Yugang Cheng

Early detection of pancreatic cancer: Where are we now and where are we going?

Pancreatic cancer (PC) is one of the most lethal malignancies. Recent studies indicate that patients with incidentally diagnosed PC have better prognosis than those with symptoms and that there is a sufficient window for early detection. However, effective early diagnosis remains difficult and depends mainly on imaging modalities and the development of screening methodologies with highly sensitive and specific biomarkers. This review summarizes recent advances in effective screening for early diagnosis of PC using imaging modalities and novel molecular biomarkers discovered from various “omics” studies including genomics, epigenomics, non‐coding RNA, metabonomics, liquid biopsy (CTC, ctDNA and exosomes) and microbiomes, and their use in body fluids (feces, urine and saliva). Although many biomarkers for early detection of PC have been discovered through various methods, larger scale and rigorous validation is required before their application in the clinic. In addition, more effective and specific biomarkers of PC are urgently needed.

Analysis of 100 consecutive cases of resectable pancreatic neuroendocrine neoplasms: clinicopathological characteristics and long-term outcomes

The incidence rate of pancreatic neuroendocrine neoplasms (pNENs) has increased rapidly in recent years. However, the clinicopathological characteristics of pNENs are poorly understood. Medical records of patients who underwent surgery and were confirmed as pNENs by pathological examination from January 2003 to February 2015 in Qilu Hospital were reviewed retrospectively. A total of 100 patients, 36 males and 64 females, were included with a mean operation age of 46.26 + 13.41 years. Among the 100 cases, 76 had insulinomas and 24 had non-functional pNENs. Tumor size ranged from 0.5 cm to 9 cm, and the mean size was 2.20 + 1.40 cm. The percentages of TNM stages I, II, III, and IV tumors were 89.0%, 8.0%, 0.0%, and 3.0%, respectively. Based on the WHO classification, pNENs were classified into three grades: G1, G2, and G3. G1, G2, and G3 tumors were confirmed in 72.9%, 23.7%, and 3.4% patients, respectively. The positive rates of CgA and Syn immunohistochemical staining were 94.5% (69/73) and 100% (74/74), respectively. Compared with insulinoma, non-functional pNENs have larger tumor sizes, more advanced TNM staging, a higher Ki-67 index, and a higher rate of liver metastasis (P < 0.05). In conclusion, pNENs are heterogeneous tumors with varying clinical manifestations, diverse tumor biological characteristics, and different prognoses. Non-functional pNENs present a more aggressive behavioral model and have poorer prognosis than functional pNENs.

Immunotherapy for pancreatic cancer: A long and hopeful journey

Multiple therapeutic strategies have been developed to treat pancreatic cancer. However, the outcomes of these approaches are disappointing. Due to deeper understandings of the pivotal roles of the immune system in pancreatic cancer tumorigenesis and progression, novel therapeutic strategies based on immune cells and the tumor microenvironment are being investigated. Some of these approaches, such as checkpoint inhibitors, chimeric antigen receptor T-cell therapy, and BiTE antibodies, have achieved exciting outcomes in preclinical and clinical trials. The current review describes the roles of immune cells and the immunosuppressive microenvironment in the development of pancreatic cancer, as well as the preclinical and clinical outcomes and benefits of recent immunotherapeutic approaches, which may help us further disclose the mechanisms of pancreatic cancer progression and the dialectical views of feasibility and effectiveness of immunotherapy in treatment of pancreatic cancer.

Bariatric Surgery Ameliorates Diabetic Cardiac Dysfunction by Inhibiting ER Stress in a Diabetic Rat Model

BackgroundCardiac dysfunction is a severe complication of diabetes, with no effective treatment. Currently, bariatric surgery is more and more widely used to attenuate diabetes-associated diseases. The mechanism is not clear. Endoplasmic reticulum (ER) stress-dependent apoptosis has been observed in the progression of diabetic myocardium damage. Therefore, this research was designed to investigate the effects of different bariatric procedures on cardiac dysfunction via ER stress-induced cardiomyocyte apoptosis pathway in a diabetic rat model.MethodsDuodenal-jejunal bypass (DJB), sleeve gastrectomy (SG), and sham surgery were performed in diabetic rats. Echocardiographic examination, H&E staining, Masson staining, and TUNEL staining were performed to measure the diabetes-caused heart damages. ER stress-associated signaling molecules like glucose-regulated protein 78 (GRP78), protein kinase RNA (PKR)-like ER protein kinase (PERK), p-PERK, inositol-requiring enzyme 1ɑ (IRE1ɑ), p-IRE1ɑ, activating transcription factor 6 (ATF6), C/EBP homologous protein (CHOP), and caspase 12 were measured and compared among DJB group, SG group, and sham group.ResultsCompared with sham group, DJB and SG groups both had significantly lower GRP78, PERK, p-PERK, CHOP, and caspase 12, though there was no statistical change on IRE1ɑ, p-IRE1ɑ, and ATF6. DJB and SG groups also showed improved heart function and lower cardiomyocyte apoptosis in diabetic rats.ConclusionDJB and SG ameliorated cardiac dysfunction by inhibiting PERK-mediated pathway. And no difference was observed on the effects of DJB and SG on ER stress-dependent myocardium damage in diabetic rats.

Effects of sleeve gastrectomy plus trunk vagotomy compared with sleeve gastrectomy on glucose metabolism in diabetic rats

AIM To investigate the effects of sleeve gastrectomy plus trunk vagotomy (SGTV) compared with sleeve gastrectomy (SG) in a diabetic rat model. METHODS SGTV, SG, TV and Sham operations were performed on rats with diabetes induced by high-fat diet and streptozotocin. Body weight, food intake, oral glucose tolerance test, homeostasis model assessment of insulin resistance (HOMA-IR), hepatic insulin signaling (IR, IRS1, IRS2, PI3K and AKT), oral glucose stimulated insulin secretion, GLP-1 and ghrelin were compared at various postoperative times. RESULTS Both SG and SGTV resulted in better glucose tolerance, lower HOMA-IR, up-regulated hepatic insulin signaling, higher levels of oral glucose-stimulated insulin secretion, higher postprandial GLP-1 and lower fasting ghrelin levels than the TV and Sham groups. No significant differences were observed between the SG and SGTV groups. In addition, no significant differences were found between the TV and Sham groups in terms of glucose tolerance, HOMA-IR, hepatic insulin signaling, oral glucose-stimulated insulin secretion, postprandial GLP-1 and fasting ghrelin levels. No differences in body weight and food intake were noted between the four groups. CONCLUSION SGTV is feasible for diabetes control and is independent of weight loss. However, SGTV did not result in a better improvement in diabetes than SG alone.

Predictors of glycemic control after sleeve gastrectomy versus Roux-en-Y gastric bypass: a meta-analysis, meta-regression and systematic review

Sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) are the most commonly performed bariatric procedures globally. However, it remains controversial which procedure provides better glycemic control. To identify predictors of glycemic control after SG versus RYGB, a systematic search of PubMed, EMBASE, and the Cochrane Library was conducted up to January 2017 for comparative studies with both SG and RYGB arms for the treatment of type 2 diabetes (T2D). A meta-analysis and systematic review was performed to evaluate glycemic control after SG versus RYGB with both short- and long-term follow-up. A meta-regression was performed to evaluate impacts of clinical indicators on glycemic control after SG versus RYGB. A total of 17 comparative studies involving 1160 patients were included. SG and RYGB achieved similar diabetic remission rates with both short- and long-term follow-up. However, SG provided lower endpoint glycosylated hemoglobin (A1C) after 1-year follow-up (mean deviation = .17, 95% confidence interval .03-.31, P = .02). When adjusted by baseline A1C, SG and RYGB provided similar percent delta A1C with 1-, 2-, 3-, and 5-year follow-up. The baseline body mass index, duration of T2D, preoperative fasting plasma glucose, and preoperative A1C had predictive value for glycemic control after SG, but only duration of T2D and preoperative A1C were correlated with that after RYGB. These findings showed that the choice of procedure between SG and RYGB predicts no better glycemic control. However, more factors should be considered when SG is recommended to a given patient with diabetes.

Deactivation of the NLRP3 inflammasome in infiltrating macrophages by duodenal-jejunal bypass surgery mediates improvement of beta cell function in type 2 diabetes

OBJECTIVE Bariatric surgery could improve pancreatic beta cell function, thereby leading to the remission of the type 2 diabetes mellitus (T2DM). However, the specific mechanism underlying this phenomenon is yet to be revealed. The aim of this study is to test the hypothesis that Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in infiltrating macrophages plays an important role in the modulation of beta cell function after duodenal-jejunal bypass (DJB) surgery. METHODS DJB and sham surgery were performed in diabetic Sprague-Dawley (SD) rats induced by high-fat diet (HFD) and streptozotocin (STZ). Body weight, food intake, and glucose tolerance test (GTT) were measured at indicated time points. Apoptosis of the beta cells was measured by Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling (TUNEL) assay. We also assessed the macrophage content and NLRP3 expression in the rat model. Furthermore, macrophage reconstitution was performed after DJB surgery. Beta cell function and NLRP3 inflammasome pathway were re-evaluated in wild-type macrophage reconstitution group and NLRP3-knockdown macrophage reconstitution group. RESULTS DJB surgery group rats displayed rapid and sustained improvement in glucose tolerance. Decreased apoptosis and improved secretion function of the beta cells were observed in DJB surgery group. NLRP3 inflammasome pathway in infiltrating macrophages was also suppressed after DJB surgery. Moreover, diabetic remission acquired by DJB sustained in NLRP3-knockdown macrophage reconstitution group, while extinguished in group reconstituted with wild-type macrophage. CONCLUSIONS NLRP3 inflammasome deactivation in infiltrating macrophages is involved in marked beta cell function improvement after DJB surgery.

Downregulation of lncRNA MALAT1 contributes to renal functional improvement after duodenal-jejunal bypass in a diabetic rat model

Ameliorated renal function has been reported after bariatric surgery, but the mechanisms underlying this phenomenon are not well-studied. To investigate whether the long non-coding RNA (lncRNA) MALAT1 mediates the amelioration of diabetic nephropathy after duodenal-jejunal bypass (DJB) surgery, rats were assigned randomly into four groups: diabetic (DM) group, DM with DJB surgery group, DM with sham surgery group, and healthy control group. Food intake, body weight, oral glucose tolerance test (OGTT), urine albumin excretion rate (UAER), and glomerular filtration rate (GFR) were measured and histological examination of renal sections was performed. For in vitro study, HK-2 cells were cultured under various glucose concentrations following MALAT1 siRNA transfection. Expression levels of MALAT1, SAA3, IL-6, and TNF-α in rat renal tissues or HK-2 cell lines were evaluated by qRT-PCR and/or ELISA. Results showed DJB surgery improved the renal function of diabetic rats, as indicated by ameliorated UAER and GFR and attenuated glomerular hypertrophy. Expression of MALAT1 and its downstream target SAA3 was significantly downregulated in renal tissues after DJB, which in turn decreased the expression of the pro-inflammatory cytokines IL-6 and TNF-α. Knockdown of MALAT1 in HK-2 cell lines further confirmed that expression levels of SAA3, IL-6, and TNF-α were regulated by MALAT1 under both low- and high-glucose conditions. Our findings suggest that MALAT1 is implicated in the improvement of renal function after DJB through regulation of its downstream targets SAA3, IL-6, and TNF-α.

Restoration of myocardial glucose uptake with facilitated GLUT-4 translocation contributes to alleviation of diabetic cardiomyopathy in rats after duodenal-jejunal bypass

Duodenal‐jejunal bypass (DJB) surgery has been reported to effectively relieve diabetic cardiomyopathy (DCM). However, the specific mechanisms remain largely unknown. The present study was designed to determine the alterations of myocardial glucose uptake (MGU) after DJB and their effects on DCM.

The modified laparoscopic keyhole parastomal hernia repair with in situ re-ostomy has low recurrence rate

PurposeThis study aimed to present a modified laparoscopic keyhole parastomal hernia repair technique with in situ re-ostomy and show its safety and feasibility at a mid-term follow-up.MethodsThe technique begins with adhesiolysis during laparoscopy. An annular incision is made between the skin and stomal mucosa. Then, after all adhesions of the stomal bowel and its mesentery are separated from the hernial sac, the stomal bowel is delivered through the keyhole mesh. The mesh is then stitched to the stomal bowel and placed intraperitoneally. The hernial ring is narrowed, and the mesh is further stitched to the hernial ring and stomal tube. After the mesh is fixed, the redundant stomal bowel is shortened, and a new in situ stoma is matured in the conventional way.ResultsAltogether, 65 consecutive patients underwent successful hernia repair via a modified laparoscopic keyhole with in situ re-ostomy. Two of the patients had recurrent parastomal hernias. No mortalities occurred during the perioperative period. Morbidities included two cases of seroma and three of ileus, all of which were cured with conservative treatment. In addition, one case of intestinal perforation was rescued by intestinal resection and enteroenterostomy. Median follow-up was 29 months (range 3–60 months). No complications of mesh-related infection or patch erosion were noted during the follow-up.ConclusionsModified laparoscopic keyhole parastomal hernia repair with in situ re-ostomy is a safe procedure with a low recurrence rate at the mid-term follow-up.