Adjuvant chemotherapy for patients with gastric neuroendocrine carcinomas or mixed adenoneuroendocrine carcinomas.

BACKGROUND: The aim of this study was to evaluate whether adjuvant chemotherapy is associated with improved survival in patients with resectable gastric neuroendocrine carcinomas (G-NECs) or mixed adenoneuroendocrine carcinomas (G-MANECs). METHODS: The study included patients with G-NECs or G-MANECs who underwent surgery in one of 21 centres in China between 2004 and 2016. Propensity score matching analysis was used to reduce selection bias, and overall survival (OS) in different treatment groups was estimated by the Kaplan-Meier method. RESULTS: In total, 804 patients with resectable G-NECs or G-MANECs were included, of whom 490 (60·9 per cent) received adjuvant chemotherapy. After propensity score matching, OS in the chemotherapy group was similar to that in the no-chemotherapy group. Among patients with G-NECs, survival in the fluorouracil (5-FU)-based chemotherapy group and the non-5-FU-based chemotherapy group was similar to that in the no-chemotherapy group. Similarly, etoposide plus cisplatin or irinotecan plus cisplatin was not associated with better OS in patients with G-NECs. Among patients with G-MANECs, OS in the non-5-FU-based chemotherapy group was worse than that in the no-chemotherapy group. Patients with G-MANECs did not have better OS when platinum-based chemotherapy was used. CONCLUSION: There was no survival benefit in patients who received adjuvant chemotherapy for G-NECs or G-MANECs.

ANTECEDENTES: El objetivo de este estudio fue evaluar si la quimioterapia adyuvante mejoraba la supervivencia en pacientes con carcinomas gástricos resecables neuroendocrinos (gastric neuroendocrine carcinomas, G-NECs) y carcinomas adenoneuroendocrinos mixtos (mixed adenoneuroendocrine carcinomas, G-MANECs). MÉTODOS: Se incluyeron pacientes con G-NECs y G-MANECs tratados quirúrgicamente en 21 centros en China entre 2004 y 2016. Se utilizó un análisis de emparejamiento por puntaje de propensión para reducir el sesgo de selección y el método de Kaplan-Meier para estimar la supervivencia global (overall survival, OS) de los pacientes en los diferentes grupos de tratamiento. RESULTADOS: En total, se incluyeron en el estudio 804 pacientes con G-NECs y G-MANECs resecables y 490 pacientes (60,9%) recibieron quimioterapia adyuvante. Después del emparejamiento por puntaje de propensión, la OS del grupo con quimioterapia fue similar a la del grupo sin quimioterapia. En los pacientes con G-NECs, la supervivencia en los grupos con quimioterapia basada en 5-FU (fluorouracilo) y de quimioterapia sin 5-FU fue similar a la del grupo sin quimioterapia. Asimismo, la combinación de etopósido y cisplatino o de irinotecán y cisplatino no se asoció con una mejor OS en pacientes con G-NECs. En pacientes con G-MANECs, la OS del grupo con quimioterapia sin 5-FU fue peor que la del grupo sin quimioterapia. Los pacientes con G-MANECs no presentaron una mejor OS cuando se administró quimioterapia basada en platinos. CONCLUSIÓN: La administración de quimioterapia adyuvante en pacientes con G-NECs y G-MANECs no mejoró la supervivencia.

[Observation on the efficacy of CT-guided lumbar sympathetic chemical destructive block in the treatment of cold sensation of limbs].

Objective: To observe the clinical effects of CT-guided chemical destructive block of lumbar sympathetic nerve in the treatment of cold sensation of limbs. Methods: In this retrospective analysis, clinical data of 43 patients with cold sensation of limbs treated by lumbar sympathetic chemical destructive block in the Affiliated Hospital of Jiaxing University from January 2015 to January 2018 were collected. The changes of heart rate, non-invasive blood pressure (NIBP), oxygen saturation (SpO(2)), plantar temperature and peripheral perfusion index (PI) of patients were recorded and analyzed before treatment and 5 min after injection of anhydrous ethanol. The patients were followed up at postoperative 1 day, 1 week, 1 month, 3 months, 6 months, 1 year and 2 years. Results: Fourty-three patients underwent bilateral lumbar sympathetic nerve chemical destructive block under the CT-guided, and all patients were punctured to the target successfully. The PI of patients before and after treatment were 1.2±0.6, 7.2±3.0 respectively, which was significantly increased after treatment compared with before treatment, and the difference was statistically significant (t=12.386, P<0.05). The plantar temperature of patients before and after treatment respectively were (29.6±1.7)℃, (34.6±1.1)℃, which was significantly increased after treatment compared with before treatment, and the difference was statistically significant (t=15.057, P<0.05). There were no significant differences in heart rate, NIBP and SpO(2) between before and after treatment (all P>0.05). Lumbar sympathetic chemical destructive block was clinically effective in 39 patients (90.7%) and ineffective in 4 patients (9.3%). Among the 39 clinically effective patients, the curative effects were excellent in 29 cases and improved in 10 cases. Postoperative recurrence occurred in 10 cases (25.6%). The satisfaction rates of patients at 1 day, 1 week, 1 month, 3 months, 6 months, 1 year and 2 years after operation were 93.0%, 90.7%, 86.0%, 76.7%, 69.7%, 65.1% and 53.4%, respectively. Conclusion: Lumbar sympathetic chemical destructive block is a safe and effective way for the treatment of cold sensation of limbs, which can improve the symptoms of cold sensation of limbs to some extent.

[Relationship between expression of high-mobility group box-1 and inflammatory cytokines in patients with bone cancer pain].

Objective: To investigate the change and relationship between serum high-mobility group box-1(HMGB1) and related inflammatory cytokines level in patients suffer with bone metastatic pain. Methods: Collection of the bone cancer pain patients who received analgesic therapy the department of pain in The First Affiliated Hospital of Jiaxing University from November 2016 to August 2016. Serum concentration of HMGB1, the Receptor of Advanced Glycation Endproducts (RAGE), monocyte chemotactic protein-1(MCP-1), tumor necrosis factor -α (TNF-α), interleukin-1ß (IL-1ß), interleukin-10 (IL-10), interleukin-13 (IL-13), and transforming growth factor-ß (TGF-ß) levels were determined in 15 healthy individuals as healthy donor and 15 patients with bone metastatic pain by enzyme-linked immunosorbent (ELISA) . The healthy individuals and patients with bone metastatic pain were collected before treatment and on 7 d after the treatment. Results: The serum concentration of HMGB1 and RAGE were significantly increased in tumorous group compared with healthy group[(8.8±2.3) vs (1.9±1.1) µg/L,(231±16) vs (46±20) ng/L); t=7.10,12.44, both P<0.05], then decreased after analgesic therapy [(4.77±1.36) µg/L, (129.80±29.32) ng/L, t=7.10, 12.44, both P<0.05]. The serum concentration of proinflammatory cytokines such as MCP-1, TNF-α, and IL-1ß were significantly increased in tumorous group when compared with healthy group, and decreased after analgesic therapy (all P<0.05). The expression of anti-inflammatory cytokines such as IL-10, IL-13, and TGF-ß were significantly increased in tumorous group when compared with healthy group, and decreased after analgesic therapy (all P<0.05).Compared with healthy group, the levels of MCP-1/IL-10, MCP-1/IL-13, MCP-1/TGF-ß, TNF-α/IL-10, TNF-α/IL-13, TNF-α/TGF-ß, IL-1ß/IL-10, IL-1ß/IL-13, IL-1ß/TGF-ß were significantly increased in tumorous group (all P<0.05). Conclusion: HMGB1 may adjust the proinflammatory-anti-inflammatory system homeostasis to participate in the development of bone metastatic pain.

[Relationship between C-C chemokine receptor type 2 and P38 mitogen-activated protein kinase signaling pathway in the spinal cord of rats with bone cancer pain].

Objective: To investigate the relationship between C-C chemokine receptor type 2(CCR2) and P38 mitogen-activated protein kinase (P38MAPK) signaling pathway in the spinal cord of rats and further clarify the mechanism of bone cancer pain (BCP). Methods: A total of 92 healthy female SD rats, of which 60 were subjected to behavioral tests using a ciliary mechanical stimulation needle. SD rats were randomly divided into six groups: sham operation group (group S), bone cancer pain group (group B), sham operation + DMSO solvent group (group SD), bone cancer pain + DMSO solvent group (group BD), sham operation + RS102895 CCR2 inhibitor group (group SR), bone cancer pain + RS102895 CCR2 inhibitor group (group BR), and Von Frey was used in the behavioral test. Another 32 SD rats were randomly divided into the following 8 groups (n=4): sham operation group (group S), bone cancer pain 5 d group (group B5), bone cancer pain 9 d group (group B9), bone cancer pain 14 d group (group B14), bone cancer pain + DMSO solvent group (group BD), bone cancer pain + RS102895 CCR2 inhibitor 0.5 h group (group BR0.5 h), bone cancer pain + RS102895 CCR2 inhibitor 4 h group (group BR4 h), bone cancer pain + RS102895 CCR2 inhibitor 12 h group (group BR12 h). Western blot was used to detect the expression of P38, p-P38 and CCR2 in spinal cord of rats. Results: At day 5, 7, 9, 14, 21 post-injection, mechanical withdrawal thresholds of group S were(30.9±1.5), (31.9±1.2), (32.0±1.1), (31.6±1.5), (32.2±1.4)g respectively, the mechanical withdrawal thresholds of group B were( 26.4±0.7), (24.4±0.8), (21.4±0.8), (13.5±0.4), (9.9±0.2)g respectively, the mechanical withdrawal thresholds in group B decreased obviously versus group S, and the differences were statistically significant(t=-13.177, -16.660, -23.778, -35.574, -48.401, all P<0.01). At day 9 post-injection, the mechanical withdrawal thresholds in SD, BD, SR and BR groups were (32.4±1.7), (19.4±1.1), (32.1±1.3), (26.3±1.0) g respectively, the difference was statistically significant (F=224.681, P<0.01), and the mechanical withdrawal thresholds in group BD decreased obviously versus group SD, while the mechanical withdrawal thresholds in group BR increased obviously versus group BD. The expression levels of p-P38 in spinal cord of group S, group B5, group B9 and group B14 were(0.08±0.03), (0.20±0.05), (0.40±0.17), (0.65±0.14)respectively, the expression levels of CCR2 were(0.08±0.04), (0.18±0.05), (0.30±0.09), (0.58±0.07)respectively, the difference was statistically significant(F=19.123, 40.746, all P<0.01), and the expression of p-P38 and CCR2 in group B9 were showed a significant up-regulation versus group S. The expression levels of p-P38 in spinal cord of group BD, group BR0.5 h, group BR4 h and group BR12 h were (0.57±0.06), (0.17±0.11), (0.03±0.01), (0.25±0.11)respectively, and the difference was statistically significant(F=29.582, P<0.01). The expression of p-P38 in group BR0.5 h, BR4 h, BR12 h showed a significant down-regulation versus group BD. Conclusion: CCR2 in the spinal cord may be involved in the development of bone cancer pain by activating P38MAPK signaling pathway in rats.

Partial stapled hemorrhoidopexy versus circular stapled hemorrhoidopexy for grade III-IV prolapsing hemorrhoids: a two-year prospective controlled study.

BACKGROUND: Circular stapled hemorrhoidopexy (CSH) is an effective technique for treating prolapsing hemorrhoids; but urgency and anal stenosis are common postoperative complications. The aim of this study was to assess the efficacy and postoperative outcomes of partial stapled hemorrhoidopexy (PSH), compared with CSH. METHODS: Seventy-two consecutive patients with grade III and IV hemorrhoids who met the inclusion/exclusion criteria were divided in a non-randomized manner to undergo either PSH (n = 34) or CSH (n = 38). Intraoperative and postoperative parameters in both groups were collected and compared. RESULTS: The postoperative visual analog score for pain at first defecation was significantly lower in the PSH group than that in the CSH group (P = 0.001). Fewer patients in the PSH group experienced postoperative urgency, compared with those in the CSH group at 12 h, 1 day, and 7 days after surgery (P = 0.025, P = 0.019, and P = 0.043, respectively). Gas incontinence occurred in 3 patients (7.9%) in the CSH group, but in none of patients in the PSH group (P = 0.242). Postoperative anal stenosis developed in one patient (2.6%) in the CSH group, but in none of the patients in the PSH group (P = 1.0). The 2-year recurrence rate was 2.9 and 5.3%, respectively, in the PSH and CSH groups (P = 1.0). CONCLUSIONS: The 2-year recurrence rate is similar in patients with grade III-IV hemorrhoids treated with PSH or CSH. However, PSH is associated with less postoperative pain, fewer episodes of urgency, and no anal incontinence or anal stenosis.

Activation of p38MAPK in spinal microglia contributes to autologous nucleus pulposus-induced mechanical hyperalgesia in a modified rat model of lumbar disk herniation.

Recent studies have implicated the activation of p38 mitogen-activated protein kinase (MAPK) and glial cells contribute to hyperalgesia following nerve injury or nerve compression. In our work, we investigated the underlying mechanisms of autologous nucleus pulposus (NP)-induced mechanical hyperalgesia in a modified rat model of lumbar disk herniation (LDH). Firstly, our results showed that 50% mechanical withdrawal threshold (50% MWT) decreased on postoperative day (POD) 1 and significantly minimally reduced on POD 7 and lasted for day 28 after surgery (P < 0.05). Secondly, phosphorylation of p38MAPK (p-p38MAPK) and glial cells were monitored on POD 1, 3, 7, 14 and 28 using immunofluorescence staining. P38MAPK activation, observed in the spinal cord, began to increase on POD 1, peaked on POD 3, and significantly decreased on POD 14 and POD 28 (P < 0.05). Microglia activation was initiated at day 1, maximal at day 3, and maintained until day 14 after surgery (P < 0.05). Astrocytic activation was found in 7 to 14 days after modelling (P < 0.05). Then, double immunostaining method was applied to observe the co-expression of p-p38MAPK and glial cells, and it showed that p-p38MAPK was mainly expressed in activated microglia, rarely in neurons, and none in astrocytes. Lastly, we discovered that both SB203580 (50ug, p38MAPK inhibitor) and minocycline (0.5 mg, microglial inhibitor) would inhibit the p-p38MAPK protein expression tested by western blot analysis and reduce mechanical hyperalgesia. In conclusion, current study suggest that activation or phosphorylation of p38MAPK in spinal microglia contributes to autologous NP-induced mechanical hyperalgesia in our animal model.

GLI2 induces PDGFRB expression and modulates cancer stem cell properties of gastric cancer.

OBJECTIVE: In this study, we aimed to investigate the downstream effector of GLI2 in gastric cancer (GC) and their regulative effect on cancer stem cell (CSC) properties of GC. MATERIALS AND METHODS: Bioinformatic data mining was performed in TCGA-Stomach Adenocarcinoma (STAD), as well as in Kaplan-Meier plotter. Moderate-differentiated GC cell line SGC-7901 and poor-differentiated GC cell line MKN-45 were used as in-vitro model to investigate the regulative effect of GLI2 on PDGFRB expression. MKN-45 cells were further used to explore the effect of GLI2 shRNA or PDGFRB shRNA on CSC properties of the cells. RESULTS: Bioinformatic results showed that GLI2 is usually upregulated in GC tissues than in normal tissues, and high GLI2 expression is associated with unfavorable first progression free survival (PFS) and also worse overall survival (OS) in patients with GC. PDGFRB is co-upregulated with GLI2 in GC and its promoter region contains a putative GLI2 binding site. The results of dual luciferase assay confirmed this binding site. Enforced GLI2 expression elevated PDGFRB expression at both mRNA and protein level. GLI2 or PDGFRB knockdown showed similar effect on reducing spheroid colony formation and on reducing the expression of CSC related genes, including CD44, Nanog, and Oct4 in MKN-45 cells. CONCLUSIONS: High GLI2 or PDGFRB expression is associated with unfavorable survival in GC patients. GLI2 can induce PDGFRB expression in GC cells via directly binding to its promoter. In addition, the GLI2-PDGFRB axis might be an important signaling pathway modulating CSC properties of GC cells.

Pseudogap and proximity effect in the Bi2Te3/Fe1+yTe interfacial superconductor.

In the interfacial superconductor Bi2Te3/Fe1+yTe, two dimensional superconductivity occurs in direct vicinity to the surface state of a topological insulator. If this state were to become involved in superconductivity, under certain conditions a topological superconducting state could be formed, which is of high interest due to the possibility of creating Majorana fermionic states. We report directional point-contact spectroscopy data on the novel Bi2Te3/Fe1+yTe interfacial superconductor for a Bi2Te3 thickness of 9 quintuple layers, bonded by van der Waals epitaxy to a Fe1+yTe film at an atomically sharp interface. Our data show highly unconventional superconductivity, which appears as complex as in the cuprate high temperature superconductors. A very large superconducting twin-gap structure is replaced by a pseudogap above ~12 K which persists up to 40 K. While the larger gap shows unconventional order parameter symmetry and is attributed to a thin FeTe layer in proximity to the interface, the smaller gap is associated with superconductivity induced via the proximity effect in the topological insulator Bi2Te3.

The regulatory effects of cytokines on lymphatic angiogenesis.

The effects of fibroblast growth factor basic (bFGF), transforming growth factor alpha (TGF alpha), recombinant human epidermal growth factor (EGF), recombinant human tumor necrosis factor alpha (TNF alpha), and recombinant interleukin 1 alpha (IL-1 alpha) on lymphatic angiogenesis were assessed in cultured newborn bovine lymphatic endothelial cells (NBLEC). bFGF, TGF alpha, and EGF stimulated the proliferation of NBLEC in a dose-dependent manner, but the combination of either two growth factors did not show synergistic effects on NBLEC DNA synthesis. TNF alpha and IL-1 alpha suppressed the multiplication of NBLEC. Treatment with bFGF markedly increased the migration of NBLEC. The tissue plasminogen activator (t-PA) activity was enhanced by bFGF. TNF alpha also promoted NBLEC t-PA activity. These results suggest that bFGF is a major multifunctional lymphatic endothelial cell targeted cytokine, and both growth and pro-inflammatory cytokines exert differential regulatory effects on lymphatic endothelial cell proliferation, migration and t-PA activity.