Rapamycin Attenuates Splenomegaly in both Intrahepatic and Prehepatic Portal Hypertensive Rats by Blocking mTOR Signaling Pathway.

BACKGROUND:Spleen enlargement is often detected in patients with liver cirrhosis, but the precise pathogenetic mechanisms behind the phenomenon have not been clearly elucidated. We investigated the pathogenetic mechanisms of splenomegaly in both portal hypertensive patients and rats, and tried to identify the possible therapy for this disease. METHODS:Spleen samples were collected from portal hypertensive patients after splenectomy. Rat models of portal hypertension were induced by common bile duct ligation and partial portal vein ligation. Spleen samples from patients and rats were used to study the characteristics of splenomegaly by histological, immunohistochemical, and western blot analyses. Rapamycin or vehicle was administered to rats to determine the contribution of mTOR signaling pathway in the development of splenomegaly. RESULTS:We found that not only spleen congestion, but also increasing angiogenesis, fibrogenesis, inflammation and proliferation of splenic lymphoid tissue contributed to the development of splenomegaly in portal hypertensive patients and rats. Intriguingly, splenomegaly developed time-dependently in portal hypertensive rat that accompanied with progressive activation of mTOR signaling pathway. mTOR blockade by rapamycin profoundly ameliorated splenomegaly by limiting lymphocytes proliferation, angiogenesis, fibrogenesis and inflammation as well as decreasing portal pressure. CONCLUSIONS:This study provides compelling evidence indicating that mTOR signaling activation pathway plays a key role in the pathogenesis of splenomegaly in both portal hypertensive patients and rats. Therapeutic intervention targeting mTOR could be a promising strategy for patients with portal hypertension and splenomegaly

Outcomes of Surgical Treatment for Graves’ Disease: A Single-Center Experience of 216 Cases

Background: The role of surgery in the treatment of Graves’ disease (GD) needs to be revisited. The aims of the present retrospective study were to evaluate the outcomes of the current surgical strategy as a definitive treatment of GD at our center and to explore the clinical association between GD and thyroid cancer. Methods: A patient cohort of 216 cases from 2013 to 2020 was involved in this retrospective study. The data of the clinical characteristics and follow-up results were collected and analyzed. Results: There were 182 female and 34 male patients. The mean age was 43.9 ± 15.0 years old. The mean duration of GD reached 72.2 ± 92.7 months. Of the 216 cases, 211 had been treated with antithyroid drugs (ATDs) and hyperthyroidism had been completely controlled in 198 cases. A total (75%) or near-total (23.6%) thyroidectomy was performed. Intraoperative neural monitoring (IONM) was applied to 37 patients. The failure of ATD therapy (52.3%) was the most common surgical indication, followed by suspicion of a malignant nodule (45.8%). A total of 24 (11.1%) patients had hoarseness after the operation and 15 (6.9%) patients had transient vocal cord paralysis; 3 (1.4%) had this problem permanently. No bilateral RLN paralysis occurred. A total of 45 patients had hypoparathyroidism and 42 of them recovered within 6 months. Sex showed a correlation with hypoparathyroidism through a univariate analysis. A total of 2 (0.9%) patients underwent a reoperation because of hematomas. A total of 104 (48.1%) cases were diagnosed as thyroid cancer. In most cases (72.1%), the malignant nodules were microcarcinomas. A total of 38 patients had a central compartment node metastasis. A lateral lymph node metastasis occurred in 10 patients. Thyroid carcinomas were incidentally discovered in the specimens of 7 cases. The patients with concomitant thyroid cancer had a significant difference in body mass index, duration of GD, gland size, thyrotropin receptor antibodies and nodule(s) detected. Conclusion: Surgical treatments for GD were effective, with a relatively low incidence of complications at this high-volume center. Concomitant thyroid cancer is one of the most important surgical indications for GD patients. Careful ultrasonic screening is necessary to exclude the presence of malignancies and to determine the therapeutic plan

Outcomes of Surgical Treatment for Graves’ Disease: A Single-Center Experience of 216 Cases

Background: The role of surgery in the treatment of Graves’ disease (GD) needs to be revisited. The aims of the present retrospective study were to evaluate the outcomes of the current surgical strategy as a definitive treatment of GD at our center and to explore the clinical association between GD and thyroid cancer. Methods: A patient cohort of 216 cases from 2013 to 2020 was involved in this retrospective study. The data of the clinical characteristics and follow-up results were collected and analyzed. Results: There were 182 female and 34 male patients. The mean age was 43.9 ± 15.0 years old. The mean duration of GD reached 72.2 ± 92.7 months. Of the 216 cases, 211 had been treated with antithyroid drugs (ATDs) and hyperthyroidism had been completely controlled in 198 cases. A total (75%) or near-total (23.6%) thyroidectomy was performed. Intraoperative neural monitoring (IONM) was applied to 37 patients. The failure of ATD therapy (52.3%) was the most common surgical indication, followed by suspicion of a malignant nodule (45.8%). A total of 24 (11.1%) patients had hoarseness after the operation and 15 (6.9%) patients had transient vocal cord paralysis; 3 (1.4%) had this problem permanently. No bilateral RLN paralysis occurred. A total of 45 patients had hypoparathyroidism and 42 of them recovered within 6 months. Sex showed a correlation with hypoparathyroidism through a univariate analysis. A total of 2 (0.9%) patients underwent a reoperation because of hematomas. A total of 104 (48.1%) cases were diagnosed as thyroid cancer. In most cases (72.1%), the malignant nodules were microcarcinomas. A total of 38 patients had a central compartment node metastasis. A lateral lymph node metastasis occurred in 10 patients. Thyroid carcinomas were incidentally discovered in the specimens of 7 cases. The patients with concomitant thyroid cancer had a significant difference in body mass index, duration of GD, gland size, thyrotropin receptor antibodies and nodule(s) detected. Conclusion: Surgical treatments for GD were effective, with a relatively low incidence of complications at this high-volume center. Concomitant thyroid cancer is one of the most important surgical indications for GD patients. Careful ultrasonic screening is necessary to exclude the presence of malignancies and to determine the therapeutic plan

Pathophysiology characteristic and mTOR signaling expression profile in spleens of portal hypertensive patients.

<p>(A) Representative images of spleen tissues stained with H&E showing white pulp (WP) and red pulp (RP), and immunostained for Ki67 or α-SMA (original magnification ×40). The image in the middle right is a magnified view of the region in the frame. (B) and (C) Quantitative analysis of white pulp occupied area and Ki67- and α-SMA-positive area. (D) Representative images of western blot for mTOR down-stream effectors and quantification of protein expression relative to their total protein. *<i>p</i><0.05 versus NON-PHT group, **<i>p</i><0.01 versus NON-PHT group, ***<i>p</i><0.001 versus NON-PHT group.</p

Effects of rapamycin on splenomegaly of portal hypertensive rats.

<p>(A) Representative images of western blot and quantification of protein expression relative to their total protein for mTOR down-stream effectors in rat spleens. (B) Portal pressure. (C) Representative spleen images. (D) Quantitative analysis of relative spleen weight. *: <i>p</i><0.05 versus SHAM-VEH, **: <i>p</i><0.05 versus BDL-VEH, ***: <i>p</i><0.05 versus PPVL-VEH.</p

Effects of rapamycin on the splenic lymphoid tissue in portal hypertensive rats.

<p>(A) Representative histological images of spleen tissues stained with H&E (original magnification ×40) and immunostained for Ki67 (original magnification ×100). Arrowheads point to Ki67-positive cells. (B) Representative images of western blot for caspase 3 and caspase 7. (C) Quantitative analysis of white pulp occupied area and Ki67-positive cells area to white pulp area. (D) Quantification of cleaved caspase 3 and caspase 7 protein expression relative to GAPDH. *: <i>p</i><0.05 versus SHAM-VEH, **: <i>p</i><0.05 versus BDL-VEH, ***: <i>p</i><0.05 versus PPVL-VEH.</p

Effects of rapamycin on angiogenesis of splenic red pulp in portal hypertensive rats.

<p>(A) Representative images of western blot for VEGF and α-SMA. (B) Quantification of VEGF and α-SMA protein expression relative to GAPDH. (C) Representative histological images of spleen tissues immunostained for α-SMA and Ki67 (original magnification ×40). Arrowheads point to α-SMA- and Ki67-positive cells. (D) Quantitative analysis of α-SMA and Ki67-positive cells area. *: <i>p</i><0.05 versus SHAM-VEH, **: <i>p</i><0.05 versus BDL-VEH, ***: <i>p</i><0.05 versus PPVL-VEH.</p

Learning curve of trans‐areola single‐site endoscopic thyroidectomy in a high‐volume center: A CUSUM‐based assessment

Abstract Background Limited attempts have been made in trans‐areola single‐site endoscopic thyroidectomy (TASSET) due to technical challenges and the lengthy time for proficiency. This study aimed to define the learning curve of TASSET and to describe improvements in operative performance over time. Methods Based on 222 consecutive TASSET procedures, the learning curve was established according to the operation time by using cumulative sum analysis (CUSUM). The end‐point of learning curve was defined as the number of cases necessitated to reach the initial surgical proficiency stage. The demographic information, surgical and oncological outcomes, surgical stress, and postoperative complications were also analyzed. Results There were 70 cases of simple lobectomy for benign nodules and 152 cases of lobectomy with central neck dissection (CND) for malignancy. The mean operative time was 106.54 ± 38.07 min (range: 46–274 min). The learning curve identified two phases: the skill acquisition phase (Case 1–Case 41) and the proficiency phase (Case 42–Case 222). There were no significant differences in demographic information, drainage amount and duration, oncological outcomes, and postoperative complications between the two phases (p > 0.05). Both operation time and postoperative hospitalization decreased significantly in Phase 2 (154.63 ± 52.21 vs. 95.64 ± 22.96 min, p < 0.001; 4.12 ± 0.93 vs. 3.65 ± 0.63 days, p < 0.001). Additionally, the mean variations of surgical stress factors (C‐reactive protein and erythrocyte sedimentation rate) decreased significantly as the phase progress. The case number required for proficiency phase in benign and malignant tumor were 18 and 33, respectively, and lymph node resection posed a significant impact on the endpoint of the learning curve (p < 0.001). Meanwhile, the size of nodule showed no significant impact (p = 0.622). For right‐handed surgeons, 16 cases and 25 cases were required for technical competence in left‐sided and right‐sided lesions, respectively, and no significant difference reached (p = 0.266). Conclusions TASSET has demonstrated safe and technically feasible with comparable oncological outcomes. Experience of 41 cases was required for surgical competence and proficiency. The initial learning stage could be more quickly adopted by high‐volume thyroid surgeons with standardized procedures