Short-term effects of allulose consumption on glucose homeostasis, metabolic parameters, incretin levels, and inflammatory markers in patients with type 2 diabetes: a double-blind, randomized, controlled crossover clinical trial.

PURPOSE: Allulose is a rare monosaccharide with almost zero calories. There is no study of short-term allulose consumption in patients with type 2 diabetes (T2D). Thus, we aimed to study the effect of allulose consumption for 12 weeks on glucose homeostasis, lipid profile, body composition, incretin levels, and inflammatory markers in patients with T2D. METHODS: A double-blind, randomized, controlled crossover study was conducted on sixteen patients with T2D. Patients were randomly assigned to allulose 7 g twice daily or aspartame 0.03 g twice daily for 12 weeks. After a 2-week washout, patients were crossed over to the other sweetener for an additional 12 weeks. Oral glucose tolerance tests, laboratory measurements, and dual-energy X-ray absorptiometry were conducted before and after each phase. RESULTS: This study revealed that short-term allulose consumption exerted no significant effect on glucose homeostasis, incretin levels, or body composition but significantly increased MCP-1 levels (259 ± 101 pg/ml at baseline vs. 297 ± 108 pg/mL after 12 weeks of allulose, p = 0.002). High-density lipoprotein cholesterol (HDL-C) significantly decreased from 51 ± 13 mg/dl at baseline to 41 ± 12 mg/dL after 12 weeks of allulose, p < 0.001. CONCLUSION: Twelve weeks of allulose consumption had a neutral effect on glucose homeostasis, body composition, and incretin levels. Additionally, it decreased HDL-C levels and increased MCP-1 levels. TRIAL REGISTRATION: This trial was retrospectively registered on the Thai Clinical Trials Registry (TCTR20220516006) on December 5, 2022.

Benefits of Long-Term Continuation of Low-Dose Methimazole Therapy in the Prevention of Recurrent Hyperthyroidism in Graves' Hyperthyroid Patients: A Randomized Prospective Controlled Study.

Background: The long-term continuation of the low-dose antithyroid drug (ATD) beyond the standard duration of ATD therapy of 12-18 months to prevent recurrent hyperthyroidism (RH) is recommended with low quality of evidence. Objectives: To examine whether long-term continuation of low-dose ATD beyond the recommended duration of treatment would provide a benefit in the prevention of RH in patients with Graves' hyperthyroidism (GH) who achieved euthyroid status with a standard course of ATD therapy. Methods: A 36-month prospective randomized controlled study was conducted in 184 patients who had first diagnosed GH and were treated with a standard regimen of ATD therapy using methimazole (MMI) until achieving euthyroidism that was stably maintained for at least 6 months with a low-dose of (2.5-5 mg/day) MMI. All patients had neither a history of adverse effects from MMI, recurrent GH, severe and active ophthalmopathy nor conditions known to affect thyroid function before randomization. The patients were randomized into 2 groups: one group (92 cases) was assigned to discontinue (DISCONT-MMI) and the other (92 cases) was assigned to continue low-dose MMI (CONT-MMI) that was taken at the time of enrollment. The patients in both groups were followed up at 3, 6, 12, 18, 24, 30, and 36 months. The rate of RH was compared between both groups, and the adverse effects and risk factors of RH were also studied. Results: At the end of the 36-month study, 83 cases in CONT-MMI and 90 cases in DISCONT-MMI were eligible for analysis. The cumulative rates of RH in CONT-MMI were significantly lower than those in DISCONT-MMI at every follow-up time point (1.2% vs. 11.2%, 6.8% vs. 18.4%, 11.0% vs. 27.2%, 11.0% vs. 35.0%, and 11.0% vs. 41.2% at 6, 12, 18, 24, and 36 months, respectively; p < 0.01). Cox proportional hazard multivariate analysis showed that there were 2 factors independently associated with the risk of RH, including continuation of low-dose MMI therapy, which decreased the risk of RH by 3.8 times (HR = 0.26, p = 0.007, 95% CI = 0.10-0.70) and age onset of hyperthyroidism before 40 years, which increased the risk of RH by 2.9 times (HR = 2.9, p = 0.015, 95% CI = 1.23-6.88). Neither minor nor major adverse effects of low-dose MMI therapy were observed during the study period. Conclusions: In Graves' hyperthyroid patients with no or nonsevere ophthalmopathy who have completed a standard course of methimazole therapy without an adverse effect and have achieved an euthyroid status that is stably maintained with low-dose methimazole, a long-term continuation of the low-dose methimazole of 2.5-5 mg daily is effective and safe in the prevention of recurrent hyperthyroidism or maintenance of euthyroid status as long as the low-dose methimazole is continued. (TCTR20170705002).

Incidence and Survival of Hepatocellular Carcinoma in Type 2 Diabetes Patients with Cirrhosis Who Were Treated with and without Metformin.

PURPOSE: To evaluate metformin's benefit on the incidence and survival of hepatocellular carcinoma (HCC) in cirrhosis with type 2 diabetes mellitus (T2DM) patients. PATIENTS AND METHODS: We conducted a retrospective study from 2006 to 2019. The patients were assigned to metformin exposure if they administered metformin at least 3 months after diagnosis of cirrhosis. The outcomes were incidence and survival of HCC in T2DM with cirrhosis treated with metformin compared with those who were not treated with metformin. For the incidence of HCC, the follow-up time was 5 years after cirrhosis was diagnosed. For the survival of HCC, we censored for vital status in June 2019. RESULTS: Of 1061 patients, the patients were divided into 719 patients with metformin exposure and 342 in metformin non-exposure. In metformin exposure, 125 patients (17.4%) developed HCC. In metformin non-exposure, 128 patients (37.4%) developed HCC. Metformin exposure had a significantly lower risk of developing HCC in multivariate analysis HR 0.48 (0.36-0.61); P<0.001. For the survival of HCC, 327 patients were recruited. One-hundred and sixty-two patients were in metformin exposure and 165 patients were in metformin non-exposure. Sixty patients (37%) in metformin exposure died, while 84 patients (50.9%) in metformin non-exposure died. The median survival of metformin exposure and metformin non-exposure were 6.9 years and 3.88 years, respectively; P=0.003. In univariate analysis, the metformin exposure was significantly associated with better survival than in the non-exposure group, HR 0.63 (0.45-0.88); P=0.006. No significant difference was observed in multivariate analysis between two groups, HR 1.07 (0.74-1.54); P=0.72. CONCLUSION: Metformin exposure was associated with a lower incidence of HCC in cirrhosis with T2DM patients and seemed to extend survival. Continuing metformin in patients with cirrhosis with T2DM should be considered if there was no contraindication.

Comparison of Pheochromocytoma-Specific Morbidity and Mortality Among Adults With Bilateral Pheochromocytomas Undergoing Total Adrenalectomy vs Cortical-Sparing Adrenalectomy.

Importance: Large studies investigating long-term outcomes of patients with bilateral pheochromocytomas treated with either total or cortical-sparing adrenalectomies are needed to inform clinical management. Objective: To determine the association of total vs cortical-sparing adrenalectomy with pheochromocytoma-specific mortality, the burden of primary adrenal insufficiency after bilateral adrenalectomy, and the risk of pheochromocytoma recurrence. Design, Setting, and Participants: This cohort study used data from a multicenter consortium-based registry for 625 patients treated for bilateral pheochromocytomas between 1950 and 2018. Data were analyzed from September 1, 2018, to June 1, 2019. Exposures: Total or cortical-sparing adrenalectomy. Main Outcomes and Measures: Primary adrenal insufficiency, recurrent pheochromocytoma, and mortality. Results: Of 625 patients (300 [48%] female) with a median (interquartile range [IQR]) age of 30 (22-40) years at diagnosis, 401 (64%) were diagnosed with synchronous bilateral pheochromocytomas and 224 (36%) were diagnosed with metachronous pheochromocytomas (median [IQR] interval to second adrenalectomy, 6 [1-13] years). In 505 of 526 tested patients (96%), germline mutations were detected in the genes RET (282 patients [54%]), VHL (184 patients [35%]), and other genes (39 patients [7%]). Of 849 adrenalectomies performed in 625 patients, 324 (52%) were planned as cortical sparing and were successful in 248 of 324 patients (76.5%). Primary adrenal insufficiency occurred in all patients treated with total adrenalectomy but only in 23.5% of patients treated with attempted cortical-sparing adrenalectomy. A third of patients with adrenal insufficiency developed complications, such as adrenal crisis or iatrogenic Cushing syndrome. Of 377 patients who became steroid dependent, 67 (18%) developed at least 1 adrenal crisis and 50 (13%) developed iatrogenic Cushing syndrome during median (IQR) follow-up of 8 (3-25) years. Two patients developed recurrent pheochromocytoma in the adrenal bed despite total adrenalectomy. In contrast, 33 patients (13%) treated with successful cortical-sparing adrenalectomy developed another pheochromocytoma within the remnant adrenal after a median (IQR) of 8 (4-13) years, all of which were successfully treated with another surgery. Cortical-sparing surgery was not associated with survival. Overall survival was associated with comorbidities unrelated to pheochromocytoma: of 63 patients who died, only 3 (5%) died of metastatic pheochromocytoma. Conclusions and Relevance: Patients undergoing cortical-sparing adrenalectomy did not demonstrate decreased survival, despite development of recurrent pheochromocytoma in 13%. Cortical-sparing adrenalectomy should be considered in all patients with hereditary pheochromocytoma.

Beta-cell function in type 2 diabetic patients who failed to maintain good glycemic status with a combination of maximum dosages of metformin and sulfonylurea.

Background: The aim of this study was to investigate beta-cell function and examine whether sulfonylureas (SUs) are still useful in patients with type 2 diabetes (T2DM) who failed to maintain optimal glycemic control with a combination of maximum dosages of metformin and SU. Method: T2DM who had HbA1c >8% during treatment with a combination of maximum dosages of metformin and SU were studied. After enrollment, the patients were assigned to continue maximum dosages of SU and metformin for 2 weeks and then underwent the first oral glucose tolerance test (OGTT), the Max-SU OGTT. After the Max-SU OGTT, SUs were discontinued for 4 weeks and the second OGTT, the Discont-SU OGTT, was performed. After the Discont-SU OGTT, the same SU was restarted at 25% of the maximum dosage (25%Max-SU). After taking 25%Max-SU for 4 weeks, the third OGTT, the 25%Max-SU OGTT, was performed. Metformin at the same dosage was continued throughout the study. Normal OGTT (NGT) subjects, matched for age and body mass index (BMI), were also studied. Results: There were 25 T2DM and 28 NGT subjects. There was no difference in age and BMI between the two groups. The beta-cell function during Max-SU was 0.1, which was higher than 0.06 during Discont-SU (p<0.001) and also higher than 0.09 during 25%Max-SU (p=0.269). The beta-cell function during 25%Max-SU was higher than during Discont-SU (p<0.001). The beta-cell function of the NGT group was 0.34 and higher than during Max-SU (p<0.001). Fasting capillary blood glucose (FCBG) levels during Discont-SU (14.2±3.7 mmol/L) were higher than during 25%Max-SU (12.3±3.4 mmol/L) and during Max-SU (10.3±2.4 mmol/L) (p<0.05). In addition, the FCBG during Discont-SU was higher than that during 25%Max-SU (p<0.05). Conclusion: In T2DM patients who failed to achieve glycemic control with a combination of maximum dosages of metformin and SU, the beta-cell function declined compared to NGT subjects. However, the beta-cells were still responsive to SUs, which play a significant role in glycemic control.

Nonthionamide Drugs for the Treatment of Hyperthyroidism: From Present to Future.

Hyperthyroidism is a common endocrine disease. Although thionamide antithyroid drugs are the cornerstone of hyperthyroidism treatment, some patients cannot tolerate this drug class because of its serious side effects including agranulocytosis, hepatotoxicity, and vasculitis. Therefore, nonthionamide antithyroid drugs (NTADs) still have an important role in controlling hyperthyroidism in clinical practice. Furthermore, some situations such as thyroid storm or preoperative preparation require a rapid decrease in thyroid hormone by combination treatment with multiple classes of antithyroid drugs. NTADs include iodine-containing compounds, lithium carbonate, perchlorate, glucocorticoid, and cholestyramine. In this narrative review, we summarize the mechanisms of action, indications, dosages, and side effects of currently used NTADs for the treatment of hyperthyroidism. In addition, we also describe the state-of-the-art in future drugs under development including rituximab, small-molecule ligands (SMLs), and monoclonal antibodies with a thyroid-stimulating hormone receptor (TSHR) antagonist effect.

Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

Efficacy of Once Daily versus Divided Daily Administration of Low Daily Dosage (15 mg/Day) of Methimazole in the Induction of Euthyroidism in Graves' Hyperthyroidism: A Randomized Controlled Study.

BACKGROUND: Previous studies used unequal or high daily dosages of methimazole (MMI) to compare the efficacy of once daily dose regimen (OD-MMI) with that of divided daily doses regimen (DD-MMI) in inducing euthyroidism. OBJECTIVES: To compare the efficacy of OD-MMI to that of DD-MMI using low daily dosage of MMI in inducing euthyroidism. METHODS: Fifty patients with clinically nonsevere Graves' hyperthyroidism were randomized to be treated with 15 mg/day OD-MMI or 15 mg/day DD-MMI. RESULTS: 21 cases (84%) in OD-MMI and 23 cases (92%) in DD-MMI were eligible for analyses. During the treatment, there was no difference in baseline characteristics, serum FT3 and FT4 reductions, and cumulative rate of achieving euthyroidism (4.8% versus 4.3%, 28.6% versus 34.8%, 71.4% versus 82.6%, and 85.7% versus 87.0% at 2, 4, 8, and 12 weeks, resp.) between both regimens. Hypothyroidism developed in DD-MMI significantly more than in OD-MMI (17.4% versus 0%, p < 0.05). CONCLUSIONS: Treatment with MMI at a low daily dosage of 15 mg/day OD-MMI is as effective as DD-MMI in the reduction of serum thyroid hormone levels and induction of euthyroidism. The OD-MMI regimen is preferable to the DD-MMI regimen in the treatment of clinically nonsevere Graves' hyperthyroidism. This trial is registered with Thai Clinical Trials Registry: TCTR20170529001.

The Effect of English Language on Multiple Choice Question Scores of Thai Medical Students.

BACKGROUND: Universities in Thailand are preparing for Thailand's integration into the ASEAN Economic Community (AEC) by increasing the number of tests in English language. English language is not the native language of Thailand Differences in English language proficiency may affect scores among test-takers, even when subject knowledge among test-takers is comparable and may falsely represent the knowledge level of the test-taker. OBJECTIVE: To study the impact of English language multiple choice test questions on test scores of medical students. MATERIAL AND METHOD: The final examination of fourth-year medical students completing internal medicine rotation contains 120 multiple choice questions (MCQ). The languages used on the test are Thai and English at a ratio of 3:1. Individual scores of tests taken in both languages were collected and the effect of English language on MCQ was analyzed Individual MCQ scores were then compared with individual student English language proficiency and student grade point average (GPA). RESULTS: Two hundred ninety five fourth-year medical students were enrolled. The mean percentage of MCQ scores in Thai and English were significantly different (65.0 ± 8.4 and 56.5 ± 12.4, respectively, p < 0.001). The correlation between MCQ scores in Thai and English was fair (Spearman's correlation coefficient = 0.41, p < 0.001). Of 295 students, only 73 (24.7%) students scored higher when being tested in English than in Thai language. Students were classified into six grade categories (A, B+, B, C+, C, and D+), which cumulatively measured total internal medicine rotation performance score plus final examination score. MCQ scores from Thai language examination were more closely correlated with total course grades than were the scores from English language examination (Spearman's correlation coefficient = 0.73 (p < 0.001) and 0.53 (p < 0.001), respectively). The gap difference between MCQ scores in both languages was higher in borderline students than in the excellent student group (11.2 ± 11.2 and 7.1 ± 8.2, respectively, p < 0.001). Overall, average student English proficiency score was very high, at 3.71 ± 0.35 from a total of 4.00. Mean student GPA was 3.40 ± 0.33 from a possible 4.00. English language MCQ examination scores were more highly associated with GPA than with English language proficiency. CONCLUSION: The use of English language multiple choice question test may decrease scores of the fourth-year internal medicine post-rotation final examination, especially those of borderline students.

Non-insulinoma Pancreatogeneous Hypoglycemia Syndrome with False-Positive Somatostatin Receptor Scintigraphy: A Case Report and Review of Literature.

Non-insulinoma pancreatogeneous hypoglycemia syndrome (NIPHS) is a rare cause of hypoglycemia in adults. The cause of NIPHS is diffuse hyperinsulinism. As a result, computed tomography (CT) of pancreas, endoscopic pancreatic ultrasonography (EUS), and somatostatin receptor scintigraphy (SSRS), which are usually performed to locate an insulinoma, are not able to diagnose NIPHS. Moreover, SSRS can give a false-positive result. In this case report, we introduce a 22-year-old Thai woman who presented with fasting and postprandial hyperinsulinemic hypoglycemia. Accordingly, an insulinoma was suspected. She underwent several studies to locate the lesion. Pancreatic CT and EUS failed to locate a lesion; however, SSRS showed a faint focus of increased uptake at the pancreatic head. The suspected insulinoma was not identified during a first operation. Thereafter other diagnostic methods were performed in an effort to locate the suspected insulinoma, including selective arterial calcium stimulation test. The result of the selective arterial calcium stimulation test was negative. Intraoperative ultrasonography during a second operation also failed to locate a tumor. Finally, a pancreatic head resection was performed according to SSRS result, yet capillary blood glucose levels did not increase after resection. In response, a 95% pancreatectomy was performed. The pathology report was consistent with diffuse hyperinsulinism. This report emphasizes that SSRS can give false positive result in NIPHS.

Miniature short hairpin RNA screens to characterize antiproliferative drugs.

The application of new proteomics and genomics technologies support a view in which few drugs act solely by inhibiting a single cellular target. Indeed, drug activity is modulated by complex, often incompletely understood cellular mechanisms. Therefore, efforts to decipher mode of action through genetic perturbation such as RNAi typically yields "hits" that fall into several categories. Of particular interest to the present study, we aimed to characterize secondary activities of drugs on cells. Inhibiting a known target can result in clinically relevant synthetic phenotypes. In one scenario, drug perturbation could, for example, improperly activate a protein that normally inhibits a particular kinase. In other cases, additional, lower affinity targets can be inhibited as in the example of inhibition of c-Kit observed in Bcr-Abl-positive cells treated with Gleevec. Drug transport and metabolism also play an important role in the way any chemicals act within the cells. Finally, RNAi per se can also affect cell fitness by more general off-target effects, e.g., via the modulation of apoptosis or DNA damage repair. Regardless of the root cause of these unwanted effects, understanding the scope of a drug's activity and polypharmacology is essential for better understanding its mechanism(s) of action, and such information can guide development of improved therapies. We describe a rapid, cost-effective approach to characterize primary and secondary effects of small-molecules by using small-scale libraries of virally integrated short hairpin RNAs. We demonstrate this principle using a "minipool" composed of shRNAs that target the genes encoding the reported protein targets of approved drugs. Among the 28 known reported drug-target pairs, we successfully identify 40% of the targets described in the literature and uncover several unanticipated drug-target interactions based on drug-induced synthetic lethality. We provide a detailed protocol for performing such screens and for analyzing the data. This cost-effective approach to mammalian knockdown screens, combined with the increasing maturation of RNAi technology will expand the accessibility of similar approaches in academic settings.

Diagnostic biomarkers of differentiated thyroid cancer.

The incidence of thyroid cancer has been increasing all around the world in the past decades. Early detection is one of the keys to reduce the mortality. Currently, fine-needle aspiration (FNA) guides the management of patients with a thyroid nodule. The use of FNA can reduce unnecessary thyroid surgery by twenty-five percent. However, the prevalence of non-diagnostic and indeterminate cytology from FNA is still high, approximately thirty percent. Many biomarkers were developed to differentiate between the benign and malignant thyroid nodule. This review summarizes each diagnostic biomarker of differentiated thyroid cancer. Sensitivity, specificity, and positive and negative predictive values of individual cytological laboratory need to be considered before implementation of each biomarker. Moreover, follow-up is still mandatory in negative biomarker tests because all genomic and proteomic alterations in thyroid cancer are still unknown.

Immunohistochemical analysis based Ep-ICD subcellular localization index (ESLI) is a novel marker for metastatic papillary thyroid microcarcinoma.

BACKGROUND: Thyroid cancer is among the fastest growing malignancies; almost fifty-percent of these rapidly increasing incidence tumors are less than or equal to 1cm in size, termed papillary thyroid microcarcinoma (PTMC). The management of PTMC remains a controversy due to differing natural history of these patients. Epithelial cell adhesion molecule (EpCAM) is comprised of an extracellular domain (EpEx), a single transmembrane domain and an intracellular domain (Ep-ICD). Our group reported nuclear Ep-ICD correlated with poor prognosis in thyroid cancer (Ralhan et al., BMC Cancer 2010,10:331). Here in, we hypothesized nuclear and cytoplasmic accumulation of Ep-ICD and loss of membranous EpEx may aid in distinguishing metastatic from non-metastatic PTMC, which is an important current clinical challenge. To test our hypothesis, Ep-ICD and EpEx expression levels were analyzed in PTMC and the staining was correlated with metastatic potential of these carcinomas. METHODS: Thirty-six PTMC patients (tumor size 0.5 - 1cm; metastatic 8 cases and non-metastatic 28 cases) who underwent total thyroidectomy were selected. The metastatic group consisted of patients who developed lymph node or distant metastasis at diagnosis or during follow up. The patients' tissues were stained for Ep-ICD and EpEx using domain specific antibodies by immunohistochemistry and evaluated. RESULTS: PTMC patients with metastasis had higher scores for nuclear and cytoplasmic Ep-ICD immunostaining than the patients without metastasis (1.96 ± 0.86 vs. 1.22 ± 0.45; p = 0.007 and 5.37 ± 0.33 vs. 4.72 ± 1.07; p = 0.016, respectively). Concomitantly, the former had lower scores for membrane EpEx than the non-metastatic group (4.64 ± 1.08 vs. 5.64 ± 1.51; p = 0.026). An index of aggressiveness, Ep-ICD subcellular localization index (ESLI), was defined as sum of the IHC scores for accumulation of nuclear and cytoplasmic Ep-ICD and loss of membranous EpEx; ESLI = [Ep - ICDnuc + Ep - ICDcyt + loss of membranous EpEx]. Notably, ESLI correlated significantly with lymph node metastasis in PTMC (p = 0.008). CONCLUSION: Nuclear and cytoplasmic Ep-ICD expression and loss of membranous EpEx were found to correlate positively with metastasis in PTMC patients. In addition, ESLI had the potential to identify metastatic behavior in PTMC which could serve as a valuable tool for solving a current dilemma in clinical practice.

An Ep-ICD based index is a marker of aggressiveness and poor prognosis in thyroid carcinoma.

BACKGROUND: Nuclear accumulation of the intracellular domain of epithelial cell adhesion molecule (Ep-ICD) in tumor cells was demonstrated to predict poor prognosis in thyroid carcinoma patients in our earlier study. Here, we investigated the clinical significance of Ep-ICD subcellular localization index (ESLI) in distinguishing aggressive papillary thyroid carcinoma (PTC) from non-aggressive cases. METHODS: Using domain specific antibodies against the intracellular (Ep-ICD) and extracellular (EpEx) domains of epithelial cell adhesion molecule, 200 archived tissues from a new cohort of patients with benign thyroid disease as well as malignant aggressive and non aggressive PTC were analyzed by immunohistochemistry (IHC). ESLI was defined as sum of the IHC scores for accumulation of nuclear and cytoplasmic Ep-ICD and loss of membranous EpEx; ESLI = [Ep-ICD(nuc) + Ep-ICD(cyt) + loss of membranous EpEx]. RESULTS: For the benign thyroid tissues, non-aggressive PTC and aggressive PTC, the mean ESLI scores were 4.5, 6.7 and 11 respectively. Immunofluorescence double staining confirmed increased nuclear Ep-ICD accumulation and decreased membrane EpEx expression in aggressive PTC. Receiver-operating characteristic (ROC) curve analysis showed an area under the curve (AUC) of 0.841, 70.2% sensitivity and 83.9% specificity for nuclear Ep-ICD for differentiating aggressive PTC from non-aggressive PTC. ESLI distinguished aggressive PTC from non-aggressive cases with improved AUC of 0.924, 88.4% sensitivity and 85.5% specificity. Our study confirms nuclear accumulation of Ep-ICD and loss of membranous EpEx occurs in aggressive PTC underscoring the potential of Ep-ICD and ESLI to serve as diagnostic markers for aggressive PTC. Kaplan Meier survival analysis revealed significantly reduced disease free survival (DFS) for ESLI positive (cutoff >10) PTC (p<0.05), mean DFS=133 months as compared to 210 months for patients who did not show positive ESLI. CONCLUSION: ESLI scoring improves the identification of aggressive PTC and thereby may serve as a useful index for defining aggressiveness and poor prognosis among PTC patients.

Non-Hodgkin lymphoma with adrenal insufficiency: a case report and literature review.

A 62-year-old Thai man was admitted because of nausea and vomiting with incidentally detected bilateral adrenal enlargement. The basal cortisol was low and ACTH level was elevated CT guided percutaneous needle biopsy of adrenal gland showed a diffuse infiltration of medium to large atypical lymphoid cells of B-cell immunophenotype, which are diagnostic for a diffuse large B-cell lymphoma. Involvement by large B-cell lymphoma was documented in bone marrow biopsy as well. The findings confirmed the diagnosis of primary adrenal insufficiency caused by large B-cell lymphoma involving both adrenal glands.