Liang-Yu Lin

Assessment of Bilateral Inferior Petrosal Sinus Sampling (BIPSS) in the Diagnosis of Cushing's Disease

Background: The differential diagnosis of adrenocorticotropin (ACTH)‐dependent Cushings syndrome (CS) remains a challenging issue for clinical endocrinologists. In this respect, bilateral inferior petrosal sinus sampling (BIPSS) appears to be the most sensitive and specific test. Here, we report our 15‐year experience of analyzing the performance of BIPSS, both in the correct diagnosis and in the precise lateralization of tumors in patients with Cushings disease (CD). Methods: Between 1992 and 2006, 18 patients with CD (16 females, 2 males; age range, 14‐56 years) were admitted to Taipei Veterans General Hospital and subjected to BIPSS plus ovine corticotropin‐releasing hormone (oCRH) stimulation. Four of them had previously undergone transsphenoidal hypophysectomy (TSH) and had a recurrence thereafter. BIPSS was performed by inserting a catheter in the right and left inferior petrosal sinus for ACTH assay via a femoral vein puncture. An inferior petrosal sinus/peripheral ACTH ratio (C/P ratio) = 2 at baseline or = 3 after oCRH injection indicated a pituitary origin of ACTH secretion, and an interpetrosal ACTH gradient (IPS ratio) = 1.4 at baseline or after oCRH indicated evidence of lateralization. Results: Positive BIPSS results were found in 16 patients at baseline and in 17 patients after oCRH injection. In 17 out of 18 patients, TSH was subsequently carried out and a pituitary source was confirmed on histopathologic examination. The only 1 false‐negative test result was noted in a patient who had undergone previous TSH. Thus, the sensitivities of BIPSS for the diagnosis of CD before and after oCRH stimulation were 89% and 94%, respectively. Moreover, using an IPS ratio = 1.4 as a criterion, BIPSS correctly lateralized the tumor in 9 of 17 and 10 of 17 patients at baseline and after oCRH stimulation, respectively, including in 2 patients who had a centrally located tumor and who had an IPS ratio < 1.4. Thus, the sensitivities of lateralization of BIPSS were 53% and 59%, respectively. None of the 4 patients who had previous TSH were precisely localized by BIPSS. If these 4 patients were excluded, the sensitivities of BIPSS for localizing in the patients who had not undergone previous operation increased to 70% (9/13) at baseline and 77% (10/13) after oCRH stimulation, respectively. Conclusion: BIPSS combined with oCRH stimulation is a safe and reliable examination both in the differential diagnosis of CD and in the correct lateralization of pituitary microadenoma in patients without previous pituitary surgery. Nevertheless, this procedure may provide misleading results in patients who have received previous pituitary surgery.

Chronic Myeloid Leukemia After Treatment with 131I for Thyroid Carcinoma

A 27-year-old male developed Philadelphia chromosome-positive chronic myeloid leukemia (CML) 13 years after a first dose of radioiodine ( 131 I) therapy for papillary thyroid carcinoma. He had received a cumulative 131 I dose of 670 mCi, in 8 divided doses over 8 years, up to April 1998, for ablation of 131 I avid tissues over the anterior neck region. The leukemogenic potential of radioactive iodine has been pointed out by many authors, but most reported cases have been acute leukemias. A literature review disclosed only 9 cases similar to ours. At present, there is no evidence to prove whether the development of CML after thyroid carcinoma represents a treatment-induced complication, a coincidence, or an increased susceptibility to secondary malignancies due to the malignant process itself.

Fasting Plasma Lactate Concentrations in Ambulatory Elderly Patients With Type 2 Diabetes Receiving Metformin Therapy: A Retrospective Cross-sectional Study

Background: Metformin is a worldwide accepted biguanide antidiabetic agent, and its effectiveness and benefit have already been well established. Among the side effects of metformin, lactate acidosis is the most problematic because of a high mortality rate, which impedes its use in clinical practice, especially in elderly patients with type 2 diabetes. Aging is associated with a decreased renal function and increasing comorbidities, but few data are available regarding plasma lactate levels in this unique population. In this study, we assessed fasting plasma lactate levels in ambulatory, elderly Taiwanese patients with type 2 diabetes, who were taking the drug, metformin, to identify independent risk factors for hyperlactemia in this group. Methods: Sixty‐six ambulatory type 2 diabetic patients, > 80 years of age (mean, 83.6 years; range, 80‐90 years), receiving metformin therapy, were enrolled, from January 2005 to September 2009, in the Diabetes Case Management Program. A further 79 younger patients (also type 2 diabetics on metformin) served as controls (mean age, 59.9 years; range, 37‐79 years). Fasting serum electrolytes, creatinine, bicarbonate, glycated hemoglobin, plasma glucose and lactate levels were determined. Results: Lactate levels did not differ between the elderly and control groups (13.2 +/− 5.2 mg/dL and 13.5 +/− 4.8 mg/dL, respectively). None of the patients fulfilled the lactic acidosis criteria. Patients in the elderly group had a significantly lower daily metformin dose, higher creatinine levels, and lower estimated creatinine clearance, compared with the control group (all p < 0.05). Estimated creatinine clearance was negatively associated with lactate levels in the elderly group (p < 0.05, r = −0.27), but not in the control group. Patients with fasting plasma glucose levels > 130 mg/dL had a 2.8‐fold increased risk of developing hyperlactemia. Conclusion: Plasma lactate levels in ambulatory elderly patients with type 2 diabetes receiving metformin therapy did not differ from those in a younger age group. Patients with fasting plasma glucose levels > 130 mg/dL had a 2.8‐fold risk of developing hyperlactemia, but none of them developed lactate acidosis.

The Ankle Brachial Index Exhibits Better Association of Cardiovascular Prognosis Than Non-High-Density Lipoprotein Cholesterol in Type 2 Diabetes

Objective: The association between ankle brachial index (ABI) and outcomes in diabetic subjects is controversial. The purpose of this study was to evaluate whether the ABI is more strongly associated with cardiovascular outcomes comparing with non–high‐density lipoprotein cholesterol (non–HDL‐c). Research Design and Methods: A total of 452 type 2 diabetic subjects followed up for a mean of 5.8 years were grouped by ABI (<0.9 versus ≥0.9) and non–HDL‐c (<100 mg/dL versus ≥100 mg/dL). Primary outcomes were composite events including all‐cause mortality, hospitalization for coronary artery disease, stroke, revascularization, amputation and diabetic foot, and the secondary end point was all‐cause mortality. Results: Intergroup differences in percentage of men, duration of diabetes, hemoglobin A1c, total cholesterol, low‐density lipoprotein cholesterol, triglycerides and estimated glomerular filtration rate were significant. A total of 64 composite events and 17 deaths were recorded. A higher number of composite events occurred in the group with abnormal ABI but optimal non–HDL‐c than in those with suboptimal non–HDL‐c but normal ABI (29% versus 11%, P < 0.05). A similar trend was observed in all‐cause mortality (11% versus 1%, P < 0.05). The ABI was the dominant risk factor for both end points after adjusting other factors (for composite events, hazard ratio = 0.02, 95% CI: 0.00‐0.10, P < 0.001 and for all‐cause mortality, hazard ratio = 0.01, 95% CI: 0.00‐0.28, P = 0.006). Conclusions: The ABI was more strongly associated with outcomes in diabetes than non–HDL‐c. The ABI should be routinely screened in diabetes even without symptom.

A case of adrenal Cushing’s syndrome with bilateral adrenal masses

Summary A functional lesion in corticotrophin (ACTH)-independent Cushing’s syndrome is difficult to distinguish from lesions of bilateral adrenal masses. Methods for distinguishing these lesions include adrenal venous sampling and 131I-6β-iodomethyl-19-norcholesterol (131I-NP-59) scintigraphy. We present a case of a 29-year-old Han Chinese female patient with a history of hypercholesterolaemia and polycystic ovary syndrome. She presented with a 6month history of an 8kg body weight gain and gradual rounding of the face. Serial examinations revealed loss of circadian rhythm of cortisol, elevated urinary free-cortisol level and undetectable ACTH level (<5pg/mL). No suppression was observed in both the low- and high-dose dexamethasone suppression tests. Adrenal computed tomography revealed bilateral adrenal masses. Adrenal venous sampling was performed, and the right-to-left lateralisation ratio was 14.29. The finding from adrenal scintigraphy with NP-59 was consistent with right adrenal adenoma. The patient underwent laparoscopic right adrenalectomy, and the pathology report showed adrenocortical adenoma. Her postoperative cortisol level was 3.2μg/dL, and her Cushingoid appearance improved. In sum, both adrenal venous sampling and 131I-NP-59 scintigraphy are good diagnostic methods for Cushing’s syndrome presenting with bilateral adrenal masses. Learning points The clinical presentation of Cushing’ syndrome includes symptoms and signs of fat redistribution and protein-wasting features. The diagnosis of patients with ACTH-independent Cushing’s syndrome with bilateral adrenal masses is challenging for localisation of the lesion. Both adrenal venous sampling and 131I-NP-59 scintigraphy are good methods to use in these patients with Cushing’s syndrome presenting with bilateral adrenal masses.

The ankle brachial index is associated with prognosis in patients with diabetic kidney disease.

AIMS Peripheral arterial disease (PAD) could be an additional risk factor for the clinical outcomes in different populations. The purpose of this study was to evaluate the influence of PAD on patients with diabetic kidney disease. METHODS 362 persons with type 2 diabetes were followed-up for a mean 4.8 years grouped by ankle brachial index (ABI) (<0.9 vs. ≧0.9) and albuminuria (with or without). Primary and secondary outcomes were composite events (all-cause mortality, hospitalization for coronary artery disease, stroke, re-vascularization, amputation, and diabetic foot) and all-cause mortality. RESULTS Inter-group differences in duration of diabetes, glycated hemoglobin, creatinine, and estimated glomerular filtration rate were significant. During the follow-up period, 53 composite events were recorded (14.7%) and 13 (3.5%) individuals died. Subjects with albuminuria plus ABI<0.9 had higher risk of composite events than those with albuminuria but normal ABI (p<0.05). The only trend difference between the two groups was in all-cause mortality. Albuminuria plus ABI <0.9 was associated with risk of composite events (hazard ratio [HR] 4.20, 95% confidence interval [CI] 1.77-9.92, p=0.001) and all-cause mortality (HR 17.77, 95% CI 1.93-162.20, p=0.011). CONCLUSIONS PAD might be an additional risk factor for adverse outcomes in patients with diabetic kidney disease. Further prospective data are required to validate this conclusion.

Endocan expression is correlated with poor progression-free survival in patients with pancreatic neuroendocrine tumors

Abstract Endocan expression has been reported to be associated with aggressive tumor progression and poor outcomes in various cancers, such as breast cancer, renal cell cancer, lung cancer, gastric cancer, and pituitary adenomas. However, the prognostic significance of endocan in neuroendocrine tumors remains unknown. Thus, the aim of this study was to determine the correlation between endocan expression in pancreatic neuroendocrine tumor (PNET) tissues and progression-free survival. This study included 73 patients with confirmed PNETs who were treated in a single tertiary center in north Taiwan between 1992 and 2015. Immunohistochemical endocan expression and microvessel density (MVD) were examined, and the relationships between these parameters and other clinicopathological characteristics were analyzed. The abovementioned patients were divided into groups according to their endocan expression levels (≥1% or <1%) and median MVDs. Negative endocan expression (P = .002) and a high MVD (P < .001) were significant and favorable prognostic factors for progression-free survival. However, positive endocan expression was significantly associated with a low MVD (P = .037) and tumor mitosis (Ki-67 index) (P = .028). Multivariate Cox regression analysis showed that positive endocan expression (hazard ratio: 4.778, P = .018) and lymph node involvement (hazard ratio: 5.121, P = .005) were independent prognostic factors for tumor recurrence. In conclusion, endocan expression was correlated with poor clinical outcomes in PNETs. Our data indicated that endocan expression may be a reliable marker for predicting tumor recurrence in patients with PNETs.

Toxicities, safeties and clinical response of dacarbazine-based chemotherapy on neuroendocrine tumors in Taiwan population

Background: Currently, the role of dacarbazine (DTIC) based chemotherapy in neuroendocrine tumors (NETs) in Asia is unclear. Here, we report the outcomes of dacarbazine (DTIC)‐based chemotherapy in Taiwan population. Methods: DTIC alone (250 mg/m2/day), or 5‐fluorouracil (5‐FU, 500 mg/m2/day) and DTIC (200 mg/m2/day) with or without epirubicin (200 mg/m2/day), for 3 days, every 3–4 weeks. Subgroups were analyzed by grading, and by Ki‐67 index. Results: 48 patients were reviewed in this study, including 3 had grade 1 tumors, 23 had grade 2, while 22 were grade 3. In grade 3 NEC patients, the tumor Ki‐67 index of 21–55% were noted in 8 patients, and >55% in 14 patients. Progression‐free survival (PFS) was 5.1 months, and overall survival (OS) was 31.6 months. The PFS (in months) were 12.5 and 1.8 for patients with NETs and neuroendocrine carcinomas (NECs), respectively (p < 0.001). The OS were not reached and 5.9 months for patients with NETs and NECs, respectively (p = 0.001). Patients with NECs were divided into two groups, according to their Ki‐67 index. In patients with a tumor Ki‐67 index of 21–55%, PFS was 4.1 months, and OS was not reached; in those with a tumor Ki‐67 index of >55%, they were 1.5 and 1.8 months, respectively (p < 0.001 and p = 0.013). Conclusion: NETs, and grade 3 NECs, with Ki‐67 indices of 20–55% had good responses to DTIC‐based chemotherapy, with acceptable side effects. Ki‐67 index could predict prognosis for grade 3 NEC patients, and guide further chemotherapy choices.