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Supplementary Figures 1-2 from Contribution of Granulocyte Colony-Stimulating Factor to the Acute Mobilization of Endothelial Precursor Cells by Vascular Disrupting Agents

Supplementary Methods from Contribution of Granulocyte Colony-Stimulating Factor to the Acute Mobilization of Endothelial Precursor Cells by Vascular Disrupting Agents

BackgroundThe impact of lymph nodes (LNs) removed on the survivals of patients with stage III gastric cancer, especially on that of those who undergo the adjuvant chemotherapy as a compensation for a possibly insufficient lymphadenectomy, is still unclear.MethodsConsecutive patients (n = 488) with stage III gastric cancer under R0 curative resection followed by adjuvant chemotherapy were analyzed. The overall survival (OS) was compared between patients with insufficient LNs removed (ILNr, 2 test, Akaike information criterion (AIC), Harrell’s concordance index (C-index), and area under the receiver operating characteristic curves (AUC).ResultsThe OS of patients were significantly longer in those with SLNr relative to those with ILNr (for stage IIIA, 68.2 vs. 43.2 months, P = 0.042; for stage IIIB, 43.7 vs. 24.9 months, P < 0.001; for stage IIIC, 23.9 vs. 8.3 months, P < 0.001; and for total stage III, 37.7 vs. 21.7 months, P < 0.001). However, the OS were similar between stage IIIA patients with ILNr and stage IIIB patients with SLNr (P = 0.928), between IIIB patients with ILNr and IIIC patients with SLNr (P = 0.962), and IIIC patients with ILNr and stage IV (P = 0.668), respectively. A substage increase in the AJCC classification system, from IIIA to IIIB, from IIIB to IIIC, and from IIIC to IV in patients with ILNr, enhanced the accuracy of prognostic prediction in patients with stage III gastric cancer compared to the current TNM system (Likelihood ratio χ2, 188.6 vs. 184.8; AIC, 4336.4 vs. 4340.6; C-index, 0.695 vs. 0.679, P = 0.002). The ROC curves revealed that the performance of prognostic prediction was better in the new prediction system (AUC = 0.699) compared with the current TNM system (AUC = 0.676).ConclusionsILNr (LNs

Vascular disrupting agents (VDA) cause acute shutdown of abnormal established tumor vasculature, followed by massive intratumoral hypoxia and necrosis. However, a viable rim of tumor tissue invariably remains from which tumor regrowth rapidly resumes. We have recently shown that an acute systemic mobilization and homing of bone marrow–derived circulating endothelial precursor (CEP) cells could promote tumor regrowth following treatment with either a VDA or certain chemotherapy drugs. The molecular mediators of this systemic reactive host process are unknown. Here, we show that following treatment of mice with OXi-4503, a second-generation potent prodrug derivative of combretastatin-A4 phosphate, rapid increases in circulating plasma vascular endothelial growth factor, stromal derived factor-1 (SDF-1), and granulocyte colony-stimulating factor (G-CSF) levels are detected. With the aim of determining whether G-CSF is involved in VDA-induced CEP mobilization, mutant G-CSF-R−/− mice were treated with OXi-4503. We found that as opposed to wild-type controls, G-CSF-R−/− mice failed to mobilize CEPs or show induction of SDF-1 plasma levels. Furthermore, Lewis lung carcinomas grown in such mice treated with OXi-4503 showed greater levels of necrosis compared with tumors treated in wild-type mice. Evidence for rapid elevations in circulating plasma G-CSF, vascular endothelial growth factor, and SDF-1 were also observed in patients with VDA (combretastatin-A4 phosphate)-treated cancer. These results highlight the possible effect of drug-induced G-CSF on tumor regrowth following certain cytotoxic drug therapies, in this case using a VDA, and hence G-CSF as a possible therapeutic target. [Cancer Res 2009;69(19):7524–8]

Mutations in TP53 lead to a defective G1 checkpoint and the dependence on checkpoint kinase 1 (Chk1) for G2 or S phase arrest in response to DNA damage. In preclinical studies, Chk1 inhibition resulted in enhanced cytotoxicity of several chemotherapeutic agents. The high frequency of TP53 mutations in triple negative breast cancer (TNBC: negative for estrogen receptor, progesterone receptor, and HER2) make Chk1 an attractive therapeutic target. UCN-01, a non-selective Chk1 inhibitor, combined with irinotecan demonstrated activity in advanced TNBC in our Phase I study. The goal of this trial was to further evaluate this treatment in women with TNBC. Patients with metastatic TNBC previously treated with anthracyclines and taxanes received irinotecan (100-125 mg/m(2) IV days 1, 8, 15, 22) and UCN-01 (70 mg/m(2) IV day 2, 35 mg/m(2) day 23 and subsequent doses) every 42-day cycle. Peripheral blood mononuclear cells (PBMC) and tumor specimens were collected. Twenty five patients were enrolled. The overall response (complete response (CR) + partial response (PR)) rate was 4 %. The clinical benefit rate (CR + PR + stable disease ≥6 months) was 12 %. Since UCN-01 inhibits PDK1, phosphorylated ribosomal protein S6 (pS6) in PBMC was assessed. Although reduced 24 h post UCN-01, pS6 levels rose to baseline by day 8, indicating loss of UCN-01 bioavailability. Immunostains of γH2AX and pChk1(S296) on serial tumor biopsies from four patients demonstrated an induction of DNA damage and Chk1 activation following irinotecan. However, Chk1 inhibition by UCN-01 was not observed in all tumors. Most tumors were basal-like (69 %), and carried mutations in TP53 (53 %). Median overall survival in patients with TP53 mutant tumors was poor compared to wild type (5.5 vs. 20.3 months, p = 0.004). This regimen had limited activity in TNBC. Inconsistent Chk1 inhibition was likely due to the pharmacokinetics of UCN-01. TP53 mutations were associated with a poor prognosis in metastatic TNBC.

Endovascular lung perfusion (ELP) is a technique designed to deliver high doses of cisplatin via the pulmonary artery for the treatment of lung tumors. The purpose of the current study was to evaluate variables that affect adduct formation.Thirteen swine underwent ELP. The first group (n = 6) underwent infusion of 150 mg cisplatin diluted to 0.5 mg/mL via a balloon occlusion catheter in the left pulmonary artery. Uptake was compared with that seen with systemic infusion. A second group (n = 7) underwent bilateral sequential infusion of the left pulmonary artery, followed by the right. Cisplatin (150 mg) was infused at one of three concentrations: 1 mg/mL (n = 5 lungs), 0.67 mg/mL (n = 5 lungs), or 0.5 mg/mL (n = 4 lungs). The Pearson coefficient was used to correlate uptake with infusion time, infusate concentration, animal weight, and initial mean pulmonary artery pressure.In the first group, cisplatin uptake in the control lung was less than 8% of that in the study lung. Infusion times for both groups ranged from 3 minutes to 56 minutes. Increases in infusion time correlated with increased adduct levels (r = 0.831; P.0001). Mean uptake at concentrations of 0.5, 0.67, and 1 mg/mL were 25.79, 12.43, and 13.12 fmol/mug, respectively. There was no significant correlation between pulmonary adduct levels and infusate concentration (r = 0.106; P = .72). Animal weight and initial mean pulmonary artery pressure were not correlated with adduct formation.ELP with longer infusions of cisplatin may lead to greater adduct formation in pulmonary tissues. Changes in concentration of the infusate do not affect uptake of cisplatin. Hemodynamic parameters do not affect cisplatin uptake.

Mucopolysaccharidosis I (MPS I) due to deficient alpha-L-iduronidase (IDUA) activity results in accumulation of glycosaminoglycans in many cells. Gene therapy could program liver to secrete enzyme with mannose 6-phosphate (M6P), and enzyme in blood could be taken up by other cells via the M6P receptor. Newborn MPS I mice were injected with 10(9) (high dose) or 10(8) (low dose) transducing units/kg of a retroviral vector (RV) expressing canine IDUA. Most animals achieved stable expression of IDUA in serum at 1240 +/- 147 and 110 +/- 31 units/ml, respectively. At 8 months, untreated MPS I mice had aortic insufficiency, increased bone mineral density (BMD), and reduced responses to sound and light. In contrast, MPS I mice that received high-dose RV had normal echocardiograms, BMD, auditory-evoked brain-stem responses, and electroretinograms. This is the first report of complete correction of these clinical manifestations in any model of mucopolysaccharidosis. Biochemical and pathologic evaluation confirmed that storage was reduced in these organs. Mice that received low-dose RV and achieved 30 units/ml of serum IDUA activity had no or only partial improvement. We conclude that high-dose neonatal gene therapy with an RV reduces some major clinical manifestations of MPS I in mice, but low dose is less effective.

To explore the risk factors and prognostic impact of duodenal hepatic ligamentous lymph node (No.12 LN) metastasis in cases with curable advanced distal gastric cancer.The data of 379 cases with advanced distal gastric cancer undergoing radical resection were screened from the Database of Gastric Cancer Center of Sun Yat-sen University from January 1997 to December 2010. According to No.12 LN metastasis, they were divided into negative (n = 339) and positive (n = 40) groups. Their clinicopathological parameters and surgical regimens were compared. And the risk factors and prognostic impact of No.12 LN metastasis were analyzed.No significant inter-group difference existed in gender, age, infiltration depth or differentiation degree (all P0.05). In negative and positive groups, the percent of tumor size ≥ 5 cm was 30.1% (102/339) vs 55.0% (22/40), lymph node metastasis N3 stage 8.3% (28/339) vs 42.5% (17/40), other lymph nodes except for No.12 metastasis 70.2% (238/339) vs 92.5% (37/40), distal metastasis M1 10.9% (37/339) vs 32.5% (13/40), TNM stage IV 18.6% (63/339) vs 65.0% (26/40), infiltration Borrmann type 74.3% (252/339) vs 92.5% (37/40), non-adenocarcinoma 15.9% (54/339) vs 35.0% (14/40) and positive serum-carcinoembryonic antigen (S-CEA) 12.7% (43/339) vs 32.5% (13/40). There were all with significant difference (all P0.01). Logistic regression analysis showed tumor size ≥ 5 cm, lymph node (except for No.12) metastasis, distal metastasis and positive S-CEA were independent risk factors of No.12 LN metastasis (OR = 2.144, 3.581, 2.597, 2.552; P = 0.035, 0.042, 0.019, 0.022 respectively). Cox regression analysis showed lymph nodes (except for No.12) and No.12 metastasis, distal metastasis and Borrmann type were independent prognostic factors for all cases. In negative and positive groups, median survival time was 63.0 versus 12.0 months with significant difference (P = 0.000).For cases with curable advanced distal gastric cancer, No.12 LN metastasis was an independent prognostic factor. No.12 LN should be dissected thoroughly in cases with tumor size ≥ 5 cm, lymph nodes (except No.12) metastasis, distal metastasis and positive S-CEA.

The acute-phase response can result in decreased liver-specific functions and death as a result of liver failure. We show here that lipopolysaccharide (LPS), an endotoxin that induces the acute-phase response, results in a marked decrease in the major isoforms of the transcription factor, hepatocyte nuclear factor 4 alpha (HNF-4 alpha), in livers of rats. HNF-4 alpha is a nuclear receptor that is critical for the expression of several liver-specific genes. This decrease in HNF-4 alpha is primarily the result of a posttranscriptional mechanism, because mRNA levels are normal, and there are no major changes in the splicing patterns. This decrease was of functional significance, because expression of a gene that is highly dependent on HNF-4 alpha, HNF-1 alpha, was reduced. Interleukin-1 beta (IL-1 beta) is a cytokine whose levels are increased in vivo in response to LPS. IL-1 beta resulted in a decrease in HNF-4 alpha levels in HepG2 cells. This IL-1 beta-induced decrease was likely caused by degradation via the proteasome, because it was prevented by the addition of the proteasome inhibitor, MG132. We conclude that the decrease in HNF-4 alpha that occurs in vivo after the administration of LPS may be the result of IL-1 beta-induced degradation, and likely contributes to the liver insufficiency that occurs. IL-1 beta antagonists or proteasome inhibitors might increase HNF-4 alpha protein levels in the acute-phase response, which could result in increased liver function and survival.

The liver regenerates by replication of differentiated hepatocytes after damage or removal of part of the liver. Although several growth factors and signaling pathways are activated during regeneration, it is unclear as to which of these are essential for hepatocyte replication. We show here that low- (1 mg/kg) and high- (10 mg/kg) dose hepatocyte growth factor (HGF) induced replication of 2.1% and 11.1% of hepatocytes in rats, respectively. Lipopolysaccharide (LPS), an inducer of the acute phase response, augmented hepatocyte replication in response to low- and high-dose HGF by 4- and 2-fold, respectively. HGF alone induced moderate levels of c-Jun-N-terminal kinase (JNK) and p44/p42 mitogen-activated protein kinase (MAPK), resulting in moderate levels of AP-1-DNA binding activity. The combination of LPS + HGF increased JNK and AP-1-DNA binding activity more than levels seen with LPS or HGF alone. The activation of Stat3 that was observed after administration of LPS + HGF, but not HGF alone, could contribute to increased transcription of AP-1 components. Because phosphorylation of the c-Jun component of AP-1 by JNK increases its ability to activate transcription, the AP-1 in hepatocytes from animals treated with LPS + HGF may be more active than in rats treated with LPS or HGF alone. LPS may contribute to hepatocyte replication by potentiating the effect of HGF on the activation of both AP-1-DNA binding and transcriptional activity.

Retroviral vectors can result in therapeutic and stable levels of expression of proteins from the liver. However, m ost retroviral vectors transduce only dividing cells, and hepatocytes are normally quiescent. The goal of this study was to determ ine if an adenoviral vector could transiently express hepatocyte growth factor (HG F) in order to induce hepatocyte replication and facilitate retroviral vector transduction of the liver. Intram uscular injection of an adenoviral vector that expressed human HGF from the cytomegalovirus promoter (Ad.C M V.HGF) resulted in m oderate levels of H GF in blood and liver, and replication of 3 to 12% of hepatocytes. No cytopathic effect was observed in the liver, and a control adenoviral vector induced no or lower levels of replication. W hen a retroviral vector expressing b -galactosidase cDNA was injected into a peripheral vein during the peak period of hepatocyte replication induced by intramuscularly adm inistered Ad.C M V.HG F, 8% of hepatocytes were transduced. W e conclude that intram uscular injection of Ad.C M V.HG F is a safe and effective way to induce transient systemic expression of HG F and hepatocyte replication, and to facilitate transduction of hepatocytes with a retroviral vector.

To explore the impact of clinicopathological features and extent of lymph node dissection on the prognosis in early gastric cancer (EGC) patients.A total of 142 EGC cases screened from database of gastric cancer of Sun Yat-sen University, from Aug. 1994 to Jan. 2010, were included in this study. According to the lymph node metastasis status, they were divided into lymph node negative (n = 116) and lymph node positive (n = 26) groups. The clinicopathological features of the two groups and the impact of extent of lymph node dissection on the prognosis were analyzed.There were no significant differences in age, gender, tumor size and location, Borrmann typing, WHO TNM staging, histological typing, and CEA value between the two groups (P0.05). The TNM stages in the lymph node positive group were higher than that in the lymph node negative group (P0.001). Between the cases who underwent D1 (n = 21) and D2 (n = 121) dissection, there were no significant differences in postoperative hospital days, blood transfusion volume, and operation time (P0.05). The median numbers of LN dissected in D1 and D2 cases were 4 (0 to 16) and 20 (12 to 30), with a significant difference (P = 0.000), but the number of positive LN without significant difference (P = 0.502). The postoperative complication rates were 9.5% in the D1 and 3.3% in the D2 dissection groups, without a significant difference (P = 0.128). The median survival time of the lymph node negative and positive groups was 156 vs. 96 months (P = 0.010). In cases who received D2 and D1 lymph node dissection, the median survival time (MST) was 156 vs. 96 months (P = 0.0022). In the lymph node positive group, D2 dissection prolonged survival time significantly than D1 dissection (96 vs. 27months) (P = 0.001). Cox regression analysis showed that the extent of lymph node dissection and LN metastasis were independent prognostic factors for EGC patients.It is not able to accurately assess the LN metastasis status preoperatively according to the routine clinicopathological features. For the patients with unknown LN metastasis status, D2 dissection should be the first choice. Comparing with D1 dissection, the morbidity of D2 dissection are not increased, but survival time is prolonged.

To elucidate the mechanism of Hedgehog pathway in the metastasis of gastric cancer and examine particularly the effect on epithelial-mesenchymal transition (EMT).Using pharmacological and siRNA knockdown approach, the Hedgehog pathway was inhibited. The cellular morphology, protein level, invasion and metastatic abilities were measured by microscope, Western blot, Transwell invasion assay and Transwell migration assay.Under the inhibition of Hedgehog pathway, the invasive and migration abilities of gastric cancer decreased. The transforming growth factor (TGF) -β could induce spindle-like-shaped morphological changes with a down-regulation of epithelial characteristic (decreased E-cadherin protein level) and an up-regulation of mesenchymal characteristics (increased Vimentin protein level). There were concurrent increases of invasive and migration potentials by 3 and 4 folds respectively.However, under the continuous stimulation of TGF-β, the inhibition of Hedgehog pathway could reverse the EMT changes, lower the expression of vimentin and reduce the invasion and metastatic abilities by 3 and 2 folds respectively.The inhibition of Hedgehog pathway can decrease the TGF-β-inducing EMT.It suggests that Hedgehog pathway may play a critical role in the metastasis of gastric cancer.

To evaluate the impact of different gastrectomy and reconstruction method on prognosis and quality of life in proximal gastric cancer.The 265 cases of proximal gastric cancer received radical resection, according to gastrectomy or reconstruction method, were divided into proximal gastrectomy/gastroesophagostomy group (PG) (n = 63) and total gastrectomy/esophagojejunostomy group (TG) (n = 202). The clinical pathologic features, prognosis, postoperative quality of life in 2 groups were compared.There had no significant differences in age, gender, CEA value between two groups (all P0.05). In PG and TG group, tumor size (cm), ratio of organic invasion, lymph nodes metastasis, distal metastasis, TNM IV stage, Borrmann typing, poor or undifferentiated carcinoma was 2.9 ± 1.9 vs. 4.8 ± 2.8, 9.5% vs. 32.2%, 64.7% vs. 70.6%, 0 vs. 8.4%, 6.9% vs. 31.8%, 44.4% vs. 69.2%, 31.7% vs. 53.7%, respectively, all with significant difference (t = -6.260, χ(2) = 29.473, 14.559, 5.665, 32.483, 12.588, 10.954, all P0.05). In PG and TG group, the ratio of D3 and D3(+) resection, multi-visceral resection, complications was 0 vs. 13.8%, 9.5% vs. 38.6%, 7.9% vs. 1.5% respectively, showed increasing range of resection and decreasing complications significantly in TG group (all P0.05). The median survival time (months) was 62.5 vs. 78.9 in TG and PG group respectively, without significant difference (P0.05). In 2 groups, the evaluation index of post-operative quality of life without significant differences (P0.05).For proximal gastric cancer, although the cases received TG with worse clinicopathological features, which prognosis was similar to that received PG. The postoperative quality of life without significant difference between the cases received gastroesophagostomy and esophagojejunostomy.

To investigate the effects of fast track surgery on postoperative insulin sensitivity on the basis of clinical benefits in patients undergoing elective open colorectal resection.During May 2008 to December 2008, Seventy patients with colorectal carcinoma requiring colorectal resection were randomized into two groups: a fast track group (35 cases) and a conventional care group (35 cases). All included patients received elective open colorectal resection with combined tracheal intubation and general anesthesia. Clinical parameters, stress markers and insulin sensitivity were evaluated in both groups.The 62 patients finally completed the study, 32 cases in the fast-track group and 30 cases in the conventional care group. The speed of recovery of postoperative insulin sensitivity on 7 days postoperative in the fast-track group (97% ± 9%) was significantly faster than the conventional care group (88.5% ± 9.0%, t = 2.552, P = 0.016). The hospitalization days in the fast-track group was 6 days (M(50)), and it was significantly shorter than the conventional care group ((11.7 ± 3.8) days, Z = 4.360, P = 0.000). The time of recovery of bowel function were faster in the fast-track group (time to pass flatus was 2 days (M(50))) than the conventional care group (4 days, Z = 3.976, P = 0.000). The Infectious complication rate in the fast-track group (2/32) is lower than the other group (8/30, P = 0.040).Fast track surgery accelerates recovery of postoperative insulin sensitivity in elective surgery for colorectal carcinoma with a lower rate of postoperative infectious complications and a shorter length of postoperative hospital stay.

To evaluate the impact of surgical modality for gastric cancer on operational trauma.A total of 1499 cases of gastric cancer undergoing surgical procedures were divided into the groups of radical resection (RR, n = 1344) and palliative resection group (NRR, n = 155) according to their surgical modalities. And they were further divided into sub-groups according to the profiles of gastrectomy, extent of lymphadenectomy and multi organic resection. The extent of operational trauma (as evaluated by operative duration, transfusion volume, postoperative hospital day and incidence of complications) was compared in different groups and subgroups.In RR and NRR groups, median transfusion volume (Q(1), Q(3)) was 0 (0, 600) vs 400 (0, 800) ml respectively. There was significant difference (P0.05). No significant difference existed in operative duration, postoperative hospital day or incidence of complications between two groups (all P0.05). In cases of distal gastrectomy, median transfusion volume was 0 (0, 400) vs 400 (200, 800) ml in RR and NRR groups (P0.05). No significant difference existed in operative duration, postoperative hospital day or incidence of complications between two groups (all P0.05). In cases of total gastrectomy, no significant difference existed in operative duration, postoperative hospital day, median transfusion volume or incidence of complications between two groups (all P0.05). In RR group, for the cases treated by D1, D2, D3 and paraaortic lymph node dissection (PAND), there were significant differences in operative duration ((248 ± 71), (271 ± 72), (309 ± 96), (351 ± 103) min), postoperative hospital day ((13 ± 4), (16 ± 12), (18 ± 11), (20 ± 19) days), median transfusion volume (0(0, 500), 0(0, 600), 400(0, 800), 600(200, 1000) ml) (all P0.05). But no significant difference existed in incidence of complications (P0.05). In RR group, operative duration, postoperative hospital day, median transfusion volume was (315 ± 96) vs (264 ± 66) min, (19 ± 15) vs (15 ± 11) days, 400 (0, 800) vs 0 (0, 400) ml in the patients with and without combined organic resection (all P0.05). But no significant difference existed in incidence of complications (P0.05).As compared with palliative resection, radical resection will not increase surgical trauma. For the cases of radical resection, extent of lymphadenectomy and organic resection increase surgical trauma.

Hepatic gene therapy might correct the clinical manifestations of several genetic disorders in patients. Although retroviral vectors with a strong liver-specific promoter can result in stable and therapeutic levels of expression of genes from the liver, application of these techniques in humans is limited by the need to perform one or more invasive procedures to achieve ex vivo or in vivo transduction of hepatocytes. In vivo delivery involves injection of retrovirus into the portal vein during liver regeneration. Although transduction is efficient and specific for the liver, induction of hepatocyte replication requires a 70% partial hepatectomy or administration of a liver toxin. An alternative method for inducing hepatocyte replication is to occlude branches of the portal vein. This results in apoptosis of hepatocytes in the occluded lobes and compensatory replication of the hepatocytes in the nonoccluded lobes. We demonstrate here that portal branch occlusion is nearly as effective as partial hepatectomy at facilitating retroviral vector transduction in vivo and has a lower morbidity. Portal branch occlusion could be performed in larger animals by minimally invasive techniques and has been used safely to treat human patients with liver cancer. Portal branch occlusion might ultimately be used in humans to facilitate retroviral vector transduction in vivo for the treatment of genetic diseases.

To compare Borrmann type IV gastric cancer with other types of cancer and explore their clinicopathological features and prognostic factors.We retrospectively reviewed the medical records of 893 consecutive advanced gastric cancer patients. They were divided into 2 groups: Borrmann type IV (n = 139) and other macroscopic Borrmann types of cancer (n = 754). Their clinicopathologic characteristics and overall survival data were analyzed.Borrmann type IV gastric cancer was found to be associated with more advanced and unfavorable clinicopathological features. The incidence of preoperative biopsy-negative rate of Borrmann type IV gastric cancer was much higher (15.9%) than other Borrmann types of gastric cancer. The 5-year survival rate of Borrmann type IV cancer patients was 9.9% and it was significantly lower than that of other types. Moreover, the 5-year survival rate was higher in the patients with curative resection (18.7%) (P0.05). Stratified analysis revealed that when the tumor TNM stages were of II, III, the survival data of Borrmann type IV cancer were worse than others. Multivariate analyses revealed distant metastasis and curability were independent prognostic factors for Borrmann type IV gastric cancer.Borrmann type IV carcinoma has poor clinicopathological features and survival rate compared with other types. An early detection and curative resection may improve the prognosis for the patients with Borrmann type IV cancer.

Pancreaticogastrostomy (PG) has been proposed as an alternative to pancreaticojejunostomy (PJ), assuming that postoperative complications are less frequent. The aim of this research was to compare the safety of PG with PJ reconstruction after pancreaticoduodenectomy.Articles of prospective controlled trials published until the end of December 2010 comparing PJ and PG after PD were searched by means of MEDLINE, EMBASE, Cochrane Controlled Trials Register databases, and Chinese Biomedical Database. After quality assessment of all included prospective controlled trials, meta-analysis was performed with Review Manager 5.0 for statistic analysis.Overall, six articles of prospective controlled trials were included. Of the 866 patients analyzed, 440 received PG and 426 were treated by PJ. Meta-analysis of six prospective controlled trials (including RCT and non-randomized prospective trial) revealed significant difference between PJ and PG regarding postoperative complication rates (OR, 0.53; 95%CI, 0.30 - 0.95; P = 0.03), pancreatic fistula (OR, 0.47; 95%CI, 0.22 - 0.97; P = 0.04), and intra-abdominal fluid collection (OR, 0.42; 95%CI, 0.25 - 0.72; P = 0.001). The difference in mortality was of no significance. Meta-analysis of four randomized controlled trials (RCT) revealed significant difference between PJ and PG regarding intra-abdominal fluid collection (OR, 0.46; 95% CI, 0.26 - 0.79; P = 0.005). The differences in pancreatic fistula, postoperative complications, delayed gastric emptying, and mortality were of no significance.Meta-analysis of six prospective controlled trials (including randomized controlled trials (RCT) and non-randomized prospective trial) revealed significant difference between PJ and PG regarding overall postoperative complications, pancreatic fistula, and intra-abdominal fluid collection. Meta-analysis of four RCT revealed significant difference between PJ and PG with regard to intra-abdominal fluid collection. The results suggest that PG may be as safe as PJ.

Few clinical studies or randomized clinical trial results have reported the impact of fast track surgery on postoperative insulin sensitivity. This study aimed to investigate the effects of fast track surgery on postoperative insulin sensitivity in patients undergoing elective open colorectal resection.Controlled, randomized clinical trial was conducted from November 2008 to January 2009 with one-month post-discharge follow-up. Seventy patients with colorectal carcinoma requiring colorectal resection were randomized into two groups: a fast track group (35 cases) and a conventional care group (35 cases). All included patients received elective open colorectal resection with combined tracheal intubation and general anesthesia. Clinical parameters (complication rates, return of gastrointestinal function and postoperative length of stay), stress index and insulin sensitivity were evaluated in both groups perioperatively.Sixty-two patients finally completed the study, 32 cases in the fast-track group and 30 cases in the conventional care group. Our findings revealed a significantly faster recovery of postoperative insulin sensitivity on postoperative day 7 in the fast-track group than that in the conventional care group. We also found a significantly shorter length of postoperative stay and a significantly faster return of gastrointestinal function in patients undergoing fast-track rehabilitation.Fast track surgery accelerates the recovery of postoperative insulin sensitivity in elective surgery for colorectal carcinoma with a shorter length of postoperative hospital stay.

To explore the effects of fast-track surgery on postoperative humoral immune function in patients undergoing elective colorectal resection.Seventy patients with colorectal carcinoma requiring colorectal resection were randomized into fast-track group (n = 35) and conventional care group (n = 35). The clinical parameters and markers of humeral immune function were evaluated in both groups postoperatively.Sixty-two patients finally completed the study, including 32 in the fast-track group and 30 in the conventional care group. There was a significantly faster recovery of postoperative humoral immunity: blood levels of globulin (24.1 ± 2.4 vs 22.1 ± 3.3 g/L, P = 0.025), immunoglobulin G (10.79 ± 2.39 vs 8.66 ± 2.09 g/L, P = 0.007) and complement 4 (0.24 ± 0.09 vs 0.17 ± 0.05 g/L, P = 0.035) at Day 3 postoperation were higher in the fast-track group than in the conventional care group. And there was also a significantly shorter length of postoperative stay (6.0 ± 1.0 vs 11.7 ± 3.8 d, P0.001) in patients undergoing fast-track rehabilitation.Fast-track surgery accelerates the recovery of postoperative humoral immune function in elective surgery for colorectal carcinoma with a shorter length of postoperative hospital stay.

To compare the nutritional status between pancreaticojejunostomy(PJ) and pancreaticogastrostomy(PG) following pancreaticoduodenectomy.A retrospective clinical analysis was performed on 37 patients undergoing pancreaticoduodenectomy(PD) for duodenal carcinoma and pancreatic non-epithelial tumor with PG(n=19) and PJ(n=18) in the First Hospital of Sun Yat-sen University from April 2006 to December 2010. All the patients had a needle catheter jejunostomy inserted at the conclusion of laparotomy. Postoperative early enteral nutrition and parenteral nutrition was performed for all the patients. Nutritional status of two groups was compared in body mass index (BMI), serum nutritional parameters such as albumin, transferrin and prealbumin before surgery and on 1, 3, and 6 months postoperatively.There were no significant differences between PG and PJ groups in operative time, blood loss, pancreatic fistula, perioperative death, or postoperative length of hospital stay. One month after surgery, there were no significant differences in BMI [(17.1±7.0) vs. (19.0±4.8) kg/m(2), P0.05], albumin [(30.1±0.5) vs. (32.1±1.3) g/L, P0.05], transferrin [(1.89±0.57) vs. (2.01±0.61) g/L, P0.05] and prealbumin[(0.18±0.05) vs. (0.18±0.09) g/L, P0.05]. These parameters were decreased at 1 month after surgery, and gradually recovered to baseline or higher than the preoperative levels at 6 months after surgery. However, the differences were still not statistically significant between two groups.The influence of PJ and PG on the postoperative nutritional status are comparable.

To evaluate the efficacy and influencing factors of imatinib in patients with advanced gastrointestinal stromal tumor(GIST).From April 2004 to January 2010, clinicopathological data of 73 adult patients with advanced GIST treated with imatinib at the First Affiliated Hospital of Sun Yat-sen University were retrospectively analyzed. The treatment outcomes and associated factors were investigated.Treatment outcomes included complete response in 1(1.4%) patients, partial response in 53(72.6%), stable disease in 14(19.2%), and primary resistant in 5(6.8%). All the patients had routine followed up, the length of which ranged from 12 to 76 (median 32) months. The median progression-free survival was 45.0 months(95% confidence interval, 34.2-55.8). The progression-free survival(PFS) rate was 87.7% in 1 year, 63.6% in 3 year, and 39.6% in 5 years. On multivariate analysis, both mutation status and patient performance were independent factors influencing the efficacy of imatinib treatment(both P0.01). PFS was significantly better in patients with c-kit exon 11 mutations than those with exon 9 mutations, and better in lower ECOG scales than in higher ones.Imatinib is effective in treating patients with advanced GIST, c-kit exon 9 mutations and poor performance status predict an adverse survival benefit of imatinib therapy.

To compare the reconstructing safety of pancreaticogastrostomy (PG) versus pancreaticojejunostomy (PJ) after pancreaticoduodenectomy (PD).The articles of prospectively controlled trials published until late December 2010 comparing PJ and PG after PD were searched by the means of MEDLINE, EMBASE, Cochrane Controlled Trials Register databases and Chinese Biomedical Database. After quality assessment of all included prospective controlled trials, a meta-analysis was performed with Review Manager 5.0 for statistic analysis.A total of 6 prospective controlled trials were included. Among 867 patients analyzed, 440 underwent PG and 426 PJ. A meta-analysis of 6 prospective controlled trials (including randomized control trial (RCT) and non-randomized prospective trial) revealed significant differences between PJ and PG regarding the overall postoperative complication rates [OR 0.53, 95%CI (0.30, 0.95), P = 0.03], pancreatic fistula [OR 0.47, 95%CI (0.22, 0.97), P = 0.04] and intra-abdominal fluid collection [OR 0.42, 95%CI (0.25, 0.72), P = 0.001]. The differences in biliary fistula, intra-abdominal (IAC) complications and mortality were of no significance. Meta-analysis of 4 RCTs revealed significant differences between PJ and PG regarding intra-abdominal fluid collection [OR 0.46, 95%CI (0.26, 0.79), P = 0.005]. The differences in pancreatic fistula, overall postoperative complications, biliary fistula, intra-abdominal complications and mortality were of no statistical significance.Through a meta-analysis of 6 prospective controlled trials, there are significant differences between PJ and PG regarding overall postoperative complications, pancreatic fistula and intra-abdominal fluid collection. Significant differences exist between PJ and PG regarding intra-abdominal fluid collection. The safety profiles of PG and PJ are comparable.

To compare the clinical outcomes of laparoscopic-assisted versus hand-assisted laparoscopic radical operations in colorectal cancer and evaluate the safety and indications of hand-assisted laparoscopic operations.A total of 64 consecutive colorectal cancer patients enrolled from November 2009 to December 2011 at our hospital were randomly and prospectively divided into 2 groups: hand-assisted laparoscopic operation (HALS) (n = 32) and laparoscopic-assisted operation (n = 32). And such clinicopathologic features as safety, operative curability and postoperative recovery were compared between two groups.Neither death nor conversion-to-open-surgery was reported among all patients. There were no statistical differences in such clinicopathologic features as age, gender, body mass index, mass size and location (all P0.05). There were statistically a shorter operation time [(127 ± 31) min vs (184 ± 71) min, P = 0.022] and a smaller number of Trocar (2.4 vs 5.0, P = 0.015) in the HALS group. However, the laparoscopic-assisted group had a lesser volume of blood loss [(82 ± 31) ml vs (150 ± 42) ml, P = 0.008] and a smaller postoperative 48 h drainage flow [(170 ± 52) ml vs (208 ± 58) ml, P = 0.020]. Moreover, no statistical differences existed in the length of bowel resection [(19 ± 5) cm vs (18 ± 4) cm], amount of lymph nodes dissection (16 ± 4 vs 16 ± 3), postoperative complications [12.5% (4/32) vs 25.0% (8/32)], time of intestinal function recovery [(1.7 ± 0.9) d vs (1.8 ± 0.7) d], time of semifluid tolerance [(2.9 ± 1.3) vs (2.8 ± 1.2) d], hospitalization expenses [(4.8 ± 0.6) 10 000 yuan vs (4.9 ± 0.4) 10 000 yuan] and postoperative hospital stay [(6.7 ± 2.3) d vs (6.6 ± 2.3) d] (all P0.05).HALS is both safe and efficacious for colorectal cancer patients.

To explore whether neutrophil-lymphocyte ratio (NLR) is an effective prognostic marker in gastric cancer.Clinical data of 775 patients with gastric cancer in the First Affiliated Hospital of Sun Yat-sen University from 1994 to 2006 were analyzed retrospectively. According to preoperative NLR, the patients were divided into the low NLR group (NLR≤3.79, n=652) and the high NLR group (NLR3.79, n=123). The 5-year survival rates of two groups of different TNM stage, different surgical intervention were separately analyzed.The 5-year survival rates in the low NLR group and high NLR group were 44.0% and 12.2% respectively (P0.01). In different TNM stages: stage I (97.8% vs 33.3%), stage II (55.4% vs 32.0%), stage IIIA (30.2% vs 11.1%), stage IIIB (15.5% vs 8.3%), stage IV (10.7% vs 2.1%), and in different surgical intervention: D1 curative gastrectomy (93.3% 33.3%), D2 group (51.3% vs 20.4%), D3 group (42.4% vs 10.5%), D4 group (14.3% vs 2.0%), and in palliative operation group (8.3% vs 2.2%). There were significant differences of 5-year survival rate in TNM staging and surgical procedures between the high and low NLR groups (all P0.05).Preoperative NLR may be a prognostic marker in patients with gastric cancer.

The association of hepatitis B virus (HBV) infection and pancreatic cancer is still controversial. The purpose of this study is to determine whether chronic HBV infection increases the risk.In this case-control study, there were 1,066 patients recruited, with 533 in the study group and 533 controls, frequency-matched for age and sex. Blood samples were collected to detect hepatitis viral infection.Compared to 77 patients (14.4%) in the control group, 80 pancreatic cancer patients (15.0%) were seropositive for HBV surface antigen (not statistically significant, P=0.8). The prevalence of HBV e antigen was higher in study group than that of control group (P=0.03). Further analysis indicated that HBeAg was a risk factor for pancreatic cancer (OR=2.935, 95% CI: 1.048-8.220).In HBV endemic area of China, there appears to be no significant association between chronic HBV infection and pancreatic cancer, but the role of HBeAg needs further exploration.

Splenic cysts are unusual in daily surgical practice and less than 1000 cases have been reported. Primary, true or epithelial splenic cysts, are even rarer. Usually, most of the cysts are asymptomatic until of significant size, at which time they are then detected incidentally on ultrasonography or CT scan. We report a case of a 25-year-old woman with giant epithelial splenic cyst with about 3000 ml of clear-yellow fluid was collected from the cyst. The splenectomy specimen measured 205 mm × 192 mm × 137 mm and weighed 4000 g.

To report a case of rectal non-Hodgkin lymphoma with concomitant rectal adenocarcinoma.Clinical records of a 71 years old male patient with rectal non-Hodgkin lymphoma with concomitant rectal adenocarcinoma admitted on May 19, 2010 to the First Affiliated Hospital of Sun Yet-sen University were retrospectively reviewed. Clinical manifestations, diagnosis, and treatment as well as postoperative pathology were summarized.The preoperative diagnosis of the patient was severe atypical adenomatous hyperplasia with focal carcinogenesis, and the preoperative staging was T2N0-1M0. The patient underwent a Parks procedure (rectal resection and colo-anal anastomosis) and subtotal resection of left lateral liver. The operation was successful, postoperative recovery uneventful. Postoperative pathology showed moderately differentiated tubular adenocarcinoma with deep muscular invasion, and non-Hodgkin lymphoma with marginal zone cell. Both the distal and proximal resection margins were negative and no vascular and neural invasion were seen. Immunohistochemical staining indicated L26(+), Bcl-2(+), Bcl-6(+), CD3(-), CD23(-), CK epithelial cells(+), and M-CEA luminal border(+). The pathological and immunohistochemistry results of liver specimens showed hepatic mucosa-associated marginal zone lymphoma.Rectal adenocarcinoma and lymphoma occurring at the same site simultaneously is extremely rare with unique pathologic features.

To investigate the molecular mechanism involved in the downregulation of vascular endothelial growth factor(VEGF) expression through the suppression of signal transducer and activator of transcription 3(Stat3) by(-)-Epigallocatechin-3-gallate (EGCG).After human gastric cancer cells (AGS) were treated with IL-6 (50 μg/L) and EGCG(0, 5, 10, 25 or 50 μmol/L), the expression levels of VEGF, total Stat3(tStat3), and activated Stat3(pStat3) in tumor cells were examined by Western blotting. The influence of the inhibitor of Stat3 pathway on the IL-6-induced VEGF expression was investigated. VEGF protein level in tumor cell culture medium was determined by ELISA and VEGF mRNA expression in tumor cells by RT-PCR. Tumor cell nuclear extract was prepared and nuclear expression of pStat3 was detected. Stat3-DNA binding activity was examined with chromatin immunoprecipitation (ChIP) assay.IL-6 significantly increased VEGF expression in AGS gastric cancer cells. Compared with the group without IL-6, the expression and secretion of VEGF protein, and mRNA expression increased by 2.4 fold,2.8 fold, and 3.1 fold(all P0.01), respectively. EGCG treatment markedly reduced VEGF protein, release and mRNA expression in a dose-dependent manner. When compared with the control group induced by IL-6, EGCG and AG490(a Stat3 pathway inhibitor) significantly inhibited VEGF expression induced by IL-6 (P0.01). EGCG dose-dependently inhibited pStat3 induced by IL-6(P0.05), but not tStat3 (P0.05). Stat3 nuclear translocation and Stat3-DNA binding activity in AGS cells or that induced by IL-6 were directly inhibited by EGCG(P0.05).EGCG reduces expression of VEGF in gastric cancer cells through the inhibition of Stat3 activity.

Distal pancreatectomy traditionally included splenectomy; the spleen, however, is an important organ in the immunologic defense of the host and is worthy of preservation. The aim of this research was to study the feasibility, safety and clinical effects of spleen and splenic vessel-preserving distal pancreatectomy.A retrospective review was performed for 26 patients undergoing distal pancreatectomy for benign or low grade malignant disease with splenectomy (n = 13) or splenic preservation (n = 13) at the First Hospital of Sun Yat-sen University and Guangdong General Hospital in Southern China from May 2002 to April 2009.All 26 pancreatectomies with splenectomy or splenic preservation were performed successfully. There was no statistically significant difference between two groups in mean operative time ((172 ± 47) minutes vs. (157 ± 52) minutes, P0.05), intraoperative estimated blood loss ((183 ± 68) ml vs. (160 ± 51) ml, P0.05), incidence of noninfectious and infection complication and mean length of postoperative hospital stay ((10.1 ± 2.2) days vs. (12.1 ± 4.6) days, P0.05). The platelet counts examined one week after operation were significantly higher in the distal pancreatectomy with splenectomy group than the other group ((37.3 ± 12.8) × 10(9)/L vs. (54.7 ± 13.2) × 10(9)/L, P0.05).Spleen-preserving distal pancreatectomy appears to be a feasible and safe procedure. In selected cases of benign or low-grade malignant disease, spleen-preserving distal pancreatectomy is recommended.

To investigate the clinicopathological characteristics between mucinous gastric cancer (MGC) and poorly differentiated gastric cancer(PDGC) and factors associated with prognosis.Medical records of 1016 consecutive patients with gastric cancer were retrospectively reviewed. Sixty-eight patients with MGC and 508 with PDGC were identified. Clinicopathologic characteristics and overall survival data were analyzed.As compared to PDGC patients, patients with MGC were significantly older [(59.2±11.9) years vs. (54.1±13.2) years], had significantly more distant metastasis(36.8% vs. 23.8%), more peritoneal seeding(29.4% vs. 16.9%), and less radical resection(60.3% vs. 76.6%). There were no significant differences in 5-year survival rate between MGC and PDGC patients(29.4% vs. 35.5%). However, for tumors in the middle third of the stomach, the survival rate of MGC patients was lower than that of PDGC. Using a Cox proportional hazard ratio model, lymph node involvement and radical resection were independent prognostic factors for survival of MGC patients, while tumor invasion, lymph node involvement, and radical resection were associated with survival in patients with PDGC.Although MGC and PDGC differ in age, frequencies of peritoneal seeding, distant metastasis, and rate of radical resection, overall survival is comparable.

Diabetes mellitus plays an important role in cancer prevalence and outcomes. The aim of this study was to evaluate the influence of DM on stages and outcomes among patients with colorectal cancer.The study enrolled 945 patients who were diagnosed as having colorectal carcinoma from August 1994 to December 2002. In the cohort, 26 patients were diagnosed as having DM. With a median follow-up of 45.8 months, differences in overall survival and disease-free survival between the diabetes and non-diabetes groups were analyzed.Kaplan and Meier analysis showed that there were no significant differences between the two groups in overall survival rates at 3 years or 5 years. At 5 years, patients with DM, compared with patients without diabetes, experienced a significantly lower disease-free survival rate (34.2% diabetics vs. 55.1% non-diabetics; P = 0.025).DM was associated with an increased risk of recurrence in patients with colorectal cancer.

To explore the clinical characteristics and the prognostic factors of patients with colorectal cancer.The data of 2042 cases of colorectal cancer, pathologically confirmed at our hospital from January 1995 to December 2007, were summarized and analyzed.The median age of all cases with colorectal cancer was 59 years old. The high-risk age ranged from 50 to 70 years old. The ratio of male and female was 1.4:1. The lesions located in rectum accounted for 46.2% and those for 22.0% in sigmoid. Patients under age 40 had a higher percentage of poor differentiation (33.5%) and mucinous carcinoma (16.7%). The cases with confirmed stage I, II, III and IV were 5.8%, 42.9%, 31.0% and 20.3% respectively. For all cases, the 1-, 3-, 5- and 10-year survival rates were 92.3%, 73.9%, 65.1% and 57.5% respectively. The independent risk factors for patient prognosis were age, gross type, differentiation, TNM staging and surgical type. Adjuvant chemotherapy was a protective factor. As compared with phase I (1995 - 2001), phase II (2002 - 2007) had a higher proportions of employing stapler, Dixon operation and adjuvant chemotherapy. The 1-, 3- and 5-year survival rates of phase II were higher than phase I (93.4%, 78.0% and 73.2% vs 90.6%, 69.2% and 58.8%).The prognostic factors of patients with colorectal cancer are age, gross type, differentiation, TNM staging, surgical type and adjuvant chemotherapy.

To explore the expression of serine protease Omi/HtrA2 in gastric carcinoma tissue and its association with clinicopathological features and prognosis.Omi/HtrA2 protein expression levels were detected by immunohistochemistry method in resected gastric carcinomas(n=68), adjacent noncancerous tissues(n=15), and normal tissues(n=15), and its association with clinicopathological features and prognosis were analyzed.Omi/HtrA2 expression was positive in 73.5%(50/68) of gastric cancer tissues, which was significantly higher than that in adjacent noncancerous tissues and normal tissues(P0.05). There were no significant differences in Omi/HtrA2 expression with respect to sex, age, tumor size, and depth of invasion(all P0.05). Omi/HtrA2 expression level was significantly associated with tumor differentiation, extent of lymph node metastasis, and tumor stage(all P0.05). Overall 5-year survival rate of patients with gastric carcinoma was 63.3%. Five-year survival rate was higher in Omi/HtrA2 positive cases than Omi/HtrA2 negative cases(72.0% vs. 61.1%), however the difference was not statistically significant.Omi/HtrA2 expression is more common in gastric carcinoma. Omi/HtrA2 expression is associated with tumor differentiation, extent of lymph node metastasis, and tumor stage.

To investigate the clinicopathologic features, diagnosis and treatment of neuroendocrine carcinoma (NEC) in the digestive system.Thirty-eight patients with NEC from Jan 1985 to Mar 2008 were analyzed retrospectively and the related literatures were reviewed.There were 29 males and 9 females. Common symptoms were melena or hematochezia (n=21, 55%), abdominal pain (n=19, 50%), abdominal mass (n=15, 39%), constipation (n=14, 37%), rectal mass (n=12, 32%), abdominal distention (n=11,29%) and diarrhea (n=7,18%). All the patients received surgical treatment including 1 esophagectomy, 5 radical total gastrectomies, 1 palliation proximal gastric resection, 2 local gastric resections, 6 pancreaticoduodenectomies, 1 distal pancreatectomies, 3 partial small intestine resections, 7 radical right hemicolectomies, 5 Dixon operations, 3 Miles operations, and 4 local resections of rectal tumor. Thirty-six patients received follow-up. The follow-up time ranged from 3 months to 144 months (median, 70 months). The 1-, 3- and 5-year survival rates were 94.7%, 86.8%, and 57.9% respectively. The median survival time was 62 months. The survival time of the patients with carcinoma infiltration exceeding bowel muscularis propria was (36+/-5) months, significantly shorter than that of patients without carcinoma infiltration exceeding the bowel muscularis propria [(73+/-5) months, P0.05]. The survival time of the patients with positive lymph node metastasis was (34+/-7) months, significantly shorter than that of patients with negative lymph node metastasis [(74+/-5) months, P0.05].Clinical symptoms, signs of neuroendocrine carcinoma in the digestive system are nonspecific. The correct diagnosis should depend on histopathologic examination. Systematic treatments including radical resection of NEC are the preferable treatment.

To investigate the clinical effect of surgery following systemic targeted therapy of tyrosine kinase inhibitors (TKIs) in patients with metastatic gastrointestinal stromal tumors (GIST).From June 2007 to December 2009, data of 15 consecutive patients with metastatic GIST treated with imatinib/sunitinib followed by surgery were retrospectively analyzed.Disease responses to TKI treatment was categorized into controlled disease (including partial response and stable disease) (6, 40.0%), limited progression (4, 26.7%), and generalized progression (5, 33.3%), respectively. Surgeries were performed after mean 12 months following TKI therapies. Gross complete resection or optimal debulking with minimal residual disease were managed to performed in 8/10 patients with disease controlled and limited progression, while optimal debulking only achieved in 2/5 patients with generalized progression. Surgical morbidity was 20.0% (3/15). After operation, patients with disease controlled and limited progression had a median progression-free survival of 25.0 months and 2-year overall survival rate of 100%. In contrast, for patients with generalized progression, the median progression- free survival was 3 months (P0.01), and median overall survival 10.5 months.Patients with metastatic GIST who have controlled disease or limited progression to TKI therapy can benefit from surgical resection. Surgery should be selective in patients with generalized progression since surgery hardly improves survival in these patients.

Purpose UCN-01 (7-hydroxystaurosporine) is a multi-targeted protein kinase inhibitor that exhibits synergistic activity with DNA-damaging agents in preclinical studies. We conducted a Phase I study to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic, and pharmacodynamic effects of UCN-01 and irinotecan in patients with resistant solid tumors. Experimental design Patients received irinotecan (75–125 mg/m2 IV on days 1, 8, 15, 22) and UCN-01 (50–90 mg/m2 IV on day 2 and 25–45 mg/m2 on day 23 and subsequent doses) every 42 days. Blood for pharmacokinetics of UCN-01 and irinotecan, and blood, normal rectal mucosa, and tumor biopsies for pharmacodynamic studies were obtained. Results Twenty-five patients enrolled to 5 dose levels. The MTD was irinotecan 125 mg/m2 on days 1, 8, 15, 22 and UCN-01 70 mg/m2 on day 2 and 35 mg/m2 on day 23. DLTs included grade 3 diarrhea/dehydration and dyspnea. UCN-01 had a prolonged half-life and a low clearance rate. There was a significant reduction in SN-38 Cmax and aminopentanocarboxylic acid (APC) and SN-38 glucuronide half-lives. Phosphorylated ribosomal protein S6 was reduced in blood, normal rectal mucosa, and tumor biopsies at 24 h post-UCN-01. Two partial responses were observed in women with ER, PgR, and HER2-negative breast cancers (TBNC). Both tumors were defective for p53. Twelve patients had stable disease (mean duration 18 weeks, range 7–30 weeks). Conclusion UCN-01 and irinotecan demonstrated acceptable toxicity and target inhibition. Anti-tumor activity was observed and a study of this combination in women with TNBC is underway. Electronic supplementary material The online version of this article (doi:10.1007/s00280-010-1410-1) contains supplementary material, which is available to authorized users.

To investigate clinicopathological characteristics and the pattern of lymph node metastasis of patients with gastric remnant cancer.The data of the clinicopathological characteristics and the pattern of lymph node metastasis in 56 patients with gastric remnant cancer treated from March 1994 to December 2008 was investigated and compared with those in 1171 patients with primary gastric cancer treated over the same period.Fifty-six patients (4.6%) with gastric remnant cancer were enrolled in this study during the period. Compared with patients with primary gastric cancer, the age of cancer onset was older [(64.3+/-9.0) vs. (58.3+/-12.6) yrs], lymph node metastasis rate was higher (31.8% vs. 25.5%), Borrmann's classification was later and neighbor organ resection rate was higher (57.1% vs. 26.4%) in patients with gastric remnant cancer; the differences were all significant (chi2=18.800, 11.679, 9.177, 25.190; P0.05). Patients with gastric remnant cancer who underwent lymph node dissection tended to have a higher incidence of No.10 (splenic hilar lymph node) and No.11 (splenic artery lymph node) group lymph node metastasis than those in primary gastric cancer (chi2=5.558, 6.099; P0.05). In contrast, patients with primary gastric cancer had a higher incidence of No. 2 (left cardiac lymph node), No.3 (lesser curvature lymph node) and No.8 (common hepatic artery lymph node) group lymph node metastasis than those in gastric remnant cancer (chi2=15.508, 6.003, 4.084; P0.05). The jejunal mesentery lymph node metastasis was 24.0% (6/25) in patients with gastric remnant cancer and the peripheral connective tissue infiltration rate was 14.3% (8/56).It suggested that patients with gastric remnant cancer has different clinicopathologic characteristics and the pattern of lymph node metastasis from those with primary gastric cancer. D2 lymph node dissection of proximate gastric cancer and jejunal mesentery lymph node dissection should be the standard operation for these patients; but combined neighboring organ resection should be taken into consideration.

To evaluate the value of EUS and PET-CT in combination with spiral CT in preoperative assessment of gastric cancer invasion to the pancreas.Sixty advanced gastric cancer patients with suspected pancreatic invasion detected by spiral CT were selected in this study. All the 60 cases were then examined by EUS and 14 of them by PET-CT. The results were compared and evaluated with the findings during surgical operation and pathological results.The rate of correct preoperative diagnosis of pancreatic invasion by spiral CT in advanced gastric cancer patients was 63.3%, with an overdiagnosis rate of 36.7%. The diagnostic accuracy was increased to 87.8% and overdiagnosis reduced to 7.3%, when combined with EUS. There was a significant difference in diagnostic accuracy between spiral CT alone and spiral CT combined with EUS (P0.01), but no significant difference between spiral CT alone and spiral CT combined with PET-CT (P0.05). Spiral CT-EUS was more valuable in assessment of tumor location and invasion than PET-CT (P0.01).The accuracy of spiral CT alone in the preoperative assessment of advanced gastric cancer with invasion to the pancreas is not high enough yet at present. Spiral CT combined with EUS can provide more accurate information on the tumor location, invasion site and extent of gastric cancer invasion to the pancreas, and reduce the overstaging rate caused by spiral CT alone. However, spiral CT combined with PET-CT does not show such improvement significantly.

Mesh reconstruction has been proved to be an effective method in incisional hernia repairment. This study was designed to evaluate the effect of reconstructing the pelvic floor with the high-inlay expanded polytetrafluoroethylene (ePTFE) GORE-TEX Dual Mesh (WLGore And Associates, Flagstuff, USA) in abdominoperineal resection.Sixty patients who underwent abdominoperineal resection for rectal cancer were assigned to 2 groups. The pelvic peritoneum was closed by routine sutures in group 1 and reconstructed with ePTFE in group 2. Postoperative complications and related items were evaluated and the patients were followed up.Time of confining to bed, bowel function recovery, fasting, and detaining drainage were significantly different between two groups (P0.05). In group 1, three patients developed bowel obstruction (10%), while no bowel obstruction was observed in group 2.Reconstruction of the pelvic floor using ePTFE results in quicker postoperative recovery and could decrease the risk of postoperative intestinal obstruction.

To investigate the protein expression, methylation promoter, somatic and germ-line mutations of E-cadherin gene (CDH1) in hereditary gastric cancer in China and to investigate its possible roles.Eight probands diagnosed with ICG-HGC criterion were enrolled in our database from June 1994 to October 2007. Tumor tissues were detected for CDH1 expression by using immunohistochemistry (IHC) methods. CDH1 DNA sequencing was performed for all its 16 exons both in tumor and normal tissues of the same patients to detect somatic and germ-line mutations. Methylation promoter study was performed by using specific primers and polymerase chain reaction (PCR) methods.IHC analysis confirmed that the CDH1 expression was negative in 7 probands and downregulated in the other on proband. Six mutations in five probands were found with DNA sequencing: two silent mutations and four missense mutations. All six mutations were absent in normal tissues, thereby excluded its presence in germ-line cells. Both DNA missense mutations and gene silencing through promoter methylation was found in 4 probands. Two probands has only promoter methylation and one proband had only silent mutation. No DNA missense mutations or promoter methylation was found in one proband.CDH1 gene germ-line mutations are relatively rare in hereditary gastric cancer in China, and whereas CDH1 somatic mutations and promoter methylation synergistically induce CDH1 downregulation in these patients.

To investigate the clinicopathological characteristics and prognosis of colorectal mucinous adenocarcinoma (MAC) and non-mucinous adenocarcinoma (NMAC).Clinical data of 2089 cases with colorectal cancer from 1994 to 2007 in our hospital, including 169 patients diagnosed as mucinous adenocarcinoma were analyzed retrospectively.As compared to NMAC, the tumor diameter of MAC was longer[(5.52+/-3.56) cm vs (4.62+/-2.68) cm, P0.01]; the age of MAC was younger [(52.3+/-16.5) vs (58.7+/-13.6) years, P0.01]. The rates of tumor location in colon (97 cases,57.4% vs 814 cases, 44.3%, in MAC and NMAC) were significantly different (P0.01). Compared with NMAC, MAC had more lymph node involvement (103 cases, 60.9% vs 929 cases, 50.1%), more often in serosa infiltration (116 cases, 68.7% vs 914 cases, 49.8%), more peritoneal dissemination (26 cases, 15.4% vs 125 cases, 6.8%), and adjacent organ invasion (44 cases, 26.0% vs 300 cases, 16.3%) (P0.01). The rate of radical resection (86.4% vs 91.5%), hepatic metastasis (5.3% vs 8.5%) and local recurrence had no significant difference between patients with mucinous and non-mucinous adenocarcinoma (P0.05). In comparison to NMAC patients, MAC patients were worse in long-term overall survival, the survival of receiving radical resection and of TNM stage (II+III) group (P0.01). Survivals were not significantly different in TNM stage I and IV groups between mucinous and non-mucinous adenocarcinoma (P0.05).Colorectal mucinous adenocarcinoma patients have worse outcome in comparison to non-mucinous adenocarcinoma patients. Mucinous adenocarcinoma may have special biological behavior, which is an independent prognostic factor for patients with colorectal cancer.

Previous studies have shown conflicting results on the relation between clinicopathologic features and prognosis of patients with colorectal mucinous, signet-ring cell, or non-mucinous adenocarcinoma; only few such studies have been performed in China. This retrospective study analyzed data from our department to investigate clinicopathologic characteristics, prognosis and possible correlations of three histologic types - colorectal mucinous, signet-ring cell, and non-mucinous adenocarcinoma, to clarify the bases for observed differences which may lead to development of targeted therapies.Of 2079 patients diagnosed with colorectal cancer between 1994 and 2007, 144 had mucinous, 25 had signet-ring cell, and 1837 had non-mucinous adenocarcinoma. Their clinicopathologic parameters and survival were analyzed using established statistical methodologies.Mucinous and signet-ring cell adenocarcinomas were common in younger patients (P0.001). Location, size and disease stage differed significantly among the three types. Signet-ring cell tumors were more commonly found in the rectum than mucinous and non-mucinous adenocarcinoma (P0.001). Mucinous and signet-ring cell tumors presented in a later stage in life more often than non-mucinous adenocarcinoma, with lymph node involvement, serosal infiltration, peritoneal dissemination, and adjacent organ invasion (P0.01). The rate of radical resection, hepatic metastasis and local recurrence did not differ among types (P0.05). Compared with patients with non-mucinous adenocarcinoma, patients with mucinous and signet-ring cell tumors who underwent potentially curative resections or stage II/III disease had poorer long-term overall survival. Survival did not differ by type for patients with either stage I or IV disease (P0.05).Mucinous and signet-ring cell adenocarcinoma have unique carcinogenesis and similar biologic behavior. Our study confirms that both histologic types, especially signet-ring cell tumors, are independent, negative prognostic factors for patients with colorectal cancer. Type does not appear to have a significant effect on survival when disease is either stage I or IV at presentation.

Although the indication and the timing for surgery in fulminant acute pancreatitis (FAP) are still controversial, our experience of surgical treatment for fulminant acute pancreatitis may help improve the outcome for patients.The clinical data of twenty-six patients with FAP from January 1, 2001 to October 1, 2005 were analyzed. The diagnostic criteria fitted the 2007 Guidelines for the Management of Severe Acute Pancreatitis by the Chinese Medical Association.Twenty-six patients with FAP received surgical debridement, with a mortality rate of 42.3% (11/26). The postoperative mortalities in the72 hour operation group and theor= 72 hour operation group were highly significantly different (7/8 vs 22.2% (4/18), respectively).Early surgery may reduce the intraabdominal pressure and prevent the deterioration of FAP. An operation within 72 hours from the onset of symptoms might decrease the mortality of the disease.

To evaluate and compare the results of vagina vasorum lymph node dissection (VLND) and non-vagina vasorum lymph node dissection (NVLND) in patients with gastric cancer after radical operation.A total of 759 cases of evaluable patients with gastric cancer, operated from June 1994 to April 2005, were retrospectively analyzed. Of which, 627 cases underwent radical gastrectomy: 215 patients received VLND and 412 cases received NVLND. The operation time, intraoperative blood loss, operative complications and survival rate were recorded and compared between the two groups.The 5- and 10-year overall accumulative survival rates of VLND group and NVLND group were 55.4% and 51.2%, 39.1%and 36.8%, respectively (all P0.05). No significant differences in intraoperative blood transfusion (loss), operation time, operative complication rate was found between the two groups. The 5- and 10-year accumulative survival in patients with a tumor of phase N0-N2, T2-T4, Ib-IV in VLND groups were all significant higher than those in NVLND group.VLND is a safe technique in advanced gastric cancer, it dose not prolong operation time or increase operative complications but improves survival.

To investigate whether albumin administration is beneficial in early stage of postoperative hypoalbuminemia after gastrointestinal surgery.A prospective randomized control trial was designed. One hundred and twenty-seven patients suffered from hypoalbuminemia after gastrointestinal surgery were randomly divided into albumin group (64 cases) and saline group (control group, 63 cases) by using random number form. The albumin group was given 100 ml 20% human albumin daily for 3 days; and in control group, saline 100 ml daily was administered for 3 days after the operation. The disease course of postoperative hypoalbuminemia, nutritional status, complications and hospital stay were compared between the two groups.Plasma albumin level in both groups decreased significantly after the operation (P0.05). No significant differences was found in the change of postoperative plasma albumin level between the two groups (P0.05). Postoperative plasma albumin, total protein and pre-albumin levels were similar in the two groups. Three-day and 5-day plasma albumin recovery ratios were similar in the two groups, and the 7-day recovery ratio was lower in the albumin group (P0.05). No significant difference was found in the incidence of postoperative complications between the two groups (23.4% vs. 12.7%, P = 0.116).Albumin administration in early stage of postoperative hypoalbuminemia following gastrointestinal surgery is not beneficial either in correcting hypoalbuminemia or in clinical outcomes.

To compare the clinicopathologic parameters of gastric carcinoma between different phases and to investigate the prognostic factors for gastric carcinoma.A total of 1016 consecutive gastric cancer patients were divided into two groups according to operating date, phase I (1994 - 1996) and phase II (2000 - 2006). The clinicopathologic parameters and prognosis were compared between the two phases. The prognostic factors were analyzed and compared.There were significant differences in the constituent ratio of male and female patients, the proportions of early gastric carcinoma, different TNM staged patients, specialized operation and adjuvant chemotherapy (all P0.05), but no significant differences in tumor location, peritoneal spread, lymph node metastasis and radical resection between the two phases. The overall 5-year survival rate and 5-year survival rate after curative resection were 48.1% and 61.5% respectively within phase II, significantly higher than 32.8% and 42.4% within phase I (all P0.01). Stratification analysis revealed that the survival rates of patients with curative resection, lymph node metastasis or not, advanced disease, different TNM stages, specialized operation, without adjuvant chemotherapy within phase II, were significantly higher than those within phase I (all P0.01). Multivariant regression analysis revealed that Borrmann type, histological type, depth of invasion, lymph node metastasis, curative resection, adjuvant chemotherapy and different phase were independent prognostic factors for gastric carcinoma.The therapeutic efficacy of gastric carcinoma within phase II was improved greatly as a result of elevated diagnostic rate of early gastric cancer, standardized radical operation and adjuvant chemotherapy. Gastric carcinoma within phase II was improved highly. It was elevated diagnostic rate of early gastric cancer, standardized radical operation, and adjuvant chemotherapy that contribute to such improvement.

To investigate the outcome of repairing pelvic autonomic nerve defects with the tissue-engineered nerve, in order to provide a new method and experimental evidence for solving sexual disturbance induced by pelvic autonomic nerve injury after radical resection of rectal carcinoma.Bone marrow stromal cells (BMSCs) were purified with density gradient centrifugation. A 10 mm defect of hypogastric nerve was created in 9 Beagle dogs and the 18 hypogastric nerves were randomly divided into three groups. Group A: nerve defects bridged with copolymer of lactic and glycolic acids (PLGA) tube containing BMSCs and collagen protein sponge. Group B: with PLGA tube only containing collagen protein sponge. Group C: with autologous nerve graft. The effect of nerve recovery was evaluated by morphology, HE staining, neurofilament immunohistochemistry staining, electron microscope scanning and measurement quantity of new axon 12 weeks after the transplantation.Twelve weeks after the transplantation, degradation of PLGA tubes showed in group A and group B. The nerves regenerated through defect area to distal end. The density of regeneration nerve fiber in group A and group C were better than that in group B. The difference was significant between group A or group C and group B (P0.05), and no significant difference was observed between group A and group C(P0.05).Tissue-engineered nerve, which is constructed by BMSCs mixed with collagen protein sponge and PLGA tube, can be used to bridge and repair the pelvic autonomic nerve defect.