Metabolic Disorders with Kidney Transplant.

Metabolic disorders are highly prevalent in kidney transplant candidates and recipients and can adversely affect post-transplant graft outcomes. Management of diabetes, hyperparathyroidism, and obesity presents distinct opportunities to optimize patients both before and after transplant as well as the ability to track objective data over time to assess a patient's ability to partner effectively with the health care team and adhere to complex treatment regimens. Optimization of these particular disorders can most dramatically decrease the risk of surgical and cardiovascular complications post-transplant. Approximately 60% of nondiabetic patients experience hyperglycemia in the immediate post-transplant phase. Multiple risk factors have been identified related to development of new onset diabetes after transplant, and it is estimated that upward of 7%-30% of patients will develop new onset diabetes within the first year post-transplant. There are a number of medications studied in the kidney transplant population for diabetes management, and recent data and the risks and benefits of each regimen should be optimized. Secondary hyperparathyroidism occurs in most patients with CKD and can persist after kidney transplant in up to 66% of patients, despite an initial decrease in parathyroid hormone levels. Parathyroidectomy and medical management are the options for treatment of secondary hyperparathyroidism, but there is no randomized, controlled trial providing clear recommendations for optimal management, and patient-specific factors should be considered. Obesity is the most common metabolic disorder affecting the transplant population in both the pre- and post-transplant phases of care. Not only does obesity have associations and interactions with comorbid illnesses, such as diabetes, dyslipidemia, and cardiovascular disease, all of which increase morbidity and mortality post-transplant, but it also is intimately inter-related with access to transplantation for patients with kidney failure. We review these metabolic disorders and their management, including data in patients with kidney transplants.

Recurrence and Complications in Pediatric and Adolescent Papillary Thyroid Cancer in a High-Volume Practice.

BACKGROUND: Treatment approaches for pediatric papillary thyroid cancer (PTC) are historically extrapolated from adult experience. However, pediatric PTC demonstrates a greater propensity for lymph node involvement, early metastases, and recurrence, highlighting the need for pediatric-specific treatment paradigms. MATERIALS AND METHODS: A retrospective review included patients with PTC aged ≤21 y, with ≥18 mo of follow-up, treated between 2002 and 2015. Fisher's exact test and Cox proportional hazard were used to estimate the effect of risk factors on disease recurrence. RESULTS: Seventy-two cases of PTC were identified with median age of 17.0 y and median follow-up of 64.1 mo. Disease recurred at a median of 24.6 mo (range 7.8-78.1) in 7 of 51 (13.7%) of patients with disease limited to the thyroid or central neck, 7 of 18 (39%) patients with lateral neck disease at presentation who underwent a compartment-based resection, and three of three patients (100%) with lateral neck disease who sought care after non-compartment-based resection. There were no deaths from disease. Univariate predictors of recurrence included tumor size >2 cm (P = 0.005), lateral neck disease (P = 0.004), lymphovascular invasion (P = 0.017), extracapsular invasion (P < 0.0001), multifocality (P = 0.03), and non-Caucasian race (P = 0.05). Multivariate analysis identified race (P = 0.05) as an independent predictor of recurrence. In patients without lateral neck disease, there was a trend toward lower recurrence in patients undergoing thyroidectomy with central neck dissection compared with thyroidectomy alone (P = 0.07). CONCLUSIONS: Pediatric PTC is associated with excellent survival, although recurrence is common in patients with lateral node involvement. Predictors of recurrence are multifactorial and may be influenced by extent of disease, patient or tumor biology, and aggressiveness of resection. LEVEL OF EVIDENCE: Prognosis study, level IV, retrospective case series.

Insulin-Like Growth Factor and SLC12A7 Dysregulation: A Novel Signaling Hallmark of Non-Functional Adrenocortical Carcinoma.

BACKGROUND: Insulin-like growth factor (IGF) dysregulation and gene copy number variations (CNV) are hallmarks of adrenocortical carcinoma (ACC). The contribution of IGF CNVs in adrenal carcinogenesis has not been studied previously. In addition, studies demonstrating an association between SLC12A7 gene amplifications and enhanced metastatic behavior in ACC, as well as reported IGF-SLC12A7 signaling interactions in other cancers, suggest a potential IGF-SLC12A7 signaling circuitry in ACC. Here we investigate the potential complicity of IGF-SLC12A7 signaling in ACC. STUDY DESIGN: Insulin-like growth factor CNVs were determined by whole-exome sequencing analysis in an exploratory cohort of ACC. Quantitative polymerase chain reaction methods determined IGF1 and IGF2 expression levels and were evaluated for correlation with SLC12A7 expression and tumor characteristics. Insulin-like growth factor CNVs and expression patterns were compared with The Cancer Genome Atlas. In vitro studies determined the relationship of IGF and SLC12A7 co-expression in 2 ACC cell lines, SW-13 and NCI-H295R. Immunohistochemistry assessed IGF1 receptor (IGF1R) activation. RESULTS: The IGF1 gene was amplified in 9 of 19 ACC samples, similar to findings in The Cancer Genome Atlas database. The IGF1 overexpression was observed in 5 samples and was associated with SLC12A7 overexpression and non-functional, early-stage tumors (p < 0.05). In contrast, IGF2 overexpression was associated with larger tumors (p < 0.05). In vitro IGF treatment of ACC cell lines did not stimulate SLC12A7 expression, and endogenous overexpression and silencing of SLC12A7 significantly altered IGF1 and IGF1R expression without impacting other IGFs. The IGF1R activation was associated with IGF1 overexpression in ACC tumor samples. CONCLUSIONS: These findings indicate that IGF1 overexpression, caused in part by gene amplifications, is correlated with SLC12A7 overexpression in non-functional, early-stage ACCs, suggesting a potentially targeted IGF1-SLC12A7 therapeutic opportunity for these tumors.

Lymph node ratio predicts recurrence in pediatric papillary thyroid cancer.

BACKGROUND: Regional lymph node (LN) metastasis at the time of presentation plays a significant role in predicting recurrence in patients with papillary thyroid cancer (PTC). Multiple studies in the adult population have demonstrated that the lymph node ratio (LNR) in both the central and lateral neck can improve the accuracy of recurrence prediction, but this ratio has not been studied in the pediatric population. In this study, we sought to investigate the LNR in the central and lateral compartments as a prognostic predictor for recurrence in pediatric patients with PTC. METHODS: A retrospective analysis of pediatric patients (≤21 years old) at a single institution between 2002 and 2014 who underwent total thyroidectomy with prophylactic central neck dissection (TTpCND) with at least 3 sampled nodes or total thyroidectomy with unilateral modified radical neck dissection (TTMRND) with at least 10 sampled nodes, and on whom at least 24 months of follow up data were available was performed. The LNR was defined as the ratio of metastatic LNs to total number of investigated LNs. Recurrence after TTpCND and TTMRND was examined separately as a function of LNR, using the value of 0.45 as a cutoff. RESULTS: Forty-eight patients met inclusion criteria. Thirty-two underwent TTpCND, and sixteen underwent TTMRND. Median age at time of operation was 17 years (range 6-20), and median duration of follow-up was 53.5 months (range 24-183). In the TTpCND, LNR ranged from 0 to 1.0. There were two recurrences among the eight patients (25%) undergoing TTpCND in patients with LNRs >0.45 and a single recurrence among the 24 patients (4.2%) undergoing TTpCND with an LNR ≤0.45. In the TTMRND, LNR ranged from 0.1 to 1.0. There were 3 recurrences in 12 patients with LNR ≤0.45 (30.8%%) and 4 recurrences in 4 patients with LNR >0.45 (100%) (p = 0.03). CONCLUSIONS: Although limited by small sample size, LNR may be a useful predictor to stratify the likelihood of recurrence in pediatric patients undergoing TTpCND or TTMRND for pathologic N1a or N1b PTC. TYPE OF STUDY: Prognosis study / retrospective case series. LEVEL OF EVIDENCE: Level IV.

NCCN Guidelines Insights: Thyroid Carcinoma, Version 2.2018.

The NCCN Guidelines for Thyroid Carcinoma provide recommendations for the management of different types of thyroid carcinoma, including papillary, follicular, Hürthle cell, medullary, and anaplastic carcinomas. These NCCN Guidelines Insights summarize the panel discussion behind recent updates to the guidelines, including the expanding role of molecular testing for differentiated thyroid carcinoma, implications of the new pathologic diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features, and the addition of a new targeted therapy option for BRAF V600E-mutated anaplastic thyroid carcinoma.

The Value of Negative Diagnosis in Thyroid Fine-Needle Aspiration: a Retrospective Study with Histologic Follow-Up.

The Bethesda System for reporting thyroid cytopathology (BSRTC) predicts an incidence of malignancy of less than 5% in thyroid nodules with a benign diagnosis on fine-needle aspiration (FNA). However, recent series have suggested that the true rate of malignancy might be significantly higher in this category of patients. We reviewed our experience by performing a retrospective analysis of patients with benign thyroid FNA results who underwent thyroidectomy between 2008 and 2013 at a large academic center. Information including demographics, ultrasound features, FNA diagnosis, and surgical follow-up information were recorded. Slides were reviewed on cytology-histology discrepant cases, and it was determined whether the discrepancy was due to sampling or interpretation error. A total of 802 FNA cases with a benign diagnosis and surgical follow-up were identified. FNA diagnoses included 738 cases of benign goiter and 64 cases of lymphocytic thyroiditis. On subsequent surgical resection, 144 cases were found to be neoplastic, including 117 malignant cases. False negative, defined as interpretation error and inadequate biopsy of the nodule harboring malignancy, was 6%. When cases of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) were excluded from the analysis, false-negative rate was 5%. When microPTC cases were excluded, false-negative rate was 3% and was slightly less than 3% when both microPTC and NIFTP cases were excluded from the analysis. Retrospective review of neoplastic cases showed that 57% were due to sampling error and 43% were due to interpretation error. Interpretation error was more likely to occur in follicular patterned neoplasms (75%), while sampling error was more common in non-follicular variants of papillary thyroid carcinoma (non-FVPTC) (61%). With the exclusion of microPTC, interpretation errors were still more likely to occur in follicular neoplasms (79%) but there was no significant difference in sampling error between non-FVPTC (37%) and follicular patterned neoplasms (42%). Tumor size was larger in cases with interpretation error (mean = 2.3 cm) compared to cases with sampling error (mean = 1.4 cm). This study shows that the false-negative rate of thyroid FNA at our institution is not significantly above the rate suggested by the BSRTC. Interpretation errors were more likely to occur in follicular patterned neoplasms, while non-FVPTC was more frequently found in false negative cases due to inadequate sampling.

DNA Mismatch Repair Deficiency Promotes Genomic Instability in a Subset of Papillary Thyroid Cancers.

BACKGROUND: Efficient DNA damage repair by MutL-homolog DNA mismatch repair (MMR) enzymes, MLH1, MLH3, PMS1 and PMS2, are required to maintain thyrocyte genomic integrity. We hypothesized that persistent oxidative stress and consequent transcriptional dysregulation observed in thyroid follicles will lead to MMR deficiency and potentiate papillary thyroid tumorigenesis. METHODS: MMR gene expression was analyzed by targeted microarray in 18 papillary thyroid cancer (PTC), 9 paracarcinoma normal thyroid (PCNT) and 10 normal thyroid (NT) samples. The findings were validated by qRT-PCR, and in follicular thyroid cancers (FTC) and follicular thyroid adenomas (FTA) for comparison. FOXO transcription factor expression was also analyzed. Protein expression was assessed by immunohistochemistry. Genomic integrity was evaluated by whole-exome sequencing-derived read-depth analysis and Mann-Whitney U test. Clinical correlations were assessed using Fisher's exact and t tests. RESULTS: Microarray and qRT-PCR revealed reduced expression of all four MMR genes in PTC compared with PCNT and of PMS2 compared with NT. FTC and FTA showed upregulation in MLH1, MLH3 and PMS2. PMS2 protein expression correlated with the mRNA expression pattern. FOXO1 showed lower expression in PMS2-deficient PTCs (log2-fold change -1.72 vs. -0.55, U = 11, p < 0.05 two-tailed). Rate of LOH, a measure of genomic instability, was higher in PMS2-deficient PTCs (median 3 and 1, respectively; U = 26, p < 0.05 two-tailed). No correlation was noted between MMR deficiency and clinical characteristics. CONCLUSIONS: MMR deficiency, potentially promoted by FOXO1 suppression, may explain the etiology for PTC development in some patients. FTC and FTA retain MMR activity and are likely caused by a different tumorigenic pathway.

Identification of distinct cytomorphologic features in the diagnosis of NIFTP at the time of preoperative FNA: Implications for patient management.

BACKGROUND: A major reclassification occurred with the redesignation of noninvasive encapsulated follicular variant of papillary thyroid carcinoma as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) due to its indolent nature. The aim of this study was to determine whether distinct cytomorphologic features could be identified on preoperative fine-needle aspiration (FNA) when NIFTP cases were compared with invasive follicular variant of papillary thyroid carcinoma (FVPTC) subtypes. METHODS: Thyroid resection cases with the diagnosis of FVPTC from 2012 to 2016 were reclassified as NIFTP, invasive encapsulated follicular variant of papillary thyroid carcinoma (IEFVPTC), and invasive FVPTC subtypes. Corresponding FNA specimens were retrieved and retrospectively reviewed. A univariate analysis using Fisher's exact test was performed to determine any differences in the frequencies of various cytomorphologic features among NIFTP, IEFVPTC, and FVPTC cases. A multivariate analysis was performed to identify any independent salient features that would be helpful in differentiating NIFTP from its invasive counterparts. RESULTS: The study population consisted of 93 cases, including 51 cases of NIFTP, 21 cases of IEFVPTC, and 21 cases of infiltrative FVPTC. Demographics such as age, sex, and tumor size were comparable across the 3 groups. A predominantly microfollicular pattern, an absence of nuclear pseudo-inclusions, and less frequent nuclear elongations and grooves were significantly more likely to be associated with NIFTP versus its invasive counterparts. The absence of nuclear pseudo-inclusions and the presence of a microfollicular pattern were the only independent predictors of a NIFTP diagnosis. CONCLUSIONS: This study demonstrates that NIFTP cases have distinguishing cytomorphologic characteristics in comparison with invasive FVPTC cases. Therefore, a preoperative cytologic evaluation provides clues that can aid in the distinction between NIFTP and its invasive counterparts. Cancer Cytopathol 2017;125:865-75. © 2017 American Cancer Society.

Leptin Is Produced by Parathyroid Glands and Stimulates Parathyroid Hormone Secretion.

OBJECTIVE: We asked if leptin and its cognate receptor were present in normal and diseased parathyroid glands, and if so, whether they had any functional effects on parathyroid hormone (PTH) secretion in parathyroid neoplasms. BACKGROUND: The parathyroid glands acting through PTH play a critical role in the regulation of serum calcium. Based on leptin's recently discovered role in bone metabolism, we hypothesized these glands were the sites of a functional interaction between these 2 hormones. METHODS: From July 2010 to July 2011, 96 patients were enrolled in a prospective study of leptin and hyperparathyroidism, all of whom were enrolled based on their diagnosis of hyperparathyroidism, and their candidacy for surgical intervention provided informed consent. Immediately after parathyroidectomy, 100 to 300 mg of adenomatous or hyperplastic diseased parathyroid tissue was prepared and processed according to requirements of the following: in situ hybridization, immunohistochemistry, immunofluorescence by conventional and spinning disc confocal microscopy, electron microscopy, parathyroid culture, whole organ explant, and animal model assays. RESULTS: Leptin, leptin receptor (long isoform), and PTH mRNA transcripts and protein were detected in an overlapping fashion in parathyroid chief cells in adenoma and hyperplastic glands, and also in normal parathyroid by in situ hybridization, qRT-PCR, and immunohistochemistry. Confocal microscopy confirmed active exogenous leptin uptake in cultured parathyroid cells. PTH secretion in explants increased in response to leptin and decreased with leptin receptor signaling inhibition by AG490, a JAK2/STAT3 inhibitor. Ob/ob mice injected with mouse leptin exhibited increased PTH levels from baseline. CONCLUSIONS: Taken together, these data suggest that leptin is a functionally active product of the parathyroid glands and stimulates PTH release.

Primary hyperparathyroidism with normal baseline intraoperative parathyroid hormone: A challenging population.

BACKGROUND: Patients with primary hyperparathyroidism and baseline intraoperative parathyroid hormone levels in the normal range are challenging. This study compares the predictive value of a commonly used intraoperative parathyroid hormone algorithm, a software model for cure prediction, and surgeon judgment in this population. METHODS: This was a retrospective review of consecutive patients who underwent parathyroidectomy for primary hyperparathyroidism at a single institution from March 2013 to October 2014. RESULTS: Of 541 operative patients, 114 (21.1%) had a mean normal baseline intraoperative parathyroid hormone of ≤69 pg/mL (median 59.0 ± 10.3; range 26-69). Of the 114 patients, 93 (81.6%) were women, median age was 61 years (range 18-88). Overall, 107/108 (99.1%) patients were cured; 47 (41.2%) patients had single adenomas, 16 (14%) had double adenomas, and 51 (44.7%) had multigland hyperplasia. Using the 50% decline algorithm, a correct prediction was made in 86 (75.4%) patients. Using the computer software, a correct prediction was made in 88 (77.2%) patients. Surgeon judgment, however, was 99.1% accurate. CONCLUSION: Patients with normal baseline intraoperative parathyroid hormone have a high incidence of multigland disease (58.8%), greater than reported previously. Current software modeling and the 50% decline algorithm are insufficient to predict cure in this population; intraoperative parathyroid hormone interpretation combined with operative findings and surgical judgment yield optimal outcomes.

Parathyroidectomy prior to kidney transplant decreases graft failure.

BACKGROUND: Uncorrected uremic hyperparathyroidism is associated with delayed graft function after kidney transplantation. The current guidelines of the Kidney Disease Improving Global Outcomes recommend maintaining parathyroid hormone ≤9x normal in patients pre-kidney transplantation. This study explores the effect of increased levels of serum parathyroid hormone and preoperative parathyroidectomy on outcomes after kidney transplantation. METHODS: A retrospective review was performed of adult patients who underwent kidney transplantation between January 1, 2005, and December 31, 2014, at a single institution. Biochemistries and outcomes were analyzed pre-kidney transplantation and at 30 days, 6 months, and 1 year post-kidney transplantation. RESULTS: A total of 913 patients underwent kidney transplantation from 2005-2014. Graft survival 1 year post-kidney transplantation was 97.8%. Overall, 462 (50.6%) patients had a pre-kidney transplantation diagnosis of uncorrected uremic hyperparathyroidism, which was associated with complications in the first year post-kidney transplantation (odds ratio 1.44; 95% confidence interval, 1.11-1.87); no statistical association with delayed graft function or graft failure was detected. Pre-kidney transplantation parathyroid hormone ≥6x normal was associated with post-kidney transplantation graft failure (P < .05). A total of 57 (6.2%) patients underwent pre-kidney transplantation parathyroidectomy, which was associated with lesser risk of graft failure (odds ratio: 0.547; 95% confidence interval, 0.327-0.913), but no statistically significant association with delayed graft function or complications were detected. CONCLUSION: Pre-kidney transplantation parathyroidectomy decreases post-kidney transplantation graft failure and may benefit patients whose serum parathyroid hormone levels decrease into the target range of current Kidney Disease Improving Global Outcomes guidelines.

Shifting patterns of genomic variation in the somatic evolution of papillary thyroid carcinoma.

BACKGROUND: Cancer is increasingly understood to arise in the context of dynamically evolving genomes with continuously generated variants subject to selective pressures. Diverse mutations have been identified in papillary thyroid carcinoma (PTC), but unifying theories underlying genomic change are lacking. Applying a framework of somatic evolution, we sought to broaden understanding of the PTC genome through identification of global trends that help explain risk of tumorigenesis. METHODS: Exome sequencing was performed on 53 PTC and matched adjacent non-tumor thyroid tissues (ANT). Single nucleotide substitution (SNS) signatures from each sample pair were divided into three subsets based on their presence in tumor, non-tumor thyroid, or both. Nine matched blood samples were sequenced and SNS signatures intersected with these three subsets. The intersected genomic signatures were used to define branch-points in the evolution of the tumor genome, distinguishing variants present in the tissues' common ancestor cells from those unique to each tissue type and therefore acquired after genomic divergence of the tumor, non-tumor, and blood samples. RESULTS: Single nucleotide substitutions shared by the tumor and the non-tumor thyroid were dominated by C-to-T transitions, whereas those unique to either tissue type were enriched for C-to-A transversions encoding non-synonymous, predicted-deleterious variants. On average, SNSs of matched blood samples were 81 % identical to those shared by tumor and non-tumor thyroid, but only 12.5 % identical to those unique to either tissue. Older age and BRAF mutation were associated with increased SNS burden. CONCLUSIONS: The current study demonstrates novel patterns of genomic change in PTC, supporting a theory of somatic evolution in which the zygote's germline genome undergoes continuous remodeling to produce progressively differentiated, tissue-specific signatures. Late somatic events in thyroid tissue demonstrate shifted mutational spectra compared to earlier polymorphisms. These late events are enriched for predicted-deleterious variants, suggesting a mechanism of genomic instability in PTC tumorigenesis.

Dissection of Levels II Through V Is Required for Optimal Outcomes in Patients with Lateral Neck Lymph Node Metastasis from Papillary Thyroid Carcinoma.

BACKGROUND: Completeness of surgical resection is an important determinant of outcomes in patients with papillary thyroid carcinoma and regional lymph node metastasis. The extent of therapeutic lateral neck dissection remains controversial. This study aims to assess the impact of modified radical neck dissection of levels II to V in a large patient series. STUDY DESIGN: Retrospective analysis of consecutive patients with papillary thyroid carcinoma who underwent lateral neck dissection at a single institution from June 1, 2006 to December 31, 2014 was performed. RESULTS: A total of 241 lateral neck dissections were performed in 191 patients (118 [62%] women; median age 46 years [range 6 to 87 years]; median follow-up 14.3 months [range 0.1 to 107 months]). Overall, 202 initial neck dissections (195 modified radical neck dissections and 7 less extensive dissections) were performed. Among these initial dissections, 137 (68.8%), 132 (65.7%), 105 (52.0%), and 33 (16.9%) had positive lymph nodes in levels II, III, IV, and V, respectively. Ipsilateral lymph node persistence or recurrence occurred after 22 (10.9%) initial dissections, at level II in 10 (45.5%), level III in 8 (36.4%), level IV in 7 (31.8%), and level V in 3 (13.6%). Thirty-nine reoperative lateral neck dissection were performed, including 18 cases of persistence and recurrence after our initial dissections. In reoperative dissections, positive lymph nodes were confirmed in levels II, III, IV, and V in 18 (46.2%), 10 (25.6%), 13 (33.3%), and 5 (12.8%) dissections, respectively. Temporary nerve injury occurred in 6 (3.0%) initial and 4 (10.3%) reoperative dissections, respectively. There were no permanent nerve injuries. CONCLUSIONS: Omitting levels II and V during lateral neck dissection for papillary thyroid carcinoma potentially misses level II disease in two-thirds of patients and level V disease in one-fifth of patients. Formal modified radical neck dissection is necessary to avoid the morbidity of reoperative surgery.

TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors.

The success in recent clinical trials using T cell receptor (TCR)-genetically engineered T cells to treat melanoma has encouraged the use of this approach toward other malignancies and viral infections. Although hepatitis C virus (HCV) infection is being treated with a new set of successful direct anti-viral agents, potential for virologic breakthrough or relapse by immune escape variants remains. Additionally, many HCV+ patients have HCV-associated disease, including hepatocellular carcinoma (HCC), which does not respond to these novel drugs. Further exploration of other approaches to address HCV infection and its associated disease are highly warranted. Here, we demonstrate the therapeutic potential of PBL-derived T cells genetically engineered with a high-affinity, HLA-A2-restricted, HCV NS3:1406-1415-reactive TCR. HCV1406 TCR-transduced T cells can recognize naturally processed antigen and elicit CD8-independent recognition of both peptide-loaded targets and HCV+ human HCC cell lines. Furthermore, these cells can mediate regression of established HCV+ HCC in vivo. Our results suggest that HCV TCR-engineered antigen-reactive T cells may be a plausible immunotherapy option to treat HCV-associated malignancies, such as HCC.

Hepatitis C virus-cross-reactive TCR gene-modified T cells: a model for immunotherapy against diseases with genomic instability.

A major obstacle hindering the development of effective immunity against viral infections, their associated disease, and certain cancers is their inherent genomic instability. Accumulation of mutations can alter processing and presentation of antigens recognized by antibodies and T cells that can lead to immune escape variants. Use of an agent that can intrinsically combat rapidly mutating viral or cancer-associated antigens would be quite advantageous in developing effective immunity against such disease. We propose that T cells harboring cross-reactive TCRs could serve as a therapeutic agent in these instances. With the use of hepatitis C virus, known for its genomic instability as a model for mutated antigen recognition, we demonstrate cross-reactivity against immunogenic and mutagenic nonstructural protein 3:1406-1415 and nonstructural protein 3:1073-1081 epitopes in PBL-derived, TCR-gene-modified T cells. These single TCR-engineered T cells can CD8-independently recognize naturally occurring and epidemiologically relevant mutant variants. TCR-peptide MHC modeling data allow us to rationalize how TCR structural properties accommodate recognition of certain mutated epitopes and how these substitutions impact the requirement of CD8 affinity enhancement for recognition. A better understanding of such TCRs' promiscuous behavior may allow for exploitation of these properties to develop novel, adoptive T cell-based therapies for viral infections and cancers exhibiting similar genomic instability.

Anaplastic Thyroid Carcinoma, Version 2.2015.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Thyroid Carcinoma focuses on anaplastic carcinoma because substantial changes were made to the systemic therapy recommendations for the 2015 update. Dosages and frequency of administration are now provided, docetaxel/doxorubicin regimens were added, and single-agent cisplatin was deleted because it is not recommended for patients with advanced or metastatic anaplastic thyroid cancer.

Operative failure rate and documentation of family history in young patients undergoing focused parathyroidectomy for primary hyperparathyroidism.

Primary hyperparathyroidism in multiple endocrine neoplasia type I usually affects all parathyroid glands, making focused parathyroidectomy (FP) inappropriate. The risk of previously undiagnosed multiple endocrine neoplasia type I in a younger patient with primary hyperparathyroidism is higher than in an older patient. We hypothesized that FP may lead to a higher failure rate in younger versus older patients. A retrospective review was performed of a single-institution database of patients who underwent parathyroidectomy for primary hyperparathyroidism. Routine statistical analysis was performed, including Fisher's exact test. A total of 635 patients were included. Operative failure occurred in 7/55 (13%) younger patients and 21/580 (4%) older patients (P = 0.007). In conclusion, operative failure occurred in a statistically significantly higher percentage of younger versus older patients undergoing FP. This is partly explained by undiagnosed multiple endocrine neoplasia syndrome type I in the younger patient group. Endocrine surgeons must make every effort to preoperatively identify multiple endocrine neoplasia syndrome type I in the younger patient population.

Real-Time Super Selective Venous Sampling in Remedial Parathyroid Surgery.

BACKGROUND: Remedial cervical exploration for persistent or recurrent primary hyperparathyroidism can be technically difficult, but is expedited by accurate preoperative localization. We investigated the use of real-time super selective venous sampling (sSVS) in the setting of negative noninvasive imaging modalities. STUDY DESIGN: We performed a retrospective analysis of a prospective database incorporating real-time sSVS in a tertiary academic medical center. Between September 2001 and April 2014, 3,643 patients were referred for surgical treatment of primary hyperparathyroidism. Of these, 31 represented remedial patients who had undergone one (n=28) or more (n=3) earlier cervical explorations and had noninformative, noninvasive preoperative localization studies. RESULTS: We extended the use of the rapid parathyroid hormone assay in the interventional radiology suite, generating near real-time data facilitating onsite venous localization by a dedicated interventional radiologist. The predictive value of real-time sSVS localization was investigated. Overall, sSVS correctly predicted the localization of the affected gland in 89% of cases. Of 31 patients who underwent sSVS, a significant rapid parathyroid hormone gradient was identified in 28 (90%), localizing specific venous drainage of a culprit gland. All patients underwent subsequent surgery and were biochemically cured, with the exception of one who had metastatic parathyroid carcinoma. Three patients with negative sSVS were also explored and cured. CONCLUSIONS: Preoperative parathyroid localization is of paramount importance in remedial cervical explorations. Real-time sSVS is a sensitive localization technique for patients with persistent or recurrent primary hyperparathyroidism, when traditional noninvasive imaging studies fail. These results validate the utility and benefit of real-time sSVS in guiding remedial parathyroid surgery.