Fecal short chain fatty acids modify therapeutic effects of sleeve gastrectomy.

Aims: We aimed to investigate changes of fecal short chain fatty acids (SCFAs) and their association with metabolic benefits after sleeve gastrectomy (SG). Specifically, whether pre-surgery SCFAs modify surgical therapeutic effects was determined. Methods: 62 participants with measurements of fecal SCFAs and metabolic indices before and 1, 3, 6 months after SG were included. Changes of fecal SCFAs and their association with post-surgery metabolic benefits were calculated. Then, participants were stratified by medians of pre-surgery fecal SCFAs and modification effects of pre-surgery fecal SCFAs on surgical therapeutic effects were investigated, through calculating interaction of group by surgery. Results: Fecal SCFAs were markedly changed by SG. Changes of propionate and acetate were positively correlated with serum triglycerides and total cholesterol, respectively. Notably, high pre-surgery fecal hexanoate group showed a better effect of SG treatment on lowering body weight (P=0.01), BMI (P=0.041) and serum triglycerides (P=0.031), and low pre-surgery fecal butyrate had a better effect of SG on lowering ALT (P=0.003) and AST (P=0.019). Conclusion: Fecal SCFAs were changed and correlated with lipid profiles improvement after SG. Pre-surgery fecal hexanoate and butyrate were potential modifiers impacting metabolic benefits of SG.

Hypoxia-induced long non-coding RNA LINC00460 promotes p53 mediated proliferation and metastasis of pancreatic cancer by regulating the miR-4689/UBE2V1 axis and sequestering USP10.

Long non-coding RNAs are considered to be key regulatory factors of oncogenesis and tumor progression. It is reported that LINC00460 plays the role of oncogene in some tumors. However, LINC00460's role and mechanism of action in pancreatic cancer have not yet been fully elucidated. We identified LINC00460 by analyzing data from the Gene Expression Omnibus database. The role of LINC00460 in proliferation and metastasis was examined using CCK8, colony formation, wound healing, and transwell assays. The potential mechanisms of LINC00460 in regulating mRNA levels were elucidated by RNA pull-down, RNA immunoprecipitation, Chromatin immunoprecipitation, Co-immunoprecipitation, and Immunofluorescence assays. The results showed that LINC00460 was upregulated in pancreatic cancer cells and tissues. Highly expressed LINC00460 is significantly related to short survival of pancreatic cancer patients. Inhibition of LINC00460 attenuated pancreatic cancer cell proliferation and metastasis, whereas its overexpression reversed this effect. Mechanically, LINC00460 is induced by hypoxia, through binding of the hypoxia-inducible factor 1-α in the promoter region of LINC00460. Furthermore, LINC00460 functioned as an miR-4689 sponge to regulate the downstream target gene UBE2V1, enhancing the stability of mutant p53 in pancreatic cancer cells. LINC00460 also further promotes pancreatic cancer development by sequestering USP10, a cytoplasmic ubiquitin-specific protease that deubiquitinates p53 and enhances its stability. Collectively, our study demonstrated that LINC00460 is a hypoxia-induced lncRNA that plays the role of oncogene in pancreatic cancer by modulating the miR-4689/UBE2V1 axis, sequestering USP10, and ultimately enhancing the stability of mutant p53.

Postpancreatectomy Acute Pancreatitis After Pancreaticoduodenectomy: A Distinct Clinical Entity.

OBJECTIVE: This study aimed to characterize postpancreatectomy acute pancreatitis (PPAP) after pancreaticoduodenectomy (PD) in a high-volume center. BACKGROUND: The International Study Group for Pancreatic Surgery (ISGPS) has recently proposed a new definition and grading scale of PPAP, but specific studies are lacking. METHODS: Patients who underwent PD from 2020 to 2021 were retrospectively reviewed. PPAP was defined based on the International Study Group for Pancreatic Surgery definition: sustained elevation of serum amylase levels for least the first 48 hours postoperatively and radiologic alterations consistent with PPAP. RESULTS: Among a total of 716 patients who were finally analyzed, PPAP occurred in 152 (21.2%) patients. Patients with PPAP were associated with significantly higher incidences of postoperative pancreatic fistula (POPF) (40.8% vs 11.7%, P <0.001), major complications (13.8% vs 6.6%, P =0.004), and biliary leak (11.8% vs 4.6%, P =0.001). Among them, 8 patients developed grade C PPAP leading to organ failure, reoperation, or death. Patients developing PPAP alone also demonstrated a statistically significantly increased rate of major complications than those without PPAP or POPF. In contrast, no differences were found in postoperative outcomes in patients with POPF in terms of whether they were associated with PPAP. CONCLUSION: PPAP is a distinct complication after PD with distinctive clinical outcomes. A part of PPAP presents as an inflammatory process in the early postoperative period but sometimes could lead to necrotizing pancreatitis or other severe clinical scenarios, and another part of PPAP would lead to anastomotic failure that accounts for a great proportion of POPF occurrence.

Serum lipase on postoperative day one is a strong predictor of clinically relevant pancreatic fistula after pancreaticoduodenectomy: A retrospective cohort.

BACKGROUND: Increased postoperative serum amylase has been recently reported to be associated with increased postoperative morbidity, but studies on postoperative serum lipase are limited. The aim of this study was to evaluate the value of postoperative serum lipase in predicting clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreaticoduodenectomy (PD). METHOD: A retrospective analysis was performed on 212 patients who underwent PD from September 2018 and March 2021, focusing on the association between postoperative day (POD) 1 serum lipase and CR-POPF. RESULTS: Overall, 108 (50.9%) patients had elevated serum lipase levels (>68 U/L) on POD 1. Patients with elevated serum lipase exhibited a significantly higher incidence of CR-POPF (37.0% vs. 6.7%, p < 0.001). Receiver operating characteristic (ROC) analyses showed improved diagnostic accuracy for POD 1 serum lipase compared with POD 1 serum amylase in predicting CR-POPF (AUC: 0.801 vs. 0.745, p = 0.029). Elevated serum lipase on POD 1 and elevated serum CRP on POD 3 were identified as independent predictors of CR-POPF. A simple early postoperative model, consisting of POD 1 serum lipase levels and POD 3 serum CRP levels, showed good discrimination (AUC 0.76, 95% CI 0.69-0.83) to identify the onset of CR-POPF. CONCLUSION: Serum lipase on POD 1 outperformed serum amylase on POD 1 in predicting CR-POPF after PD. The combination of POD 1 serum lipase and POD 3 serum CRP provides a reliable predicting model for CR-POPF.

Robotic versus open pancreaticoduodenectomy with vascular resection for pancreatic ductal adenocarcinoma: surgical and oncological outcomes from pilot experience.

PURPOSE: Venous resection and reconstruction (VR) is a feasible surgical technique to achieve optimal outcomes in selected patients with pancreatic ductal adenocarcinoma (PDAC) who undergo open pancreaticoduodenectomy (OPD). However, data regarding patient outcomes in patients who undergo VR in robotic-assisted pancreaticoduodenectomy (RPD) are scarce. METHODS: All patients with a diagnosis of PDAC who underwent upfront open or robotic pancreatoduodenectomy with VR in a high-volume institution for pancreatic surgery between 2011 and 2019 were retrospectively reviewed. Perioperative and long-term outcomes were compared between the RPD and OPD cohorts. RESULTS: A total of 84 patients were included in the final analysis, 14 patients underwent RPD with VR and 70 who had OPD with VR. Reconstructed venous patency, postoperative 30-day morbidity, and 90-day mortality were comparable; however, lymph node resection rates were lower in the RPC cohort (p = 0.029). No difference was identified in 3-year survival rates between the two groups (34.0% versus 25.7% respectively, p = 0.667). CONCLUSION: RPD with VR is a feasible approach for patients with PDAC and venous invasion. Further studies are needed to assess long-term outcomes compared to the open approach.

Clinical characteristics and surgical outcomes of resectable acinar cell carcinoma of the pancreas-propensity score matching analysis with pancreatic ductal adenocarcinoma.

BACKGROUND: Surgical resection is recommended for patients with resectable acinar cell carcinoma (ACC). The aim of this study was to investigate the clinical characteristics and surgical outcomes of resectable ACC in comparison to pancreatic ductal adenocarcinoma (PDAC). METHOD: A retrospective analysis was performed on all patients who consecutively underwent radical resection with pathologically confirmed ACC and PDAC from December 2011 to December 2018. Clinicopathologic characteristics and follow-up information were analyzed. A 1:3 propensity score matching (PSM) method was used to minimize the bias between ACC and PDAC. RESULTS: A total of 26 patients with ACC and 1351 with PDAC were included. Compared to PDAC, ACC tended to be larger (4.5 vs. 3.0 cm; p < 0.001) and more frequently located in the pancreatic body/tail (61.5% vs. 36.6%, p = 0.009), with lower total bilirubin levels, lower neutrophil lymphocyte ratio (NLR) levels and lower carbohydrate antigen 19-9 (CA19-9) levels and carcinoembryonic antigen (CEA) levels. There was no difference in postoperative morbidities in patients with ACC and PDAC. The median OS and RFS were longer in ACC when compared to PDAC (OS: 43.5 mo vs. 19.0 mo, p = 0.004; RFS: 24.5 mo vs. 11.6 mo, p = 0.023). After the 1:3 PSM, ACC remained to be a better histological type for OS (p = 0.024), but had comparable RFS with PDAC (p = 0.164). CONCLUSION: Patients with ACC after radical resection had better OS than that with PDAC. However, ACC is also an aggressive tumor with a similar trend of RFS with PDAC after the matching, necessitating the multidisciplinary treatment for resectable ACC disease.

Robotic distal pancreatectomy reduces pancreatic fistula in patients without visceral obesity as compared to open distal pancreatectomy: A propensity score matching retrospective cohort study.

BACKGROUND: Several studies have suggested an association between visceral obesity and adverse perioperative outcomes in pancreatic surgery. However, no study has reported the impact of visceral obesity on robotic pancreatic surgery. This study aimed to assess the impact of preoperative visceral obesity on clinically relevant postoperative pancreatic fistula (CR-POPF) in pancreatic ductal adenocarcinoma (PDAC) patients following robotic distal pancreatectomy (RDP) or open distal pancreatectomy (ODP). METHODS: A retrospective analysis was performed on all patients who consecutively underwent RDP or ODP for PDAC. The visceral adipose tissue was measured on preoperative computed tomography (CT) images at the L3 vertebra level. A 1:1 propensity score matching method was used in the visceral obesity group and the nonvisceral obesity group to minimize the bias between RDP and ODP. RESULTS: Between December 2011 and December 2018, a total of 445 patients were included. Visceral obesity (n = 219) was found to be associated with higher estimated blood loss (p = 0.033), a higher CR-POPF rate (p = 0.001), delayed drain removal (p = 0.005) and a longer length of stay (p = 0.033). In multivariable analysis, visceral obesity was an independent risk factor for CR-POPF (OR: 1.69; 95% CI 1.07-2.67, p = 0.024). Among patients without visceral obesity, the incidence of CR-POPF was lower among RDP than among ODP patients (11.27% vs. 23.87%, p = 0.028), and the difference remained after propensity score matching (9.52% vs. 26.98%, p = 0.011). However, there was no significant difference in the CR-POPF rate between RDP and ODP for visceral obesity patients. CONCLUSION: In nonvisceral obesity patients, RDP had better perioperative outcomes than ODP, with a significantly lower CR-POPF rate. However, in visceral obesity patients, RDP showed equivalent CR-POPF rate when compared to ODP.

Robotic-assisted versus open total pancreatectomy: a propensity score-matched study.

BACKGROUND: Total pancreatectomy (TP) is a complex surgical procedure with significant postoperative morbidity. Despite the narrowed range of indications for TP, the introduction of neoadjuvant chemotherapy and the increasing complexity of surgical resections performed in high-volume centers has increased the number of annually performed TPs, especially regarding malignant disease. The introduction of robotic-assisted pancreatic surgery has provided a novel and minimally invasive approach for TP, yet the feasibility of this technique is still unknown. This study assessed the safety and efficacy of robotic-assisted total pancreatectomy (RTP) compared to conventional open total pancreatectomy (OTP). METHODS: All patients who underwent TP between March 2015 and July 2019 in a high-volume institution for pancreatic surgery were included in this retrospective study. Clinical data and perioperative outcomes were derived from the prospectively maintained institutional database. A 1:1 propensity score matching (PSM) method was utilized to compare the RTP and OTP cohorts to minimize bias. RESULTS: A standardized surgical protocol was utilized for RTP following a learning curve of RPD and RDP. The median operative time for patients who underwent RTP was significantly decreased compared to those who underwent OTP [300 (IQR, 250-360) vs. 360 min (IQR, 300-525), P=0.031]. Additionally, en bloc resection and spleen-preserving rates were also higher in the RTP cohort. Major 30-day morbidity (Clavien-Dindo > IIIa) and 90-day mortality were similar between the two cohorts. After a median follow-up time of 15 (IQR, 8-24) months, both the RTP and OTP cohorts had a comparable quality of life regarding exocrine and endocrine insufficiency. CONCLUSIONS: RTP appears to be safe and feasible when utilized in high-volume centers for the indicated management of benign and highly selected malignant pancreatic disease. However, further prospective randomized studies are needed to assess the feasibility of this approach.

A Nomogram for Individual Prediction of Poor Prognosis After Radical Surgery in Patients with Primary Pancreatic Duct Adenocarcinoma.

BACKGROUND Pancreatic cancer is a highly malignant tumor characterized by poor prognosis. TNM stage cannot always provide accurate prediction of prognosis, which is vital for individualized treatment. Therefore, a novel way to identify patients with poor prognosis after radical surgery is urgently needed. MATERIAL AND METHODS The nomogram was established based on a discovery cohort that included 554 patients with PDAC who had received radical surgery from 2012 to 2016. The clinicopathological data were collected. Poor prognosis was evaluated using 25 features, in which appropriate features for a prediction model were identified. A prediction model incorporating the selected features was established. The discriminative capacity was assessed by C-index, calibration by calibration plot, and clinical usefulness by decision curve. The bootstrapping approach was used to perform internal validation. RESULTS Characteristics included in the nomogram were coronary artery disease and stroke history, elevated CA125, AJCC stage >II, R0 resection, operating time >6 h, poor differentiation, nerve invasion, length of stay >30 days, and postoperative complications. A C-index of 0.713 indicated good discrimination of the prediction model, and the calibration curve showed acceptable calibration. Survival analysis showed that this model had better discriminative capacity than the AJCC staging system and could distinguish relatively good prognosis from poor prognosis in patients at stage II (especially IIa) and IV. CONCLUSIONS Our study presents a valid and practical model to predict prognosis of pancreatic cancer patients, which contributes to individualized therapy by assisting surgeons to predict poor prognosis in patients who received radical surgery.

Robotic thyroidectomy via bilateral axillo-breast approach: Experience and learning curve through initial 220 cases.

OBJECTIVE: This study is aim to summarize the experience of robotic thyroidectomy via bilateral axillo-breast approach of our center and also to find out the learning curve of this technique. METHODS: In total 220 initial patients who have undergone robotic thyroidectomy via bilateral axillo-breast approach from May 2015 to September 2017 were involved in this study. The data of operation time, clinical characteristics, surgical outcomes and oncological outcomes were collected. The moving average method is use to explore the learning curve. RESULTS: All patients had undergone robotic thyroidectomy successfully without conversion to other surgical approaches. The mean age of the enrolled subjects was 34.4 ± 7.8 years old, while the sex ratio (male/female) was 38/182. There were 50 benign tumor cases and 170 malignant tumor cases. The mean total operation time was 105.3 ± 37.6 min. Lymph node metastasis was observed in 61 (35.9%) patients. The mean retrieved lymph node count was 5.1 ± 3.8 while the mean metastatic lymph node count was 0.7 ± 1.5. The operation time decreased significantly after about 30-35 cases and formed the plateau. After 80 cases, the operation time significantly decreased again. CONCLUSION: For skilled endocrine surgeons, robotic thyroidectomy has proved to be safe and feasible, which could be applied extensively in patients strictly selected in high-volume centers, with a relatively short learning curve of about 30-35 cases. While the surgeons getting more experienced, this technique would be more efficient.

Predictive factors for postoperative pancreatitis after pancreaticoduodenectomy: A single-center retrospective analysis of 1465 patients.

BACKGROUND: Postoperative acute pancreatitis (POAP) after pancreaticoduodenectomy (PD) has been recently recognized as an independent complication that is associated with undesirable postoperative outcomes and often precedes other complications, yet predictive factors attributable to POAP after PD remain elusive. METHODS: The data from 1465 consecutive patients who underwent laparotomy or minimally invasive robotic PD from March 2010 to December 2018 were retrospectively reviewed. POAP was defined as an elevation of the serum amylase levels above the institution's normal upper limit (100 U/L) on postoperative day (POD) 1. Univariate and multivariate analyses were performed to investigate the predictive factors for POAP after PD and the association between POAP and clinically relevant postoperative pancreatic fistulas (CR-POPFs). RESULTS: Among the 1465 patients, 411 (28%) underwent minimally invasive robotic surgeries, and the overall POAP and CR-POPFs rates were 770 (53%) and 277 (19%), respectively. The female sex (OR 1.76), a normal bilirubin level (OR 1.55), the robotic surgery (OR 1.36), a main pancreatic duct (MPD) ≤3 mm (OR 5.69) and a high-risk nonadenocarcinoma pathology (cystic disease: OR 4.33; pNETs: OR 4.34; others: OR 2.74) were considered independent risk factors for POAP. A nondilated MPD was a predominant predictor for POAP, with 72.2% sensitivity and 71.8% specificity. POAP was also an independent predictive factor for CR-POPFs (OR 3.48). CONCLUSION: A nondilated MPD, a high-risk pathology, the female sex, a normal bilirubin level and the robotic surgery were independent predictive factors for POAP after PD. Prevention and early treatment strategy changes can be made based on these preoperative predictive factors.

Resection of pancreatic metastatic renal cell carcinoma: experience and long-term survival outcome from a large center in China.

PURPOSE: This study aimed to determine the outcome of pancreatic metastatic renal cell carcinoma (PmRCC) after treatment and share the relevent results. METHODS: In total, 13 patients with PmRCC were diagnosed and treated in our institution from December 2013 to October 2017. We retrospectively reviewed the records and analyzed the patient demographics, perioperative outcomes, and overall survival. Simultaneously, our experience including treatment and misdiagnosis was shared. RESULTS: The median time between nephrectomy and reoperation for pancreatic recurrence was 11 years (range 1-20 years). Four patients had multiple tumors and nine patients had solitary tumor. Five patients accepted distal pancreatectomy, and five patients underwent pancreaticoduodenectomy. One patient underwent total pancreatectomy, one patient underwent duodenum-preserving pancreatic head resection plus distal pancreatectomy, and one patient underwent exploratory laparotomy and gastrointestinal bypass due to widespread metastasis with clear obstructive symptoms. The misdiagnosis rate of preoperative diagnosis at our center was 69.2% (9/13). The median follow-up duration was 26 months (range 7-53 months, until June 2018). By the end of follow-up, 12 patients were alive and one patient died of gastrointestinal bleeding within 1 month after surgery. CONCLUSIONS: PmRCCs are uncommon, but pancreatic metastasectomy has a relatively good prognosis and may, therefore, be a good therapeutic choice for patients with PmRCCs. Because PmRCC occurs long after the primary tumor resection, long-term follow-up is necessary. Besides, detailed medical history and specific manifestation in imaging features could contribute to avoiding misdiagnosis.

Perineural invasion is related to p38 mitogen-activated protein kinase pathway activation and promotes tumor growth and chemoresistance in pancreatic cancer.

Metastasis is a key component of cancer progression and is strongly associated with poor prognosis. Perineural invasion is thought to be related to pain, tumor recurrence, and other conditions. However, the exact molecular mechanism is unclear. This study was conducted to identify the key components and signaling pathways involved in the perineural invasion of pancreatic cancer and alterations in the phenotype after the interaction between the dorsal root ganglion (DRG) and pancreatic cancer cells. The results indicated that the p38 mitogen-activated protein kinase signaling pathway was activated after coculture of the DRG and pancreatic cancer cells and lead to the promotion of cell growth and chemoresistance.

IRX3 Promotes the Browning of White Adipocytes and Its Rare Variants are Associated with Human Obesity Risk.

BACKGROUND: IRX3 was recently reported as the effector of the FTO variants. We aimed to test IRX3's roles in the browning program and to evaluate the association between the genetic variants in IRX3 and human obesity. METHODS: IRX3 expression was examined in beige adipocytes in human and mouse models, and further validated in induced beige adipocytes. The browning capacity of primary preadipocytes was assessed with IRX3 knockdown. Luciferase reporter analysis and ChIP assay were applied to investigate IRX3's effects on UCP1 transcriptional activity. Moreover, genetic analysis of IRX3 was performed in 861 young obese subjects and 916 controls. RESULTS: IRX3 expression was induced in the browning process and was positively correlated with the browning markers. IRX3 knockdown remarkably inhibited UCP1 expression in induced mouse and human beige adipocytes, and also repressed the uncoupled oxygen consumption rate. Further, IRX3 directly bound to UCP1 promoter and increased its transcriptional activity. Moreover, 17 rare heterozygous missense/frameshift IRX3 variants were identified, with a significant enrichment in obese subjects (P=0.038, OR=2.27; 95% CI, 1.02-5.05). CONCLUSIONS: IRX3 deficiency repressed the browning program of white adipocytes partially by regulating UCP1 transcriptional activity. Rare variants of IRX3 were associated with human obesity.

Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention.

Emerging evidence has linked the gut microbiome to human obesity. We performed a metagenome-wide association study and serum metabolomics profiling in a cohort of lean and obese, young, Chinese individuals. We identified obesity-associated gut microbial species linked to changes in circulating metabolites. The abundance of Bacteroides thetaiotaomicron, a glutamate-fermenting commensal, was markedly decreased in obese individuals and was inversely correlated with serum glutamate concentration. Consistently, gavage with B. thetaiotaomicron reduced plasma glutamate concentration and alleviated diet-induced body-weight gain and adiposity in mice. Furthermore, weight-loss intervention by bariatric surgery partially reversed obesity-associated microbial and metabolic alterations in obese individuals, including the decreased abundance of B. thetaiotaomicron and the elevated serum glutamate concentration. Our findings identify previously unknown links between intestinal microbiota alterations, circulating amino acids and obesity, suggesting that it may be possible to intervene in obesity by targeting the gut microbiota.