Characterization of Mammary Tumors Arising from MMTV-PyVT Transgenic Mice.

Among genetically engineered mouse models of breast cancer, MMTV-PyVT is a mouse strain in which the oncogenic polyoma virus middle T antigen is driven by the mouse mammary tumor virus promoter. The aim of the present study was to perform morphologic and genetic analyses of mammary tumors arising from MMTV-PyVT mice. To this end, mammary tumors were obtained at 6, 9, 12, and 16 weeks of age for histology and whole-mount analyses. We conducted whole-exome sequencing to identify constitutional and tumor-specific mutations, and genetic variants were identified using the GRCm38/mm10 mouse reference genome. Using hematoxylin and eosin analysis and whole-mount carmine alum staining, we demonstrated the progressive proliferation and invasion of mammary tumors. Frameshift insertions/deletions (indels) were noted in the Muc4. Mammary tumors showed small indels and nonsynonymous single-nucleotide variants but no somatic structural alterations or copy number variations. In summary, we validated MMTV-PyVT transgenic mice as a multistage model for mammary carcinoma development and progression. Our characterization may be used as a reference for guidance in future research.

Investigating the risk of metabolic and cardiovascular comorbidities among patients with parathyroid cancer: a nationwide representative cohort study in Taiwan.

BACKGROUND: This study aimed to determine whether primary parathyroid cancer patients were associated with increased metabolic and cardiovascular comorbidities in comparison to the general population. METHODS: We used the National Taiwan Cancer Registry Database to construct a cohort of patients with parathyroid cancer from January 1, 2004, to December 31, 2019. We compared the incidence of hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, coronary heart disease, and heart failure with the general population matched based on a propensity score in a one-to-five fashion. RESULTS: A total of 72 parathyroid cancer patients and 360 matched general population (mean age: 55 years; 59% women) were included, with different exclusive numbers for each metabolic and cardiovascular comorbidity cohort. The number of cases based on a total of 2347.7 person-years of observation included 53 deaths, 29 hypertension, 9 diabetes, 13 hyperlipidemia, 10 atrial fibrillation, 18 coronary artery disease, and 13 heart failure. According to multivariate analysis, parathyroid cancer remained significantly associated with diabetes [hazard ratio (HR): 9.28; 95% confidence interval (CI): 1.72-50.07], hyperlipidemia (HR: 5.86; 95% CI: 1.61-21.31), and heart failure (HR: 4.46; 95% CI: 1.18-16.84). Sub-distribution of competing mortality events and subgroup analysis showed robust evidence of metabolic and cardiovascular comorbidities. This national cohort study demonstrated that adult parathyroid cancer patients had a significantly higher incidence of diabetes mellitus, hyperlipidemia, and heart failure than the general population. CONCLUSIONS: An increased risk of metabolic and cardiac comorbidities among parathyroid cancer patients required great caution.

Downregulation of cellular retinoic acid binding protein 1 fosters epithelial-mesenchymal transition in thyroid cancer.

Cellular retinoic acid binding protein 1 (CRABP1) participates in the regulation of retinoid signaling. Previous studies showed conflicting results regarding the role of CRABP1 in tumor biology, including protumorigenic and tumor-suppressive effects in different types of cancer. Our bioinformatics analyses suggested that CRABP1 expression was downregulated in thyroid cancer. Ectopic expression of CRABP1 in thyroid cancer cells suppressed migratory and invasive activity without affecting cell growth or cell cycle distribution. In transformed normal thyroid follicular epithelial cells, silencing of CRABP1 expression increased invasiveness. Additionally, CRABP1 overexpression was associated with downregulation of the mesenchymal phenotype. Kinase phosphorylation profiling indicated that CRABP1 overexpression was accompanied by a decrease in phosphorylation of epidermal growth factor (EGF) receptor and downstream phosphorylation of Akt, STAT3, and FAK, which were reversed by exogenous EGF treatment. Immunohistochemical analysis of our tissue microarrays revealed an inverse association between CRABP1 expression and disease stage of differentiated thyroid cancer. Taken together, our results suggest that CRABP1 expression is aberrantly lost in thyroid cancer, and this downregulation promotes the epithelial-mesenchymal transition at least partly through modulating EGF receptor signaling.

Trends in thyroid cancer burden in Taiwan over two decades.

PURPOSE: Thyroid cancer incidence has increased over recent decades with considerable geographic variations in incidence patterns. Here, we analyzed temporal trends in the incidence and mortality rates of thyroid cancer in Taiwan. METHODS: We obtained age-standardized rates at a national level using data from the Taiwan Cancer Registry annual reports from 1995 to 2019. Trends in age-standardized rates were characterized by joinpoint regression analysis. RESULTS: The age-standardized incidence rate of thyroid cancer increased from 3.00 per 100,000 person-years in 1995 to 15.46 per 100,000 person-years in 2019 (p < 0.001). Significant upward trends were observed in virtually all age groups, including adolescents and the geriatric population. The average annual percent changes were 7.97%, 2.60%, 2.77%, and 1.43% for papillary, follicular, medullary, and anaplastic thyroid cancers, respectively. The mortality rate from thyroid cancer decreased over time in women but remained stable in men. CONCLUSION: The incidence rates of thyroid cancer have steadily increased across gender, age groups, and tumor types over the past two decades. Future studies are needed to investigate potential etiological factors other than overdiagnosis that may drive these trends.

Impact of social and economic factors on global thyroid cancer incidence and mortality.

PURPOSE: The incidence of thyroid cancer has increased substantially over the past few decades and is partially explained by overdiagnosis. Geographical variations in incidence rates were reported to be related to national development status. This study aimed to gain deeper insights into global thyroid cancer burden by incorporating additional social and economic factors to account for cross-national disparities. METHODS: We performed a multivariate analysis of age-standardized incidence and mortality data from the GLOBOCAN 2020 database for 126 countries that had more than 100 incident cases of thyroid cancer. The human development index (HDI), current health expenditure, and additional Global Health Observatory indicators were extracted from multiple sources. RESULTS: Age-standardized incidence was highly correlated with HDI (standardized coefficient beta = 0.523, 95% confidence interval [CI] = 0.275-0.771) among the countries studied. The prevalence of raised fasting blood glucose was associated with age-standardized mortality (beta = 0.277, 95% CI = 0.038-0.517). Generally, the mortality-to-incidence ratio was higher in males than in females. In multivariate analysis, HDI (beta = - 0.767, 95% CI = - 0.902 to - 0.633), current health expenditure (beta = 0.265, 95% CI = 0.137-0.394), and fine particulate matter (PM2.5) concentrations (beta = 0.192, 95% CI = 0.086-0.298) were associated with mortality-to-incidence ratios. CONCLUSIONS: National developments gauged by HDI explain the majority of the variation in incidence rates of thyroid cancer but play a smaller role in disparities in mortality rates. The association between air pollution and thyroid cancer outcomes warrants further investigation.

Propensity Score-Matched Analysis to Identify Pathways Associated with Loss of Sodium Iodide Symporter in Papillary Thyroid Cancer.

Sodium iodide symporter (NIS) expression in thyroid follicular cells plays an important role in normal physiology and radioactive iodine therapy for thyroid cancer. Loss of NIS expression is often seen in thyroid cancers and may lead to radioiodine refractoriness. To explore novel mechanisms of NIS repression beyond oncogenic drivers, clinical and RNA-seq data from the thyroid cancer dataset of The Cancer Genome Atlas were analyzed. Propensity score matching was used to control for various genetic background factors. We found that tumoral NIS expression was negatively correlated with tumor size. Additionally, low NIS expression was the only factor associated with recurrence-free survival in a Cox multivariate regression analysis. After matching for clinicopathologic profiles and driver mutations, the principal component analysis revealed distinct gene expressions between the high and low NIS groups. Gene set enrichment analysis suggested the downregulation of hedgehog signaling, immune networks, and cell adhesions. Positively enriched pathways included DNA replication, nucleotide excision repair, MYC, and Wnt/ß-catenin pathways. In summary, we identified several potential targets which could be exploited to rescue the loss of NIS expression and develop redifferentiation strategies to facilitate radioactive iodine therapy for thyroid cancer.

Computer-Analyzed Ultrasound Predictors of the Treatment Efficacy of Radiofrequency Ablation for Benign Thyroid Nodules.

AIM: Radiofrequency ablation (RFA) is a relatively safe and efficient alternative to surgery for patients with benign thyroid nodules. We investigated predictive factors associated with volume reduction using digital imaging analysis. METHODS: In this retrospective study, a prospectively maintained database containing the data of patients who received treatment from April 2019 to March 2020 was analyzed. Computerized analysis for quantitative measurement of echogenicity, heterogeneity, and the proportion of cystic components was performed on ultrasonographic images. The volume reduction rate (VRR) was calculated during follow-up. Treatment efficacy was defined as a volume reduction greater than 50% of baseline volume. RESULTS: The median volume of 58 benign thyroid nodules before RFA was 22.7 mL. Of 53 nodules with sufficient follow-up, the median VRR was 46.4%, 61.5%, 63.4%, and 67.4% at 1, 3, 6, and 12 months, respectively. Overall, at one-year follow-up, treatment efficacy was achieved in 39 (74%) nodules. In a multivariate regression analysis, the proportion of cystic components and RFA treatment time were independently associated with treatment efficacy. A subgroup analysis focusing on solid nodules indicated a negative correlation between echogenicity and VRR. CONCLUSIONS: The proportion of cystic components in thyroid nodules is the main predictor of RFA treatment efficacy. In solid nodules, higher echogenicity is associated with a lower volume reduction.

Double water-clear cell parathyroid adenoma: a case report and literature review.

Water-clear cell parathyroid adenoma is an uncommon cause of primary hyperparathyroidism. Herein, we report an interesting case of a 56-year-old man who presented with weight loss, bone pain, fatigue, and a palpable right neck mass. Laboratory tests indicated hypercalcemia, elevated parathyroid hormone (PTH) levels, and normal thyroid function. Further examinations detected osteoporosis and kidney stones. The ultrasound of neck revealed bilateral extrathyroidal tumors, which were sestamibi-avid. The patient underwent resection of the large right inferior and left inferior parathyroid tumors. Histopathology revealed a double water-clear cell parathyroid adenoma. His serum calcium and PTH levels normalized after surgery. The literature review identified 37 cases of water-clear cell parathyroid adenoma between 1985 and 2021. The median age at diagnosis was 56 years. Classic complications were common, including nephrolithiasis in nine and skeletal presentations in 10 patients. Before surgery, the median calcium and PTH levels were 12.0 mg/dL and 290 pg/mL, respectively. Overall, 89% were localized on ultrasonography, and 60% were positive on scintigraphy. Four patients had double adenomas. The median maximum diameter was 3.8 cm, and the median weight of the resected adenoma was 5.27 g. In summary, water-clear cell parathyroid adenoma has certain unique features. These include larger tumor size, relatively indolent biochemical profile, high prevalence of complications and nonspecific symptoms, an isoechoic appearance on ultrasonography, and reduced scintigraphic sensitivity.

Trilostane, a 3ß-hydroxysteroid dehydrogenase inhibitor, suppresses growth of hepatocellular carcinoma and enhances anti-cancer effects of sorafenib.

Background Human 3ß-hydroxysteroid dehydrogenase type 1 (HSD3B1) is an enzyme associated with steroidogenesis, however its' role in hepatocellular carcinoma (HCC) biology is unknown. Trilostane is an inhibitor of HSD3B1 and has been tested as a treatment for patients with breast cancer but has not been studied in patients with HCC. Methods and Results The expression of HSD3B1 in HCC tumors in 57 patients were examined. A total of 44 out of 57 tumors (77.2%) showed increased HSD3B1 expression. The increased HSD3B1 in tumors was significantly associated with advanced HCC. In vitro, the knockdown of HSD3B1 expression in Mahlavu HCC cells by a short hairpin RNA (shRNA) led to significant decreases in colony formation and cell migration. The suppression of clonogenicity in the HSD3B1-knockdown HCC cells was reversed by testosterone and 17ß-estradiol. Trilostane-mediated inhibition of HSD3B1 in different HCC cells also caused significant inhibition of clonogenicity and cell migration. In subcutaneous HCC Mahlavu xenografts, trilostane (30 or 60 mg/kg, intraperitoneal injection) significantly inhibited tumor growth in a dose-dependent manner. Furthermore, the combination of trilostane and sorafenib significantly enhanced the inhibition of clonogenicity and xenograft growth, surpassing the effects of each drug used alone, with no documented additional toxicity to animals. HSD3B1 blockade was found to suppress the phosphorylation of extracellular signal-regulated kinase (ERK). The decreased ERK phosphorylation was reversed by testosterone or 17b-estradiol. Conclusions Trilostane significantly inhibited the growth of HCC by inhibiting HSD3B1 function and augmenting the efficacy of sorafenib.

Overexpression of chitinase-3-like protein 1 is associated with structural recurrence in patients with differentiated thyroid cancer.

We previously identified that the expression of chitinase-3-like protein 1 (CHI3L1) was upregulated during thyroid cancer progression. Here, we investigated the prognostic significance of CHI3L1 expression in thyroid neoplasms and examined the potential oncogenic roles. CHI3L1 immunochemical staining was performed on tissue microarrays of benign and malignant thyroid tumours. Compared with normal thyroid tissue and benign thyroid lesions that had low or no detectable CHI3L1 expression, CHI3L1 was overexpressed in both differentiated and undifferentiated thyroid cancer. High CHI3L1 expression was associated with extrathyroidal extension, lymph node metastasis, and shorter recurrence-free survival in differentiated thyroid cancer. The biological roles of CHI3L1 were further investigated by gain- and loss-of-function assays. CHI3L1 silencing suppressed clonogenicity, migration, invasion, anoikis resistance, and angiogenesis in thyroid cancer cells, although exogenous CHI3L1 treatment promoted these malignant phenotypes. Cysteine-rich angiogenic inducer 61 (CYR61) was identified as a downstream target of CHI3L1 by RNA-seq analysis. CYR61 silencing or treatment reversed the alterations induced by CHI3L1 modulation. Our results demonstrate that CHI3L1 is overexpressed in thyroid cancer and is associated with an increased risk of disease recurrence. Additionally, CYR61 may participate in CHI3L1-mediated tumour progression. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Learning curve analysis of radiofrequency ablation for benign thyroid nodules.

BACKGROUND: Radiofrequency ablation (RFA) has been increasingly accepted as an alternative to surgery in the treatment of symptomatic benign thyroid nodules. However, the learning curve of thyroid RFA has yet to be defined. We hypothesized a temporal relationship between proficiency of the skill and midterm volume reduction. METHODS: Consecutive patients who underwent RFA and had at least a six-month follow-up were identified from an institutional database. The cumulative sum (CUSUM) analysis was applied to visualize the learning curve on the adjusted volume reduction rate (VRR). RESULTS: A total of 102 nodules in 93 patients were included in the analysis. Linear regression revealed that nodule composition was the main predictor of the VRR. The composition-adjusted VRR increased with the chronological treatment order. The series was divided into three phases based on inflection points of the CUSUM analysis: the initial learning phase (case 1-20), consolidation phase (case 21-65), and proficiency phase (case 66-102). In the later phase, more solid nodules were treated, power output used by the operator was higher, and RFA treatment time was longer. CONCLUSION: The treatment efficiency of thyroid RFA was associated with technical proficiency, suggesting the presence of a learning curve effect.

Osteocalcin is an Independent Predictor for Hungry Bone Syndrome After Parathyroidectomy.

BACKGROUND: Hungry bone syndrome is characterized by prolonged and severe hypocalcemia following parathyroidectomy. Previously, we reported that preoperative alkaline phosphatase is a major factor predicting prolonged hospital stay. Nonetheless, some patients with low alkaline phosphatase levels presented with hungry bone syndrome, suggesting that additional factors may play a role. METHODS: From September 2010 to December 2017, consecutive dialysis patients who underwent parathyroidectomy for secondary hyperparathyroidism were analyzed. Length of hospital stay was used as a surrogate marker for postoperative bone hunger. RESULTS: A total of 260 patients were included in the study. The median postoperative hospital stay was 3 days, and 69 (27%) patients had a stay longer than 3 days. Multivariate logistic regression analysis revealed that alkaline phosphatase (odds ratio [OR] = 1.005), osteocalcin (OR = 1.001), and subtotal parathyroidectomy (OR = 0.061) were associated with prolonged hospital stay. Multivariate linear regression analysis indicated that age (ß = - 0.170), alkaline phosphatase (ß = 0.430), and osteocalcin (ß = 0.166) were correlated with the length of stay. After surgery, the median osteocalcin level increased from 264 to 478 ng/mL (P < 0.001). CONCLUSIONS: Alkaline phosphatase is the main predictor of hungry bone syndrome after parathyroidectomy, and preoperative osteocalcin is an additional independent predictor. Patients with a high osteocalcin level may prone to have a higher demand for calcium supplementation.

A benchmark for comparing precision medicine methods in thyroid cancer diagnosis using tissue microarrays.

Motivation: The aim of precision medicine is to harness new knowledge and technology to optimize the timing and targeting of interventions for maximal therapeutic benefit. This study explores the possibility of building AI models without precise pixel-level annotation in prediction of the tumor size, extrathyroidal extension, lymph node metastasis, cancer stage and BRAF mutation in thyroid cancer diagnosis, providing the patients' background information, histopathological and immunohistochemical tissue images. Results: A novel framework for objective evaluation of automatic patient diagnosis algorithms has been established under the auspices of the IEEE International Symposium on Biomedical Imaging 2017- A Grand Challenge for Tissue Microarray Analysis in Thyroid Cancer Diagnosis. Here, we present the datasets, methods and results of the challenge and lay down the principles for future uses of this benchmark. The main contributions of the challenge include the creation of the data repository of tissue microarrays; the creation of the clinical diagnosis classification data repository of thyroid cancer; and the definition of objective quantitative evaluation for comparison and ranking of the algorithms. With this benchmark, three automatic methods for predictions of the five clinical outcomes have been compared, and detailed quantitative evaluation results are presented in this paper. Based on the quantitative evaluation results, we believe automatic patient diagnosis is still a challenging and unsolved problem. Availability and implementation: The datasets and the evaluation software will be made available to the research community, further encouraging future developments in this field. (http://www-o.ntust.edu.tw/cvmi/ISBI2017/). Contact: cweiwang@mail.ntust.edu.tw. Supplementary information: Supplementary data are available at Bioinformatics online.

Inhibition of 3ß-Hydroxysteroid Dehydrogenase Type 1 Suppresses Interleukin-6 in Breast Cancer.

BACKGROUND: Recently, we demonstrated that the expression of 3ß-hydroxysteroid dehydrogenase type 1 (HSD3B1) in breast cancer is associated with shorter recurrence-free survival, and genetic or pharmacologic inhibition of HSD3B1 reduced colony formation and xenograft growth. However, the mechanisms are unclear. METHODS: Triple-negative MDA-MB-231 and BT-20 breast cancer cells underwent HSD3B1 silencing. Microarray and bioinformatic analysis were performed. The interleukin-6 (IL-6) expression and secretion were evaluated using real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Clonogenic ability and cell viability were determined in the absence or presence of recombinant IL-6. RESULTS: Functional and pathway enrichment analyses showed that HSD3B1 silencing modulates the expression of several growth factors and cytokines. Cells transfected with HSD3B1-targeting small interfering RNA or treated with an HSD3B1 inhibitor (trilostane) had decreased IL-6 expression and secretion. HSD3B1 inhibition reduced colony formation, which was partially rescued by IL-6 supplementation. The HSD3B1 knockdown enhanced paclitaxel sensitivity, and IL-6 treatment partially reversed the augmented cytotoxicity. CONCLUSIONS: Our findings suggest that the therapeutic potential of targeting HSD3B1 is in part mediated by IL-6 suppression.

Is papillary thyroid microcarcinoma a biologically different disease? A propensity score-matched analysis.

BACKGROUND: Papillary thyroid microcarcinoma exhibits an indolent clinical course and could be a candidate for active surveillance in the appropriate setting. It remains unknown whether papillary microcarcinoma is biologically different from larger papillary carcinoma >1 cm. METHODS: We analyzed clinicopathological information and transcriptome data of papillary thyroid cancer samples from The Cancer Genome Atlas. Propensity-score matching was used to construct a matched cohort consisting of 29 microcarcinomas and 58 carcinomas. Principal component analysis and unsupervised hierarchical cluster analysis were carried out to investigate the similarity of gene expression profiles. RESULTS: After adjustment for differences in baseline clinicopathological and genetic factors, transcriptome could be grouped mainly on the basis of tumor class (BRAF-like vs RAS-like) and tumor size (microcarcinoma vs carcinoma). The gene set enrichment analysis showed that extracellular matrix-associated pathways were enriched in the MSigDB database. CONCLUSION: Papillary thyroid microcarcinomas display a distinct gene expression pattern different from the corresponding carcinomas. We hypothesize that tumor microenvironment may play a role in the microcarcinoma/carcinoma phenotypic divergence.

A Novel Prediction Model for Bloodstream Infections in Hepatobiliary-Pancreatic Surgery Patients.

BACKGROUND: Bloodstream infections (BSI) are an important source of postoperative mortality in hepatobiliary-pancreatic surgery (HBPS) patients, and no prediction model has been analyzed before. METHODS: Using big data from the electronic medical records of the administrative and culture databases of MacKay Memorial Hospital, we identified the potential risk factors for community-acquired and healthcare-associated BSI and mortality of patients who received HBPS. Subsequently, we analyzed the microorganisms' profiles and antimicrobial susceptibility patterns for these BSI. RESULTS: BSI were found in 6.3% patients (349 of 5513 HBPS patients), and hospital mortality was 1.48% (82 of 5513). Dividing patients into low-, intermediate-, and high-risk groups on the basis of sex, age, status of comorbidity (renal failure, peptic ulcer disease, fluid and electrolyte disorders, and acute cholecystitis), a predictive BSI risk score model was developed. According to this model, BSI risk ranged from 1.43% to 11.95%; AUROC to predict BSI risk was 0.72 (95% CI 0.69-0.75). From this retrospective study, Enterobacteriaceae were the most common microorganisms that were isolated from BSI. For both community-acquired and healthcare-associated BSI, imipenem and colistin are the most successful. CONCLUSION: This novel model can be useful to predict who is at risk of BSI after HBPS, and new prophylactic protocols for these patients are needed.

Expression of serine peptidase inhibitor Kunitz type 1 in differentiated thyroid cancer.

SPINT1, also known as HAI-1, is a Kunitz-type serine protease inhibitor that inhibits multiple proteases including hepatocyte growth factor (HGF) activator and matriptase. SPINT1 has been shown to modulate HGF/MET activation in certain cancer types. In the present study, we analyzed microarray datasets and found that SPINT1 was consistently upregulated in differentiated thyroid cancer. SPINT1 protein expression was investigated using tissue microarrays and independent samples of our 143 patients. Strong SPINT1 expression was observed in 61-68% of papillary thyroid cancer and 41-50% of follicular thyroid cancer. The overexpression diminished in anaplastic thyroid cancer. The SPINT1 expression in normal thyroid tissues and benign thyroid lesions was low. Furthermore, we noted that the SPINT1 expression was associated with extrathyroidal invasion, lymphovascular invasion, lymph node metastasis, advanced TNM stage, and a higher risk of recurrence in differentiated thyroid cancer. The results were in accordance with our analysis of The Cancer Genome Atlas data. In conclusion, an overexpression of SPINT1 appears to be associated with an invasive phenotype in differentiated thyroid cancer.

Parathyroidectomy decreases neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios.

BACKGROUND: Systemic inflammation has been implicated in complications and heightened mortality of patients with secondary hyperparathyroidism. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are widely available surrogate markers of inflammation. This study sought to delineate the changes in NLR and PLR after parathyroidectomy. METHODS: A total of 213 patients undergoing initial parathyroidectomy from 2010 to 2015 for secondary hyperparathyroidism were identified from a prospectively maintained clinical database. Among 183 patients free of persistent or recurrent disease, follow-up NLR and PLR were available for analysis in 85 patients. RESULTS: In the whole study population, the baseline NLR was positively correlated with male sex, total white blood cell count, height, serum phosphorus, and calcium-phosphorus product levels. The baseline PLR was positively correlated with platelet count, serum phosphorus, and calcium-phosphorus product levels and negatively associated with patient age. Postoperative parathyroid hormone levels were positively correlated with NLR and PLR at follow-up. For patients who had successful parathyroidectomy, there was a decrease in NLR (P = 0.0006), PLR (P = 0.0003), and platelet count (P = 0.033), whereas hemoglobin significantly increased (P = 0.0002) after surgery. Those with persistent or recurrent hyperparathyroidism had no change in NLR, PLR, hemoglobin, total white blood cell, or platelet count. CONCLUSIONS: Successful parathyroidectomy is associated with a decrease in NLR and PLR. The modulatory effects of parathyroidectomy on systemic inflammation may partially explain the benefits of surgery in secondary hyperparathyroidism.

An Increased Neutrophil-to-Lymphocyte Ratio Predicts Incomplete Response to Therapy in Differentiated Thyroid Cancer.

Background: Previously we have shown that an elevated baseline neutrophil-to-lymphocyte ratio (NLR) was associated with a high risk of recurrence in patients with differentiated thyroid cancer. The clinical significance of the longitudinal changes in NLR following treatment remained unestablished. Methods: Adults patients with differentiated thyroid cancer were included in the study if the follow-up NLR data at 6 to 18 months after initial treatment were available. The response to treatment was categorized as excellent, indeterminate, biochemical incomplete, and structural incomplete as per guidelines of the American Thyroid Association. Results: Among 151 patients with thyroid cancer, a significant decrease in NLR following treatment was observed in those with stage I disease, those with low risk of recurrence, and those with an excellent response to therapy. Patients with a structural incomplete response had a significant increase in NLR at follow-up (p = 0.012). On multivariate analysis, incomplete response to therapy was associated with male sex (odds ratio [OR] = 3.35), tumor size (OR = 1.63), lymph node metastasis (OR = 4.80), distant metastasis (OR = 12.95), and increased NLR (OR = 13.68). Conclusions: An increase in systemic inflammation following treatment as measured by NLR is independently associated with an incomplete response to therapy in differentiated thyroid cancer.

Heme Oxygenase-1 Inhibitors Induce Cell Cycle Arrest and Suppress Tumor Growth in Thyroid Cancer Cells.

Heme oxygenase-1 (HO-1) is induced by a variety of stimuli and plays a multifaceted role in cellular protection. We have shown that HO-1 is overexpressed in thyroid cancer and is associated with tumor aggressiveness. Therefore, we set out to assess the effects of HO-1 inhibitors on the biology of thyroid cancer cells. Two different classes of HO-1 inhibitors were used, including a metalloporphyrin, zinc protoporphyrin-IX (ZnPP), and an azole antifungal agent, ketoconazole. The viability and colony formation of thyroid cancer cells decreased in a concentration- and time-dependent fashion following treatment with HO-1 inhibitors. Cancer cells exhibited a higher sensitivity to HO-1 inhibitors than non-malignant cells. HO-1 inhibitors induced a G0/G1 arrest accompanied by decreased cyclin D1 and CDK4 expressions and an increase in levels of p21 and p27. HO-1 inhibitors significantly increased intracellular ROS levels and suppressed cell migration and invasion. Oxygen consumption rate and mitochondrial mass were increased with ZnPP treatment. Mice treated with ZnPP had a reduced xenograft growth and diminished cyclin D1 and Ki-67 staining in tumor sections. Taken together, HO-1 inhibitors might have therapeutic potential for inducing cell cycle arrest and promoting growth suppression of thyroid cancer cells in vitro and in vivo.