Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial.

BACKGROUND: The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy. METHODS: We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral capecitabine 1000 mg/m2 twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral S-1 40-60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day one of each 21 day plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546. FINDINGS: Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5-56·3) in the adjuvant-CapOx group, 56·5% (51·0-61·7) in the adjuvant-SOX group, and 59·4% (53·8-64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61-0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68-1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3-4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported. INTERPRETATION: Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer. FUNDING: National Key Research and Development Program of China, Beijing Scholars Program 2018-2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Surgical treatment of huge hepatocarcinoma with invasion or severe adhesion of diaphragm using the technique of orthotopic liver resection.

BACKGROUND/AIMS: To explore the clinical application and significance of the technique of orthotopic liver resection. METHODOLOGY: From January 2004 to December 2011, five patients with huge hepatocellular carcinoma with invasion or severe adhesion of diaphragm were undergone right semi-liver resection using the technique of orthotopic liver resection. The right hemi-liver was isolated from the first liver portal, second liver portal and third liver portal, then isolated from the normal liver, finally the tumor and the invaded diaphragm were resected or removed from the severe adhesion. The approach to hepatic resection involved routine use of Peng's multifunctional operative dissector, selective control of in and out-flow of liver, control of inferior vena cava (IVC) and liver hanging maneuver, anterior approach, etc. RESULTS: The operations were successfully performed in 5 patients. Operative time was 120, 180, 150, 150 and 160 min, respectively. The amount of blood loss were 350, 350, 400, 450, 600 ml, respectively. Postoperative complications were pleural effusion in 3 cases, and other 2 cases recovered without complications. CONCLUSIONS: Although the technique of orthotopic liver resection has a high technical requirement for surgeons, it provides a surgical method and operative opportunity for the patients whose tumor has invaded diaphragm or has been severe adhesion with diaphragm and conventional liver resection cannot be performed.

Circulating methylated MINT2 promoter DNA is a potential poor prognostic factor in gastric cancer.

BACKGROUND AND AIM: Aberrant DNA methylation has been shown to be associated with the growth, development, metastasis, and prognosis of tumors. Methylated DNAs may be suitable biomarkers for cancer patients. Here, we investigated whether circulating methylated MINT2 DNAs represent a potential poor prognostic factor in gastric cancer (GC). METHODS: MINT2 methylation was detected by real-time methylation-specific PCR in tumor tissues, pairing preoperative peritoneal lavage fluid (PPLF) and blood from 92 GC patients. The theory meaning and clinical practicality value of MINT2 methylation in different specimens were analyzed. RESULTS: The methylation status of the MINT2 gene was found to be significantly higher in tumor tissues (44.6%, 41/92) than in adjacent normal tissues (3.3%, 3/92). No MINT2 methylation was found in healthy controls, and partial MINT2 methylation was observed in three (6.25%, 3/48) patients with chronic atrophic gastritis. The frequency of MINT2 methylation in pairing PPLF and blood samples from 92 GC patients was 40.2% (37/92) and 39.1% (36/92), respectively. Methylated MINT2 in tumor tissues, pairing PPLF, and blood samples were very approximate. Aberrant MINT2 methylation in tumor tissues and pairing PPLF or blood samples were closely related to peritoneal dissemination, tumor progression, and poor prognosis (all P < 0.0001). CONCLUSIONS: Aberrant MINT2 methylation in PPLF/blood may predict peritoneal micrometastasis for GC patients, which is a potential poor prognostic factor in GC.

Belinostat-induced apoptosis and growth inhibition in pancreatic cancer cells involve activation of TAK1-AMPK signaling axis.

Pancreatic cancer accounts for more than 250,000 deaths worldwide each year. Recent studies have shown that belinostat, a novel pan histone deacetylases inhibitor (HDACi) induces apoptosis and growth inhibition in pancreatic cancer cells. However, the underlying mechanisms are not fully understood. In the current study, we found that AMP-activated protein kinase (AMPK) activation was required for belinostat-induced apoptosis and anti-proliferation in PANC-1 pancreatic cancer cells. A significant AMPK activation was induced by belinostat in PANC-1 cells. Inhibition of AMPK by RNAi knockdown or dominant negative (DN) mutation significantly inhibited belinostat-induced apoptosis in PANC-1 cells. Reversely, AMPK activator AICAR and A-769662 exerted strong cytotoxicity in PANC-1 cells. Belinostat promoted reactive oxygen species (ROS) production in PANC-1 cells, increased ROS induced transforming growth factor-ß-activating kinase 1 (TAK1)/AMPK association to activate AMPK. Meanwhile, anti-oxidants N-Acetyl-Cysteine (NAC) and MnTBAP as well as TAK1 shRNA knockdown suppressed belinostat-induced AMPK activation and PANC-1 cell apoptosis. In conclusion, we propose that belinostat-induced apoptosis and growth inhibition require the activation of ROS-TAK1-AMPK signaling axis in cultured pancreatic cancer cells.

Is surgery necessary for patients with hepatic angiomyolipoma? Retrospective analysis from eight Chinese cases.

BACKGROUND AND AIM: Hepatic angiomyolipoma (AML) is a rare, hepatic mesenchymal neoplasm. Its preoperative diagnosis is very difficult, and the treatment is still controversial. The aim is to summarize experience in diagnosis and management of hepatic AML from a cancer center. METHODS: We retrospectively reviewed the clinical presentation, histopathological, features and treatment of the tumors encountered at our institute from January 2000 to December 2012. RESULTS: The patients included six females and two males, with female preponderance. Six patients are asymptomatic. Laboratory tests lack specificity. Combining imaging modality, only one patient obtained the accurate diagnosis of hepatic AML and was confirmed by fine-needle aspiration biopsy combined with homatropine methylbromide-45 staining. All other patients received hepatic resection. There was no tumor recurrence or increase of tumor size within the follow-up period. CONCLUSION: We suggest fine-needle aspiration combined with homatropine methylbromide-45 staining should be performed in all patients who are asymptomatic and without serological abnormalities. Surgical resection might be considered only if the malignant potential of the lesion cannot be ruled out or the tumor size is increasing during observation.

The PI3K/Akt pathway mediates the protection of SO(2) preconditioning against myocardial ischemia/reperfusion injury in rats.

AIM: To explore the mechanisms underlying the protection by SO2 preconditioning against rat myocardial ischemia/reperfusion (I/R) injury. METHODS: Male Wistar rats underwent 30-min left coronary artery ligation followed by 120-min reperfusion. An SO2 donor (1 µmol/kg) was intravenously injected 10 min before the ischemia, while LY294002 (0.3 mg/kg) was intravenously injected 30 min before the ischemia. Plasma activities of LDH and CK were measured with an automatic enzyme analyzer. Myocardial infarct size was detected using Evans-TTC method. The activities of caspase-3 and -9 in myocardium were assayed using a commercial kit, and the levels of p-Akt, Akt, PI3K and p-PI3K were examined with Western blotting. RESULTS: Pretreatment with SO2 significantly reduced the myocardial infarct size and plasma LDH and CK activities, as well as myocardial caspase-3 and -9 activities in the rats. Furthermore, the pretreatment significantly increased the expression levels of myocardial p-Akt and p-PI3K p85. Administration of the PI3K inhibitor LY294002 blocked all the effects induced by SO2 pretreatment. CONCLUSION: The results suggest that the PI3K/Akt pathway mediates the protective effects of SO2 preconditioning against myocardial I/R injury in rats.

Stepwise cumulation of RUNX3 methylation mediated by Helicobacter pylori infection contributes to gastric carcinoma progression.

BACKGROUND: Helicobacter pylori has been recognized as a definite carcinogen for gastric cancer (GC); however, the pathogenesis of H. pylori infection remains unclear. Runt-related transcription factor 3 (RUNX3) is a candidate tumor suppressor gene whose deficiency is causally related to GC. However, in H. pylori infection-associated GC, the role of RUNX3 has not been studied. METHODS: The authors used real-time methylation-specific polymerase chain reaction analysis to determine methylation status of the RUNX3 promoter in a spectrum of gastric lesions, including 220 samples of chronic atrophic gastritis, 196 samples of intestinal metaplasia, 134 samples of gastric adenoma, 102 samples of dysplasia, and 202 samples of GC with paired noncancerous mucosa tissues and corresponding blood specimens. The association of abnormal methylation with precancerous gastric lesions was evaluated along with the association between RUNX3 methylation and H. pylori infection, and the concordance of methylation levels was investigated between serum and tissues. RESULTS: The results indicated that increasing RUNX3 promoter methylation was correlated with distinct stages of GC progression. GC tissues had the highest methylation proportion (75.2%) compared with precancerous gastric lesions, including chronic atrophic gastritis (15.9%), intestinal metaplasia (36.7%), gastric adenoma (41.8%), and dysplasia (54.9%). H. pylori infection, a major risk factor for GC, contributed to the inactivation of RUNX3 in gastric epithelial cells through promoter hypermethylation. The levels of RUNX3 methylation in serum were in significant concordance with the methylation levels observed in GC tissues (P = .887). CONCLUSIONS: The current findings supported RUNX3 methylation as a risk factors for the carcinogenesis of chronic atrophic gastritis with H. pylori infection and indicated that circulating RUNX3 methylation is a valuable biomarker for the detection of early GC.

CDH1 methylation in preoperative peritoneal washes is an independent prognostic factor for gastric cancer.

BACKGROUND AND OBJECTIVES: To investigate the clinical value of CDH1 methylation in preoperative peritoneal washes (PPW) from gastric cancer patients. METHODS: CDH1 methylation was detected by real-time methylation specific-PCR in tumor tissues and corresponding PPW from 92 gastric cancer patients, gastric mucosa from 40 chronic gastritis patients and 48 normal persons. RESULTS: CDH1 methylation was found in 75 of 92 (81.5%) gastric cancer tissues, which significantly correlated with size, growth pattern, differentiation, lymphatic invasion, venous invasion, invasion depth, lymph node metastasis, distant metastasis, and TNM stage of tumor (all P < 0.05), but its relationship to age, gender, tumor site, and H. pylori infection was not found (all P > 0.05). The percentage of CDH1 methylation in PPW was 48.9%, of which the Aζ value of ROC curve was 0.8 compared to that in gastric cancer tissues. Kaplan-Meier analysis showed that there was a significant difference in disease-free survival (DFS) between the patients with or without methylated CDH1 in their PPW (χ(2) = 109.64, P < 0.000). Cox regression analysis revealed CDH1 methylation in PPW was an independent risk factor for gastric cancer patients, with a remarkable decrease in DFS after postoperative 30 months. CONCLUSIONS: Methylated CDH1 in PPW predicts poor prognosis for gastric cancer patients.

CDK Inhibition Reverses Acquired 5-Fluorouracil Resistance in Hepatocellular Carcinoma Cells.

Background: 5-Fluorouracil (5-FU) has been widely applied in treating cancers. However, its usage is largely limited in hepatocellular carcinoma (HCC), due to acquired resistance. Here, we aim to identify target proteins and investigate their roles in 5-FU sensitivity of HCC cells. Methods: Mass spectrometry (MS) proteomics was performed on 5-FU-resistant cell line (BEL7402/5-FU) and its parental cell line (BEL7402) with 5-FU treatment. In order to identify potential targets, we compared the proteomics between two cell line groups and used bioinformatics tools to select hub proteins from all differentially expressed proteins. Results: We finally focused on a group of cell cycle-related kinases (CDKs). By CCK8 assay, we confirmed that the CDK inhibitor significantly decreased the IC50 of 5-FU-resistant cells. Conclusions: Our study verified that CDK inhibition can reverse 5-FU resistance of HCC cells.

Effect of S-1 Plus Oxaliplatin Compared With Fluorouracil, Leucovorin Plus Oxaliplatin as Perioperative Chemotherapy for Locally Advanced, Resectable Gastric Cancer: A Randomized Clinical Trial.

IMPORTANCE: Perioperative chemotherapy is a potential treatment for locally advanced gastric cancer. However, the optimal chemotherapy regimen remains unknown. OBJECTIVE: To investigate the safety and efficacy of S-1 plus oxaliplatin (SOX) vs fluorouracil, leucovorin, and oxaliplatin (FOLFOX) as a perioperative chemotherapy regimen for patients with locally advanced gastric cancer. DESIGN, SETTING, AND PARTICIPANTS: In this phase 3, open-label, multicenter, randomized clinical trial, patients from 12 Chinese hospitals were enrolled between June 2011 and August 2016, with a last follow-up date of September 2019. The primary tumor was evaluated as either invading the serosa or the adjacent structures with or without metastatic lymph nodes, and with no evidence of distant metastases. Data were analyzed from December 2019 to June 2020. INTERVENTIONS: Patients were randomly assigned (1:1) to receive either 6 perioperative (2-4 preoperative and 2-4 postoperative) 3-week cycles of 130 mg/m2 oxaliplatin on day 1 and 80 to 120 mg/d S-1 orally daily for 2 weeks (SOX) or 130 mg/m2 oxaliplatin, 400 mg/m2 fluorouracil, 400 mg/m2 leucovorin, and 2400 mg/m2 fluorouracil as 46-hour infusion on day 1 (FOLFOX). MAIN OUTCOMES AND MEASURES: The primary end point was 3-year overall survival (OS). An absolute noninferiority margin of -8% was chosen. RESULTS: A total of 583 patients were enrolled; 293 were randomized to the SOX group and 290 were randomized to the FOLFOX group. Twelve patients (2.1%) refused preoperative chemotherapy (5 patients in the SOX group and 7 patients in the FOLFOX group), leaving a total of 288 patients in the SOX group (median [range] age, 61 [24 to 78] years; 197 men [68.4%]) and 283 patients in the FOLFOX group (median [range] age, 62 [24 to 80] years; 209 men [73.9%]) who received preoperative chemotherapy. The 3-year OS rate was 75.2% (95% CI, 70.3% to 80.5%) in the SOX group and 67.8% (95% CI, 62.5% to 73.5%) in the FOLFOX group. The absolute difference of 3-year OS rate between the 2 groups was 7.4% (95% CI, -0.1% to 14.9%), which was greater than the prespecified noninferiority margin (-8%) and showed the noninferiority of perioperative chemotherapy with SOX compared with FOLFOX. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, SOX was noninferior to FOLFOX as perioperative chemotherapy for patients with locally advanced gastric cancer and could be recommended as an alternative treatment for these patients in Asia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01364376.

Effect of sulfur dioxide preconditioning on rat myocardial ischemia/reperfusion injury by inducing endoplasmic reticulum stress.

Sulfur dioxide has recently been found to be produced endogenously in the cardiovascular system and have important positive biological effects. However, it is unknown whether sulfur dioxide preconditioning has a protective effect on rat myocardial ischemia/reperfusion (I/R) injury and whether this process involves endoplasmic reticulum stress (ERS). In this study, we showed that preconditioning with sulfur dioxide 10 min before ischemia (with a low concentration of sulfur dioxide of 1-10 µmol/kg) could reduce myocardial infarct size and plasma activities of lactate dehydrogenase and creatine kinase in rats with I/R in vivo. Sulfur dioxide preconditioning also reduced myocardium apoptosis induced by I/R. In addition, sulfur dioxide preconditioning increased cardiac function in vitro. Sulfur dioxide preconditioning induced expression of myocardial glucose-regulated protein 78 (GRP78) and phosphorylated eukaryotic initiation of the factor 2α-subunit (p-eIF2α) prior to myocardial I/R but suppressed expression of myocardial GRP78, C/EBP homologous protein, and p-eIF2α during myocardial I/R, in association with improved myocardial injury in vivo and in vitro. Pretreatment with dithiothreitol, an ERS stimulator mimicked the above cardioprotective effect. However, pretreatment with the ERS inhibitor 4-phenylbutyrate reversed the cardioprotection provided by sulfur dioxide preconditioning. These data indicated that sulfur dioxide preconditioning reduced I/R-induced myocardial injury in vivo and in vitro, and that augmenting ERS by sulfur dioxide preconditioning prior to I/R contributed to protection against myocardial I/R injury.

Solid pseudopapillary tumor of the pancreas: clinical analysis of 11 cases.

BACKGROUND/AIMS: This study is designed to describe the clinicopathological features, diagnosis, surgical treatment and outcome of solid pseudopapillary tumor in a single institution. METHODOLOGY: A retrospective study of clinical data from a series of eleven patients with SPT managed in Zhejiang Cancer Hospital between October 2001 and November 2008. RESULTS: All of the 11 patients were female and the average age at diagnosis was 29.5 years (range 16 to 55). The tumor was located in the body and/or tail in 8 patients and in the head in 3 patients (27.3%). The median tumor size was 5.32 cm (range 2 to 10). All 11 patients had curative resections including 5 distal pancreatectomies, 4 local resections, one pancreaticoduodenectomy and one central pancreatectomy. 2 patients required concomitant splenic vein resection due to local tumor invasion. All patients were alive and disease-free at a median follow-up of 45.4 months (range 5-90 months). There were no significant associations between clinicopathological factors and malignant potential of SPT. Ki-67 was detected to be positive in two patients with pancreatic parenchymal invasion. CONCLUSIONS: SPTs are rare neoplasms with malignant potential typically affecting young women without notable symptoms. Aggressive surgical resection is warranted even in the presence of local invasion or metastases, as patients demonstrate excellent long-term survival. Positive immunoreactivity for Ki-67 may predict the malignant potential of SPTs.

Effect of sulfur dioxide on vascular biology.

Gasotransmitters, such as nitric oxide, carbon monoxide and hydrogen sulfide, can be generated endogenously. These gasotransmitters play important roles in vascular biology, including vasorelaxation and inhibition of vascular smooth muscle cell (VSMC) proliferation. In recent years, sulfur dioxide (SO2) has been considered as a fourth gasotransmitter. SO2 is present in air pollution. Moreover, SO2 toxicity, including oxidative stress and DNA damage, has been extensively reported in previous studies. Recent studies have shown that SO2 can be endogenously generated in various organs and vascular tissues, where it regulates vascular tone, vascular smooth cell proliferation and collagen synthesis. SO2 can decrease blood pressure in rats, inhibit smooth muscle cell proliferation and collagen accumulation and promote collagen degradation, and improve vascular remodelling. SO2 can decrease cardiovascular atherosclerotic plaques by enhancing the antioxidant effect and upregulating nitric oxide/nitric oxide synthase and hydrogen sulfide/cystathionine-γ-lyase pathways. SO2 can also ameliorate vascular calcification via the transforming growth factor - ß1/Smad pathway. The effect of SO2 on vascular regulation has attracted great interest. SO2 may be a novel mediator in vascular biology.

Significance of endogenous sulphur-containing gases in the cardiovascular system.

1. The sulphur-containing gases hydrogen sulphide and sulphur dioxide can be generated endogenously in mammalian tissues and exert significant biological effects in the cardiovascular system. Hydrogen sulphide is considered to be the third novel gasotransmitter in addition to nitric oxide and carbon monoxide. The present review describes the effects of hydrogen sulphide on the cardiovascular system and its possible mechanisms under physiological conditions. We also discuss the pathophysiological effects of hydrogen sulphide on cardiovascular diseases. The therapeutic potential of hydrogen sulphide is summarized. 2. We recently discovered that sulphur dioxide, another endogenous sulphur-containing gas, has important physiological and pathophysiological roles in the cardiovascular system. To some extent, the effect of sulphur dioxide is similar to that of the other gasotransmitters nitric oxide, carbon monoxide and hydrogen sulphide. Sulphur dioxide may also be a novel gas mediator in the cardiovascular system.

[Risk factors and prognosis for patients with residual tumor after radiofrequency ablation of hepatocellular carcinoma].

OBJECTIVE: To investigate the risk factors and prognosis of patients with residual tumor after radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). METHODS: The clinicopathological data of 114 patients with HCC undergoing RFA in our hospital from May 2000 to March 2007 were retrospectively studied, and the prognostic factors of residual tumor were analyzed. RESULTS: After one session of RFA, 90 patients had complete ablation and 24 had residual tumor. The median overall survivals in the complete ablation group and residual tumor group were 40 and 29 months, respectively. There was no statistically significant difference between those two groups (P = 0.242). 24 patients with residual tumor were re-treated by RFA or hepatectomy or TACE. Among them 11 patients achieved complete response and 13 incomplete response, their median overall survival were 53 and 28 months, respectively. There was no significant difference between first complete ablation group and second complete response group (P = 0.658). However, compared with the first complete ablation group, the incomplete response group had poor prognosis (P = 0.012). Multivariate analysis showed that tumor size > 3 cm (P = 0.007) and proximity to a large vessel (P = 0.042) were independent risk factors for residual tumor after RFA. CONCLUSION: Tumor size > 3 cm and proximity to a large vessel are independent risk factors for residual tumor after RFA. Further treatment of residual tumor is necessary to eliminate the tumor and improve prognosis.

The effects of gasotransmitters on bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD), which remains a major clinical problem for preterm infants, is caused mainly by hyperoxia, mechanical ventilation and inflammation. Many approaches have been developed with the aim of decreasing the incidence of or alleviating BPD, but effective methods are still lacking. Gasotransmitters, a type of small gas molecule that can be generated endogenously, exert a protective effect against BPD-associated lung injury; nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) are three such gasotransmitters. The protective effects of NO have been extensively studied in animal models of BPD, but the results of these studies are inconsistent with those of clinical trials. NO inhalation seems to have no effect on BPD, although side effects have been reported. NO inhalation is not recommended for BPD treatment in preterm infants, except those with severe pulmonary hypertension. Both CO and H2S decreased lung injury in BPD rodent models in preclinical studies. Another small gas molecule, hydrogen, exerts a protective effect against BPD. The nuclear factor erythroid-derived 2 (Nrf2)/heme oxygenase-1 (HO-1) axis seems to play a central role in the protective effect of these gasotransmitters on BPD. Gasotransmitters play important roles in mammals, but further clinical trials are needed to explore their effects on BPD.

[Prognostic factors and outcome in patients with intrahepatic recurrence after hepatectomy for hepatocellular carcinoma].

OBJECTIVE: To investigate the prognostic factors and treatment choice for intrahepatic recurrence after hepatectomy in patients with hepatocellular carcinoma (HCC). METHODS: Clinicopathological data of 184 HCC patients with intrahepatic recurrence after hepatectomy were collected. The influences of twenty one clinicopathological factors and treatment modalities on the survival after recurrence were retrospectively analyzed. RESULTS: Univariate analysis showed that preoperative serum alpha-fetoprotein (AFP) >100 ng/ml, microscopic venous invasion, patients classified as Child-Pugh class B or C at diagnosis of recurrence, multiple recurrence foci and early recurrence (< or =12 months) were poor prognostic factors. Cox multivariate analysis showed that Child-Pugh class at diagnosis of recurrence, number of recurrent foci and time to recurrence were independent risk factors for survival in patients with recurrence. Median survival after recurrence was 34 months, 23 months, 15 months and 9 months, respectively, in patients treated by repeated hepatectomy, local ablation therapy, transcatheter arterial chemoembolization (TACE) or non-treatment in 69 patients with solitary recurrence. There were statistically significant differences among these four groups (P < 0.05). CONCLUSION: classification of Child-Pugh class A at the first time of diagnosis, solitary recurrence, late recurrence (> 12 months), and intrahepatic recurrence occurred after repeated hepatectomy or local ablation therapy are better prognostic factors in patients with HCC recurrence.

CTGF: A potential therapeutic target for Bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that often occurs in preterm infants. However, there is still no effective treatment for BPD. Recent studies demonstrated that connective tissue growth factor (CTGF) is involved in the development of BPD in experimental models. CTGF, also known as CCN2, is the second member of the CCN family and is necessary for normal lung development. The expression of CTGF is increased in lung tissues in infants with BPD. Hyperoxia, inflammation and mechanic ventilation increase CTGF expression which may promote fibroblast proliferation, matrix production and vascular remodeling. Conditional overexpression of CTGF in alveolar epithelial type II cells disrupts alveolarization and vascular development, induces vascular remodeling, and results in pulmonary hypertension, the pathological hallmarks of severe BPD. Further studies have shown that inhibition of CTGF by a CTGF monoclonal antibody improved alveolarization and vascular development, and decreased pulmonary vascular remodeling and pulmonary hypertension in a rodent model of BPD induced by hyperoxia. CTGF may be a novel target for BPD therapy in preterm infants.

Potential therapeutic effect of SO2 on fibrosis.

Fibrosis is a pathological feature of most chronic diseases and leads to the dysfunction of various organs. However, there is currently no effective method for treating fibrosis. In recent years, a small gas, sulfur dioxide (SO2), which can be generated endogenously in mammals, has been found to have vasorelaxation activity, improve cardiac function and decrease myocardial injury. Endogenous SO2 also mediates the process of fibrosis. Inhibition of endogenous SO2 can aggravate small pulmonary artery remodeling and abnormal collagen accumulation. SO2 treatment significantly improves pulmonary fibrosis and pulmonary arterial remodeling. Overexpression of the key enzymes associated with endogenous SO2 generation, aspartate aminotransferase (AAT) 1 and AAT2, mimics the effect of SO2 on the down-regulation of collagen synthesis, while AAT1 or AAT2 knockdown aggravates abnormal collagen accumulation in vascular smooth muscle cells (VSMCs). SO2 also improves myocardial fibrosis induced by myocardial infarction or diabetes in rats, and inhibits myocardial fibroblast proliferation and migration by the extracellular signal-regulated protein kinase pathway. The mechanisms underlying the inhibition of fibrosis by SO2 are related to its antioxidant effect, anti-inflammation effect, improvement in cardiac function, and cell proliferation inhibition. Therefore, SO2 has a potential therapeutic effect on fibrosis.

Pancreaticoduodenectomy for advanced gastric cancer with pancreaticoduodenal region involvement.

AIM: To characterize the factors of the improved survival following combined pancreaticoduodenectomy (PD) and gastrectomy for the treatment of advanced gastric cancer with pancreaticoduodenal region involvement. METHODS: From 1995 to 2004, 53 patients with primary gastric cancer were diagnosed with synchronous (n = 44) or metachronous (n = 9) pancreaticoduodenal region involvement. Of these, 17 patients (32%) underwent total gastrectomy (TG) or distal subtotal gastrectomy (SG) combined with PD simultaneously. The preoperative demographic, clinical information, clinicopathologic features and the surgical results of these 17 patients were considered as factors influencing survival and were analyzed by the Kaplan-Meier method with log-rank comparison. RESULTS: The actual 1- and 3-year survival rates of these 17 patients after resection were 77% and 34%, respectively, and three patients survived for more than 5 years after surgery. The tumor-free resection margin (P = 0.0174) and a well-differentiated histologic type (P = 0.0011) were significant prognostic factors on univariate analysis. No mortality occurred within one mo after operation, postoperative weight loss of different degree was present in all the patients with TG and 12 cases had other complications. There were 9 (53%) cases of recurrence in 5-48 mo after operation. The survival rate in the palliative and explorative group was significantly (P = 0.0064) lower than in the combined PD group. CONCLUSION: Judicious use of en bloc PD and gastrectomy and strictly preventing postoperative complications may improve the long-term survival for advanced gastric cancer patients with pancreaticoduodenal region involvement. Well-differentiated histology and negative resection margin are the most important predictors of long survival.