsilateral lobe and isthmus, bilateral disease was present in 6/212 (2.8%) cases. When disease was multifocal in the ipsilateral lobe or isthmus, then bilateral disease was present in 8/37 (21.6%) cases (p < 0.001). No geographic differences in focality were identified., Conclusions: The 5.6% prevalence of bilateral foci in sMTC suggests that total thyroidectomy should remain the standard of care for initial surgery, as less complete thyroid surgery may fail to address fully the primary site of disease. Whether ipsilateral tumor focality should be an independent factor determining the need for completion thyroidectomy when sMTC is diagnosed after hemithyroidectomy remains to be determined.

Context: Calcitonin (CT) is a sensitive marker of medullary thyroid carcinoma (MTC) and is used for primary diagnosis and follow-up after thyroidectomy. However, persistently elevated CT is observed even after complete surgical removal without evidence of a recurrent or persistent tumor., Objective: To investigate the presence of assay interference in the serum CT of MTC patients who are apparently without a structural disease., Patients and Methods: We studied three index MTC cases for CT assay interference and 14 patients with metastatic MTC. The CT level was measured using an immunofluorometric assay. Screening for assay interference was performed by determination of CT levels before and after serum treatment with polyethylene glycol. Additionally, samples were analyzed by chromatography on ultra-performance liquid chromatography and protein A-Sepharose., Results: Patients with biochemical and structural disease showed CT mean recovery of 84.1% after polyethylene glycol treatment, whereas patients suspected of interference showed recovery from 2-7%. The elution profile on UPLC showed that the immunometric CT from these three patients behaved like a high molecular mass aggregate (>300 kDa). Additionally, when these samples were applied to the protein A-Sepharose, CT immunoreactivity was retained on the column and was only released after lowering the pH., Conclusions: For the first time, our results show the presence of a novel pitfall in the CT immunoassay: "macrocalcitonin." Its etiology, frequency, and meaning remain to be defined, but its recognition is of interest and can help clinicians avoid unnecessary diagnostic investigations and treatment during the follow-up of MTC.

Medullary thyroid carcinoma (MTC), a neuroendocrine tumor originating from thyroid parafollicular cells, has been demonstrated to be associated with mutations in RET, HRAS, KRAS and NRAS. However, the role of other genes involved in the oncogenesis of neural crest tumors remains to be fully investigated in MTC. The current study aimed to investigate the presence of somatic mutations in BRAF, CDKN2A and PI3KCA in MTC, and to investigate the correlation with disease progression. DNA was isolated from paraffin‑embedded tumors and blood samples from patients with MTC, and the hotspot somatic mutations were sequenced. A total of 2 novel HRAS mutations, p.Asp33Asn and p.His94Tyr, and polymorphisms within the 3' untranslated region (UTR) of CDKN2A (rs11515 and rs3088440) were identified, however, no mutations were observed in other genes. It was suggested that somatic point mutations in BRAF, CDKN2A and PI3KCA do not participate in the oncogenesis of MTC. Further studies are required in order to clarify the contribution of the polymorphisms identified in the 3'UTR of CDKN2A in MTC.

Objective: Staging systems applied to medullary thyroid cancer (MTC) rely on initial clinical and pathological features and do not consider the response to treatment. To determine whether MTC staging can be improved by incorporating the first postoperative calcitonin measurement., Patients and Measurements: Eighty-five patients being monitored for MTC (median follow-up 5 years) were retrospectively classified according to both the American Joint Committee on Cancer (AJCC) and the proposed combined risk stratification system (low, intermediate and high risk), which incorporates the first postoperative calcitonin measurement, using the outcomes no evidence of disease (NED), biochemical evidence of disease, structurally identifiable disease and death., Results: Ninety per cent of AJCC I patients were classified as NED at final follow-up. When we added a postoperative calcitonin measurement, 95% low-risk patients were classified as NED at final follow-up. AJCC stages I and IV were associated, respectively, with no occurrence and a high rate (63%) of structurally identifiable disease. Stages II and III yielded similar predictions of structurally identifiable disease, 13% and 14%, respectively. When we included the postoperative calcitonin level, the patients with structural evidence of disease included none from the low-risk group, 10% from the intermediate group and 63% from the high-risk group. The proportion of variance explained analysis (PVE) was better for the combined risk stratification system (54%) than for the AJCC system alone (32%)., Conclusion: Including the first postoperative calcitonin measurement with the anatomical staging system can better predict the clinical outcome of patients with MTC and refine the follow-up of these patients., (© 2014 John Wiley & Sons Ltd.)

Accurate interpretation of germline mutations of the rearranged during transfection (RET) proto-oncogene is vital for the proper recommendation of preventive thyroidectomy in medullary thyroid carcinoma (MTC)-prone carriers. To gain information regarding the most disputed variant of RET, ATA-A Y791F, we sequenced blood DNA samples from a cohort of 2904 cancer-free elderly individuals (1261 via Sanger sequencing and 1643 via whole-exome/genome sequencing). We also accessed the exome sequences of an additional 8069 individuals from non-cancer-related laboratories and public databanks as well as genetic results from the Catalogue of Somatic Mutations in Cancer (COSMIC) project. The mean allelic frequency observed in the controls was 0.0031, with higher occurrences in Central European populations (0.006/0.008). The prevalence of RET Y791F in the control databases was extremely high compared with the 40 known RET pathogenic mutations (P=0.00003), while no somatic occurrence has been reported in tumours. In this study, we report new, unrelated Brazilian individuals with germline RET Y791F-only: two tumour-free elderly controls; two individuals with sporadic MTC whose Y791F-carrying relatives did not show any evidence of tumours; and a 74-year-old phaeochromocytoma patient without MTC. Furthermore, we showed that the co-occurrence of Y791F with the strong RET C634Y mutation explains the aggressive MTC phenotypes observed in a large affected family that was initially reported as Y791F-only. Our literature review revealed that limited analyses have led to the misclassification of RET Y791F as a probable pathogenic variant and, consequently, to the occurrence of unnecessary thyroidectomies. The current study will have a substantial clinical influence, as it reveals, in a comprehensive manner, that RET Y791F only shows no association with MTC susceptibility., (© 2015 The authors.)

Background: Risk stratification in medullary thyroid cancer (MTC) has traditionally relied on standardized anatomic staging systems that, despite providing valuable prognostic information, do not adequately predict the risk of persistent or recurrent disease. As dynamic risk stratification has been demonstrated to be clinically valuable in nonmedullary thyroid cancer, we adapted our response to therapy definitions in order to apply them to MTC. In this study, we evaluate and compare the clinical utility of our previously proposed MTC response to therapy stratification with a traditional standardized anatomic staging system., Methods: Both the Tumor, Node, Metastasis/American Joint Cancer Committee (TNM/AJCC) staging system and our previously proposed response to initial therapy staging system was evaluated in 287 MTC patients followed for a median of five years., Results: The TNM/AJCC staging system provided adequate risk stratification with regard to disease-specific mortality and the likelihood of having no evidence of disease at final follow-up, but did not adequately stratify patients with regard to the likelihood of having structural persistent disease, biochemical persistent disease, or recurrence. However, the response to initial therapy risk stratification system provided clinically useful risk stratification with regard to disease-specific mortality, the likelihood of having no evidence of disease at final follow-up, the likelihood of having a biochemical persistent disease at final follow-up, and the likelihood of having structural persistent disease at final follow-up. Furthermore, the response to therapy risk stratification system demonstrated a higher proportion of variance explained (54.3%) than the TNM/AJCC system (23.9%)., Conclusion: Our data demonstrate that a dynamic risk stratification system that uses response to therapy variables to adjust risk estimates over time provides more useful clinical prognostic information than static initial anatomic staging in MTC thyroid cancer.

Thyrotoxicosis is the most common cause of the acquired flaccid muscle paralysis in adults called thyrotoxic periodic paralysis (TPP) and is characterised by transient hypokalaemia and hypophosphataemia under high thyroid hormone levels that is frequently precipitated by carbohydrate load. The sulphonylurea receptor 1 (SUR1 (ABCC8)) is an essential regulatory subunit of the β-cell ATP-sensitive K(+) channel that controls insulin secretion after feeding. Additionally, the SUR1 Ala1369Ser variant appears to be associated with insulin sensitivity. We examined the ABCC8 gene at the single nucleotide level using PCR-restriction fragment length polymorphism (RFLP) analysis to determine its allelic variant frequency and calculated the frequency of the Ala1369Ser C-allele variant in a cohort of 36 Brazilian TPP patients in comparison with 32 controls presenting with thyrotoxicosis without paralysis (TWP). We verified that the frequency of the alanine 1369 C-allele was significantly higher in TPP patients than in TWP patients (61.1 vs 34.4%, odds ratio (OR)=3.42, P=0.039) and was significantly more common than the minor allele frequency observed in the general population from the 1000 Genomes database (61.1 vs 29.0%, OR=4.87, P<0.005). Additionally, the C-allele frequency was similar between TWP patients and the general population (34.4 vs 29%, OR=1.42, P=0.325). We have demonstrated that SUR1 alanine 1369 variant is associated with allelic susceptibility to TPP. We suggest that the hyperinsulinaemia that is observed in TPP may be linked to the ATP-sensitive K(+)/SUR1 alanine variant and, therefore, contribute to the major feedforward precipitating factors in the pathophysiology of TPP., (© 2014 Society for Endocrinology.)