Lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells.

Tumor-infiltrating myeloid cells (TIMs) are crucial cell populations involved in tumor immune escape, and their functions are regulated by multiple epigenetic mechanisms. The precise regulation mode of RNA N6-methyladenosine (m6A) modification in controlling TIM function is still poorly understood. Our study revealed that the increased expression of methyltransferase-like 3 (METTL3) in TIMs was correlated with the poor prognosis of colon cancer patients, and myeloid deficiency of METTL3 attenuated tumor growth in mice. METTL3 mediated m6A modification on Jak1 mRNA in TIMs, the m6A-YTHDF1 axis enhanced JAK1 protein translation efficiency and subsequent phosphorylation of STAT3. Lactate accumulated in tumor microenvironment potently induced METTL3 upregulation in TIMs via H3K18 lactylation. Interestingly, we identified two lactylation modification sites in the zinc-finger domain of METTL3, which was essential for METTL3 to capture target RNA. Our results emphasize the importance of lactylation-driven METTL3-mediated RNA m6A modification for promoting the immunosuppressive capacity of TIMs.

Early identification of postoperative remission for thyrotropin-secreting adenomas.

OBJECTIVE: Thyrotropin-secreting adenoma (TSHoma) is a rare type of pituitary adenoma, occurring in one per million people. Little is known about TSHoma. We summarized the demographic, clinical and hormonal characteristics of TSHoma based on a single-centre experience. Moreover, we explored the predictive value of postoperative thyroid function for long-term remission. DESIGN, PATIENTS AND MEASUREMENTS: We retrospectively analysed 63 patients who were diagnosed as TSHoma and surgically treated at our hospital from January 2015 to June 2021. The preoperative clinical characteristics were analysed and compared between remission and nonremission groups. Thyroid function was measured at 1 day, 1 month, 3 months, 6 months, 12 months and over 12 months after surgery to determine whether they could predict long-term remission. RESULTS: The male to female ratio for TSHoma was 1.25. The mean age at diagnosis was 45 ± 12 years. Clinical presentation was varied, presenting with hyperthyroidism (68.25%), space-occupying effect (15.87%), amenorrhea (7.14% of female patients) and nonsymptoms (22.22%). 88.14% of patients achieved postoperative endocrinological remission. Larger tumour size and tumour invasion into cavernous sinus and suprasellar with chiasmal compression were strong predictors of lower rates of endocrinological remission. Postoperative thyroid function at 3 months was a viable diagnostic predictor for postoperative remission, especially for FT4 level with a 20.65 pmol/L cutoff. CONCLUSIONS: Tumour size and extent are major prognostic factors for remission. Postoperative thyroid function at 3 months could be used as a clinical prediction tool for long-term endocrinological remission.

Clinical Characteristics of Adipsic Diabetes Insipidus.

OBJECTIVE: Adipsic diabetes insipidus (ADI) is a life-threatening disease. It is characterized by arginine vasopressin deficiency and thirst absence. Data about clinical characteristics of ADI were scarce. This study investigated the clinical features of hospitalized ADI patients. METHODS: A retrospective study was conducted of hospitalized ADI patients admitted to the Endocrinology Department of Huashan Hospital between January 2014 and December 2021, and compared with central diabetes insipidus (CDI) patients with normal thirst. RESULTS: During the study period, there were a total of 507 hospitalized CDI patients, among which 50 cases were ADI, accounting for 9.9%. Forty percent of ADI patients were admitted due to hypernatremia, but there were no admissions due to hypernatremia in the control group. The lesions of ADI patients were more likely to be located in the suprasellar area (100% vs 66%, P < .05). Higher prevalence of hypothalamic dysfunction (76% vs 8%, P < .001), central hypothyroidism (100% vs 90%, P = .031), hyperglycemia (66% vs 32%, P < .001), dyslipidemia (92% vs 71%, P = .006), and hyperuricemia (64% vs 37%, P = .003) was found in the ADI group than in the control group. The proportions of hypernatremia were higher in the ADI group both at admission and at discharge (90% vs 8%, 68% vs 8%, respectively, both with P < .001), contributing to higher prevalence of complications, such as renal insufficiency, venous thrombosis, and infection. CONCLUSION: ADI patients were found with higher prevalence of hypernatremia, hypopituitarism, hypothalamic dysfunction, metabolic disorders, and complications, posing a great challenge for comprehensive management.

Low-rank fusion convolutional neural network for prediction of remission after stereotactic radiosurgery in patients with acromegaly: a proof-of-concept study.

Artificial intelligence approaches to analyze pathological images (pathomic) for outcome prediction have not been sufficiently considered in the field of pituitary research. A total of 5,504 hematoxylin & eosin-stained pathology image tiles from 58 acromegalic patients with a good or poor outcome were integrated with other clinical and genetic information to train a low-rank fusion convolutional neural network (LFCNN). The model was externally validated in 1,536 patches from an external cohort. The primary outcome was the time to the first endocrine remission after stereotactic radiosurgery (SRS). The median time of initial endocrine remission was 43 months (interquartile range [IQR]: 13-60 months) after SRS, and the 24-month initial cumulative remission rate was 57.9% (IQR: 46.4-72.3%). The patient-wise accuracy of the LFCNN model in predicting the primary outcome was 92.9% in the internal test dataset, and the sensitivity and specificity were 87.5 and 100.0%, respectively. The LFCNN model was a strong predictor of initial cumulative remission in the training cohort (hazard ratio [HR] 9.58, 95% confidence interval [CI] 3.89-23.59; p < 0.001) and was higher than that of established prognostic markers. The predictive value of the LFCNN model was further validated in an external cohort (HR 9.06, 95% CI 1.14-72.25; p = 0.012). In this proof-of-concept study, clinically and genetically useful prognostic markers were integrated with digital images to predict endocrine outcomes after SRS in patients with active acromegaly. The model considerably outperformed established prognostic markers and can potentially be used by clinicians to improve decision-making regarding adjuvant treatment choices. © 2022 The Pathological Society of Great Britain and Ireland.

Contrast-enhanced 3D-T2-weighted SPACE sequence for MRI detection and localization of adrenocorticotropin (ACTH)-secreting pituitary microadenomas.

OBJECTIVE: Cushing disease is a potentially fatal endocrine disorder caused by adrenocorticotropin (ACTH)-secreting microadenomas in the pituitary gland. Accurate detection and localization of the adenomas is the key to clinical treatment. This study analysed the value of contrast-enhanced Sampling Perfection with Application-optimized Contrasts using different flip angle Evolutions (SPACE) sequence in magnetic resonance imaging (MRI) assessment of ACTH-secreting pituitary microadenomas. DESIGN AND PATIENTS: We carried out a retrospective study in which 45 patients with ACTH-secreting pituitary microadenomas were enrolled. Dynamic contrast-enhanced (DCE) coronal T1-SE sequence was performed. A contrast-enhanced coronal SPACE sequence was added immediately after DCE MRI finished. Two independent observers assessed the tumour existence and location, then the results were compared with surgical findings. RESULTS: Twenty-four lesions (53.3%) were detected by the DCE T1-SE sequence alone, while 35 lesions (80.0%) were detected with the addition of contrast-enhanced SPACE sequence. The sensitivity (58.5% vs. 85.3%; p < .05) and best diagnostic accuracy (62.0% vs. 84.4%; p < .05) were significantly better for addition with SPACE sequence than DCE-SE images alone in detection of ACTH-secreting pituitary microadenomas. For lesions <5 mm, the detected numbers were 4 (16.6%) versus 10 (27.8%) by DCE T1-SE sequence and combined DCE T1-SE with SPACE sequence. CONCLUSIONS: A combination of contrast-enhanced SPACE with DCE T1-SE sequence could improve the detection of ACTH-secreting pituitary microadenomas. Contrast-enhanced SPACE sequence could be a supplementary sequence for imaging of ACTH-secreting pituitary adenomas when T1-SE sequence provides negative or equivocal findings.

Effects of Long-Acting Somatostatin Analogues on Lipid Metabolism in Patients with Newly Diagnosed Acromegaly: A Retrospective Study of 120 Cases.

The short-term effects of long-acting somatostatin analogues (SSAs) on lipid profiles in patients with acromegaly are not well studied. We retrospectively analyzed the effects of SSAs on lipid profiles and associated cardiovascular risk factors in a cohort of 120 newly diagnosed acromegaly patients. In this study, 69 females and 51 males were included. These patients were treated with either octreotide LAR (OCT) or lanreotide SR (LAN) for 3 months. After SSAs treatment, both GH and IGF-1 significantly decreased (p<0.001). Triglyceride (TG), total to high-density lipoprotein cholesterol (HDL-C) ratio, and lipoprotein (a) [Lp(a)] levels were significantly decreased, while HDL-C levels were increased (p<0.05). The reduction of mean serum GH (GHm) was positively associated with the decrease of TG (r=0.305, p=0.001) and Lp(a) (r=0.257, p=0.005), as well as the increase of HDL-C (r=-0.355, p<0.001). The changes of lipid profiles were observed only in OCT group, but not in LAN group. In addition, systolic blood pressure (SBP) had significantly declined after SSAs treatment, with an average reduction of 4.4 mmHg (126.7±1.28 vs. 122.3±1.44 mmHg, p=0.003), while no change was observed regarding diastolic blood pressure (DBP) (p>0.05). Fasting insulin, fasting C-peptide, and HOMA-IR were significantly decreased after SSAs treatment. In conclusion, our current study revealed that short-term SSAs treatment improves lipid profiles and other cardiovascular risk factors in patients with acromegaly.

Radiomics analysis allows for precise prediction of silent corticotroph adenoma among non-functioning pituitary adenomas.

OBJECTIVE: To predict silent corticotroph adenomas (SCAs) among non-functioning pituitary adenomas preoperatively using noninvasive radiomics. METHODS: A total of 302 patients including 146 patients diagnosed with SCAs and 156 patients with non-SCAs were enrolled (training set: n = 242; test set: n = 60). Tumor segmentation was manually generated using ITK-SNAP. From T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and contrast-enhanced T1WI, 2550 radiomics features were extracted using Pyradiomics. Pearson's correlation coefficient values were calculated to exclude redundant features. Several machine learning algorithms were developed to predict SCAs incorporating the radiomics and semantic features including clinical, laboratory, and radiology-associated features. The performance of models was evaluated by AUC. RESULTS: Patients in the SCA group were younger (49.5 vs 55.2 years old) and more female (85.6% vs 37.2%) than those in the non-SCA group (p < 0.001). More invasiveness (p = 0.011) and cystic and microcystic change (p < 0.001) were observed in patients with SCAs. The ensemble algorithm presented the largest AUC of 0.927 among all the algorithms trained in the test set, and the accuracy, specificity, and sensitivity of predicting SCAs were all 0.867 (at cut-off 0.5). The overall model performed better than that only using semantic features available in the clinic. Radiomics prediction was the most important feature, with gender ranking second and age ranking third. Radiomics features on T2WI were superior to those on other MR modalities in SCA prediction. CONCLUSION: Our ensemble learning model outperformed current clinical practice in differentiating patients with SCAs and non-SCAs using radiomics, which might help make appropriate treatment strategies. KEY POINTS: • Radiomics might improve the preoperative diagnosis of SCAs by MR images. • T2WI was superior to T1WI and CE-T1WI in the preoperative diagnosis of SCAs. • The ensemble machine learning model outperformed current clinical practice in SCAs diagnosis and treatment decision-making could be more individualised using the nomogram.

Establishment of reference intervals of monomeric prolactin to identify macroprolactinemia in Chinese patients with increased total prolactin.

BACKGROUND: Macroprolactin is responsible for pseudohyperprolactinemia and is a common pitfall of the prolactin immunoassay. We aimed to determine the frequency of macroprolactinemia in Chinese hyperprolactinemic patients using monomeric prolactin discriminated by precipitation with polyethylene glycol (PEG). METHODS: Post-PEG monomeric prolactin gender-specific reference intervals were established for the Elecsys immunoassay method (Roche Diagnostics) using sera from healthy female (n = 120) and male (n = 120) donors. The reference intervals were validated using 20 macroprolactinemic (as assessed by gel filtration chromatography (GFC)) sera samples, and presence of monomeric prolactin was discriminated by GFC. Patients with high total prolactin were then screened by PEG precipitation to analyze macroprolactin. The demographic and biochemical details of patients with true hyperprolactinemia and macroprolactinemia were compared. RESULTS: Reference intervals for monomeric prolactin in females and males were 3.4-18.5 and 2.7-13.1 ng/mL, respectively. Among 1140 hyperprolactinemic patients, macroprolactinemia was identified in 261 (22.9 %) patients while the other 879 (77.1 %) patients were diagnosed with true hyperprolactinemia. Menstrual disturbances were the most common clinical feature in both groups. Galactorrhea, amenorrhea, and visual disturbances occurred more frequently in true hyperprolactinemic patients (P < 0.05). CONCLUSIONS: The prevalence of macroprolactin in Chinese patients with hyperprolactinemia was described for the first time. Monomeric prolactin concentration, along with a reference interval screening with PEG precipitation, provides a diagnostic approach for hyperprolactinemia with improved accuracy.

Machine learning in predicting early remission in patients after surgical treatment of acromegaly: a multicenter study.

PURPOSE: Accurate prediction of postoperative remission is beneficial for effective patient-physician communication in acromegalic patients. This study aims to train and validate machine learning prediction models for early endocrine remission of acromegalic patients. METHODS: The training cohort included 833 patients with growth hormone (GH) secreting pituitary adenoma from 2010 to 2018. We trained a partial model (only using pre-operative variables) and a full model (using all variables) to predict off-medication endocrine remission at six-month follow-up after surgery using multiple algorithms. The models were validated in 99 prospectively collected patients from a second campus and 52 patients from a third institution. RESULTS: C-statistic and the accuracy of the best partial model was 0.803 (95% CI 0.757-0.849) and 72.5% (95% CI 67.6-77.5%), respectively. C-statistic and the accuracy of the best full model was 0.888 (95% CI 0.861-0.914) and 80.3% (95% CI 77.5-83.1%), respectively. The c-statistics (and accuracy) of using only Knosp grade, total resection, or postoperative day 1 GH level as the single predictor were lower than our partial model or full model (p < 0.001). C-statistics remained similar in the prospective cohort (partial model 0.798, and full model 0.903) and in the external cohort (partial model 0.771, and full model 0.871). A web-based application integrated with the trained models was published at  https://deepvep.shinyapps.io/Acropred/ . CONCLUSION: We developed and validated interpretable and applicable machine learning models to predict early endocrine remission after surgical resection of a GH-secreting pituitary adenoma. Predication accuracy of the trained models were better than those using single variables.

Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas.

Pituitary adenoma (PA) is one of the most common intracranial neoplasms. Several genetic predisposing factors for PA have been identified, but they account for a small portion of cases. In this study, we sought to identify the PA genetic risk factors by focusing on causative mutations for PAs. Among the 4 affected and 17 asymptomatic members from one family with familial PA, whole-exome sequencing identified cosegregation of the PA phenotype with the heterozygous missense mutation c.4136G>T (p.Arg1379Leu) in cadherin-related 23 (CDH23). This mutation causes an amino acid substitution in the calcium-binding motif of the extracellular cadherin (EC) domains of CDH23 and is predicted to impair cell-cell adhesion. Genomic screening in a total of 12 families with familial PA (20 individuals), 125 individuals with sporadic PA, and 260 control individuals showed that 33% of the families with familial PA (4/12) and 12% of individuals with sporadic PA (15/125) harbored functional CDH23 variants. In contrast, 0.8% of the healthy control individuals (2/260) carried functional CDH23 variants. Gene-based analysis also revealed a significant association between CDH23 genotype and PA (p = 5.54 × 10-7). Moreover, PA individuals who did not harbor functional CDH23 variants displayed tumors that were larger in size (p = 0.005) and more invasive (p < 0.001). Therefore, mutations in CDH23 are linked with familial and sporadic PA and could play important roles in the pathogenesis of PA.

Pituitary Dysfunction in Patients with Intracranial Germ Cell Tumors Treated with Radiotherapy.

OBJECTIVE: To evaluate the endocrine abnormalities in intracranial germ cell tumors (iGCTs) treated with radio-therapy (RT), and to discuss the effects of RT on pituitary functions. METHODS: Seventy-seven patients diagnosed with iGCTs who had received RT and endocrine follow-up in Huashan Hospital between January 2010 and July 2017 were retrospectively analyzed, consisting of 49 germinomas and 28 NGGCTs. The median follow-up period was 50.0 months. Fifty-one patients had radiologically proved suprasellar/sellar lesions. RESULTS: The male to female ratio was 62/15. The median endocrine follow-up period was 19 (4, 42) months. The median age at the last endocrine visit was 18 (16, 20) years old. The 5-year overall and recurrence-free survival were both 98.7%. The overall prevalence of central adrenal insufficiency (CAI), central hypothyroidism (CHT), central hypogonadism (CHG), hyperprolactinemia, and central diabetes insipidus (CDI) was 57.3%, 56%, 56.6%, 35.3%, and 52.1%, respectively, after RT. Patients having suprasellar/sellar lesions showed significantly higher post-therapeutic prevalence of hypopituitarism than those who didn't. Compared to that before RT, CAI, CHT, and CHG weren't significantly improved while the levels of prolactin and the prevalence of CDI declined significantly (P =.03 and.001). The radiation doses to pituitary and hypothalamus between those with and without CAI, CHT, and CHG weren't significantly different. CONCLUSION: The prevalence of hypopituitarism was high in iGCTs, especially in those with suprasellar/sellar involvement. The levels of prolactin and the prevalence of CDI declined significantly after RT. The hypopituitarism in iGCTs was mainly induced by tumor effects, and RT showed no additional damage to pituitary functions in our study. ABBREVIATIONS: AFP = alpha-fetoprotein; CAI = central adrenal insufficiency; CDI = central diabetes insipidus; CHG = central hypogonadism; CHT = central hypothyroidism; CT = computed tomography; DA = dopamine; GH = growth hormone; ßHCG = beta-human chorionic gonadotropin; HPA = hypothalamus-pituitary-adrenal; HPG = hypothalamus-pituitary-gonadal; HPL = hyperprolactinemia; HPT = hypothalamus-pituitary-thyroid; iGCT = intracranial germ cell tumor; IGF-1 = insulin-like growth factor 1; NGGCT = nongerminomatous germ cell tumors; OS = overall survival; PFS = progression-free survival; PRL = hypothalamus-pituitary-prolactin; RT = radiotherapy.

Surgical outcomes and multidisciplinary management strategy of Cushing's disease: a single-center experience in China.

OBJECTIVE: The primary aim of this study was to investigate the value of multidisciplinary team (MDT) management in treating patients with Cushing's disease (CD). The secondary aim was to assess the concordance of bilateral inferior petrosal sinus sampling (BIPSS) lateralization with intraoperative observations. METHODS: The authors recruited 124 consecutive patients (128 procedures) who had undergone endoscopic endonasal resection of adrenocorticotropic hormone-secreting pituitary adenomas from May 2014 to April 2018 and assessed their clinical characteristics, surgical outcomes, and adjuvant therapies. The criteria for surgical remission were normalized serum and urinary cortisol levels, which could be suppressed by a low-dose dexamethasone suppression test at 3-months' follow-up without adjuvant treatment. RESULTS: The remission rates of the 113 patients with long-term follow-up (20.3 ± 12.2 months) were 83.2% after surgery alone and 91.2% after adjuvant therapy. The surgical remission rates of macroadenomas, MRI-visible microadenomas, and MRI-negative tumors were 66.7% (12/18), 89.3% (67/75), and 75% (15/20), respectively (p = 0.039). The surgical remission rates had a trend of improvement during the study period (87.5% in 2017-2018 vs 76.5% in 2014, p = 0.517). Multivariate regression analysis showed that a history of previous pituitary surgery (OR 0.300, 95% CI 0.100-0.903; p = 0.032) and MRI-visible microadenoma (OR 3.048, 95% CI 1.030-9.019; p = 0.044) were independent factors influencing surgical remission. The recurrence rate was 3.2% after a mean of 18 months after surgery. The remission rate of postoperative MDT management in patients with persistent disease was higher than non-MDT management (66.7% vs 0%, p = 0.033). In cases with preoperative BIPSS lateralization, 84.6% (44/52) were concordant with intraoperative findings. CONCLUSIONS: MRI-visible microadenoma and primary surgery were independent predictors of surgical remission in CD. The MDT management strategy helps to achieve a better overall outcome. BIPSS may help to lateralize the tumor in MRI-negative/equivocal microadenomas.

Platelets Express Activated P2Y12 Receptor in Patients With Diabetes Mellitus.

BACKGROUND: Platelets from patients with diabetes mellitus are hyperactive. Hyperactivated platelets may contribute to cardiovascular complications and inadequate responses to antiplatelet agents in the setting of diabetes mellitus. However, the underlying mechanism of hyperactivated platelets is not completely understood. METHODS: We measured P2Y12 expression on platelets from patients with type 2 diabetes mellitus and on platelets from rats with diabetes mellitus. We also assayed platelet P2Y12 activation by measuring cAMP and VASP phosphorylation. The antiplatelet and antithrombotic effects of AR-C78511 and cangrelor were compared in rats. Finally, we explored the role of the nuclear factor-κB pathway in regulating P2Y12 receptor expression in megakaryocytes. RESULTS: Platelet P2Y12 levels are 4-fold higher in patients with type 2 diabetes mellitus compared with healthy subjects. P2Y12 expression correlates with ADP-induced platelet aggregation (r=0.89, P<0.01). P2Y12 in platelets from patients with diabetes mellitus is constitutively activated. Although both AR-C78511, a potent P2Y12 inverse agonist, and cangrelor have similar antiplatelet efficacy on platelets from healthy subjects, AR-C78511 exhibits more powerful antiplatelet effects on diabetic platelets than cangrelor (aggregation ratio 36±3% versus 49±5%, respectively, P<0.05). Using a FeCl3-injury mesenteric arteriole thrombosis model in rats and an arteriovenous shunt thrombosis model in rats, we found that the inverse agonist AR-C78511 has greater antithrombotic effects on GK rats with diabetes mellitus than cangrelor (thrombus weight 4.9±0.3 mg versus 8.3±0.4 mg, respectively, P<0.01). We also found that a pathway involving high glucose-reactive oxygen species-nuclear factor-κB increases platelet P2Y12 receptor expression in diabetes mellitus. CONCLUSIONS: Platelet P2Y12 receptor expression is significantly increased and the receptor is constitutively activated in patients with type 2 diabetes mellitus, which contributes to platelet hyperactivity and limits antiplatelet drug efficacy in type 2 diabetes mellitus.

Magnetic Resonance Imaging Features of Solitary Hypothalamitis.

OBJECTIVE: The study aimed to characterize magnetic resonance imaging (MRI) findings of solitary hypothalamitis and evaluate their clinical value in diagnosis. METHODS: Magnetic resonance imaging scans, including T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and contrast-enhanced T1-weighted sequences, of 8 biopsy-proven hypothalamitis lesions were retrospectively analyzed along with MRI features including size, shape, signal intensity, enhancement pattern, correlation with adjacent tissues, and changes in infundibular stalk and sella turcica. RESULTS: Of 8 patients, 5 were diagnosed with lymphoplasmacytic proliferative inflammation, 2 with Langerhans cell histocytosis, and 1 with Rosai-Dorfman disease. Solitary hypothalamitis predominantly demonstrated mild hypointensity/isointensity in T1WI and mild hyperintensity in T2-weighted imaging. In contrast-enhanced T1WI, all lesions showed heterogeneous but primarily peripheral enhancement patterns. Seven cases showed the polygon sign. In T1WI, the normal high signal intensity of neurohypophysis was absent from all patients, with no infundibular stalk thickening. Seven patients presented with optic chiasma edema, and 5 with edema-like changes along the optic tract (OTE), but most showed no visual impairment (n = 7). CONCLUSIONS: Magnetic resonance imaging, particularly postcontrast MRI, is the optimal modality for assessment of hypothalamic lesions. Peripheral enhancement with polygon sign and optic tract or chiasm edema without visual impairment are highly suggestive of hypothalamitis.

Predictive value of T2 relative signal intensity for response to somatostatin analogs in newly diagnosed acromegaly.

INTRODUCTION: The difficulty of predicting the efficacy of somatostatin analogs (SSA) is not fully resolved. Here, we quantitatively evaluated the predictive value of relative signal intensity (rSI) on T1- and T2-weighted magnetic resonance imaging (MRI) for the short-term efficacy (3 months) of SSA therapy in patients with active acromegaly and assessed the correlation between MRI rSI and expression of somatostatin receptors (SSTR). METHODS: This was a retrospective review of prospectively recorded data. Ninety-two newly diagnosed patients (37 males and 55 females) with active acromegaly were recruited. All patients were treated with pre-surgical SSA, followed by reassessment and transspenoidal surgery. rSI values were generated by calculating the ratio of SI in the tumor to the SI of normal frontal white matter. The Youden indices were calculated to determine the optimal cutoff of rSI to determine the efficacy of SSA. The correlation between rSI and expression of SSTR2/5 was analyzed by the Spearman rank correlation coefficient. RESULTS: T2 rSI was strongly correlated with biochemical sensitivity to SSA. The cutoff value of T2 rSI to distinguish biochemical sensitivity was 1.205, with a positive predictive value (PPV) of 81.5 % and a negative predictive value (NPV) of 77.3 %. No correlation was found between MRI and tumor size sensitivity. Moreover, T2 rSI was negatively correlated with the expression of SSTR5. CONCLUSION: T2 rSI correlates with the expression of SSTR5 and quantitatively predicts the biochemical efficacy of SSA in acromegaly.

The value of an acute octreotide suppression test in predicting short-term efficacy of somatostatin analogues in acromegaly.

Predicting the efficacy of long-acting somatostatin analogues (SSA) remains a challenge. We aim to quantitatively evaluate the predictive value of the octreotide suppression test (OST) in short-term efficacy of SSA in active acromegaly. Sixty-seven newly diagnosed acromegaly patients were assessed with OST. Subsequently, all patients were treated with long-acting SSA for 3 months, followed by reassessment. Nine parameters were tested, including GHn (the nadir GH during OST), ΔGH1 (= [GH0h-GHn]/GH0h, GH0h was the baseline GH during OST), ΔGH2 (= [GHm-GHn]/GHm, GHm was the mean GH on day curve), AUC(0-6h) (the GH area under the curve during OST) , ΔAUC1 (= [GH0h-AUC(0-6h)]/GH0h), ΔAUC2 (=[GHm-AUC(0-6h)]/GHm), AUC(m-6h) (the GH AUC during OST where GHm was used instead of GH0h), ΔAUC1' (=[GH0h-AUC(m-6h)]/GH0h) and ΔAUC2' (=[GHm-AUC(m-6h)]/GHm). The Youden indices were calculated to determine the optimal cutoffs to predict the short-term efficacy of SSA. ΔGH2 more than 86.83%, ΔAUC2 more than -57.48% and ΔAUC2' more than -57.98% provided the best predictors of a good GH response (sensitivity 93.8%, specificity 85.7%). ΔGH2 more than 90.51% provided the best predictor of a good tumor size response (sensitivity 84.8%, specificity 87.5%). The percentage fall of GHn (ΔGH) was a better predictive parameter than GHn. OST showed higher efficiency in predicting the efficacy of octreotide LAR than lanreotide SR. In conclusion, OST is a valid tool to predict both GH and tumor size response to short-term efficacy of SSA in acromegaly, especially for octreotide LAR. GHm is better to be used as basal GH than GH0 during OST.

Association between the clinical classification of hypothyroidism and reduced TSH in LT4 supplemental replacement treatment for pregnancy in China.

The study was aimed to evaluate the effects of levothyroxine (LT4) supplemental replacement treatment for pregnancy and analyze the associations between the clinical classification of hypothyroidism and reduced thyroid-stimulating hormone (TSH) in LT4 therapy. Totally, 195 pregnant women with hypothyroidism receiving routine prenatal care were enrolled. They were categorized into three groups: overt hypothyroidism (OH), subclinical hypothyroidism (SCH) with negative thyroperoxidase antibody (TPOAb), and SCH with positive TPOAb. The association between the clinical classification and reduced TSH in LT4 supplemental replacement treatment was assessed. The results indicated that reduced TSH was significantly different among the groups according to the clinical classifications (p = 0.043). The result was also significantly different between patients with OH and patients with SCH and negative TPOAb (p = 0.036). Similar result was reported for the comparison between patients with OH and patients with SCH and positive TPOAb (p = 0.016). Multiple variable analyses showed that LT4 supplementation, gestational age and the variable of clinical classifications were associated with reduced TSH independently. Our data suggested that the therapeutic effect of substitutive treatment with LT4 was significantly associated with different clinical classifications of hypothyroidism in pregnancy and the treatment should begin as soon as possible after diagnosis.

The Diagnostic Value of Neuropathy Symptom and Change Score, Neuropathy Impairment Score and Michigan Neuropathy Screening Instrument for Diabetic Peripheral Neuropathy.

AIMS: This study aims to evaluate the diagnostic capabilities of neuropathy symptom and change (NSC) score, neuropathy impairment score (NIS) and Michigan neuropathy screening instrument (MNSI) in diagnosing diabetic peripheral neuropathy (DPN). METHODS: A total of 131 patients with type II diabetes received NSC, NIS and MNSI scoring systems. Electromyography/nerve conduction velocity (EMG/NCV) test was taken as gold standard. Correlations between EMG/NCV test and the 3 scorings, and their sensitivity, specificity, positive and negative predictive values, accuracy and kappa (x03BA;) value were analyzed. RESULTS: The prevalence of DPN was 43.5% according to EMG/NCV findings. EMG/NCV test was significantly positive correlated with all the 3 scorings, highest with NIS scoring (r = 0.653, p < 0.001). Compared with EMG/NCV test, NSC score was most sensitive (85.96%) but least specific (77.03%); NIS score had lower sensitivity (59.65%) but best specificity (98.65%) and accuracy (81.68%). Both had high concordance with EMG/NCV test (x03BA; = 0.61). Sensitivity, specificity and accuracy of MNSI were highest (70.18, 98.65 and 80.15%) at the cutoff values of >1.0, >2.5 and >1.5, respectively (x03BA; = 0.58). CONCLUSIONS: Both NSC and NIS were accurate and reliable diagnostic methods for DPN. The combined application of NSC and NIS was recommended in DPN diagnosis.

Chronic intermittent hypoxia leads to insulin resistance and impaired glucose tolerance through dysregulation of adipokines in non-obese rats.

BACKGROUND AND OBJECTIVES: The aim of this study was to determine whether chronic intermittent hypoxia (CIH) could affect the secretion of adipokines, such as resistin, leptin, and adiponectin, in non-obese rats and to investigate the potential mechanisms. METHODS: An established rodent model of CIH was utilized, in which rats were exposed to varying oxygen levels (7-21 %) respectively over a period of 5 weeks. The area under the curve (AUCG) and the insulin resistance index (homeostasis model of assessment for insulin resistance index, HOMA-IR) were calculated. The levels of several secretory factors in the blood were measured by enzyme-linked immunosorbent assay (ELISA). The mRNA levels and protein expression in adipose tissues was measured by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Glucose tolerance and the levels of adiponectin in non-obese rats were decreased in the CIH group both in the serum and adipose tissue compared with the controls, while the insulin resistance index and the levels of resistin and leptin were increased. Moreover, the expressions of hypoxia inducible factor-1α and lactate dehydrogenase A were significantly higher in chronic intermittent hypoxia rats than in control rats, suggesting the presence of adipose tissue hypoxia. CONCLUSIONS: These results show that CIH leads to insulin resistance (IR) and impaired glucose tolerance (IGT) in a non-obese rodent model of obstructive sleep apnea-hypopnea syndrome, and these effects may be due to the dysregulation of adiponectin, resistin, and leptin.