Tsang-En Wang

A randomised phase II study of pegylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients

Background:Human hepatocellular carcinoma (HCC) cells are largely deficient of argininosuccinate synthetase and thus auxotrophic for arginine. This study aims to investigate the efficacy and pharmacodynamics of pegylated arginine deiminase (ADI-PEG 20), a systemic arginine deprivation agent, in Asian HCC patients.Methods:Patients with advanced HCC who were not candidates for local therapy were eligible and randomly assigned to receive weekly intramuscular injections of ADI-PEG 20 at doses of 160 or 320 IU m−2. The primary end point was disease-control rate (DCR).Results:Of the 71 accruals, 43.6% had failed previous systemic treatment. There were no objective responders. The DCR and the median overall survival (OS) of the intent-to-treat population were 31.0% (95% confidence interval (CI): 20.5–43.1) and 7.3 (95% CI: 4.7–9.9) months respectively. Both efficacy parameters were comparable between the two study arms. The median OS of patients with undetectable circulating arginine for more than or equal to and <4 weeks was 10.0 (95% CI: 2.1–17.9) and 5.8 (95% CI: 1.4–10.1) months respectively (P=0.251, log-rank test). The major treatment-related adverse events were grades 1–2 local and/or allergic reactions.Conclusions:ADI-PEG 20 is safe and efficacious in stabilising the progression of heavily pretreated advanced HCC in an Asian population, and deserves further exploration.

Association of T-Cell Regulatory Gene Polymorphisms With Susceptibility to Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

PURPOSE Helicobacter pylori infection and host susceptibility interact to develop gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and activation of specific T cells might play a crucial role in this process. Recent investigations show that the CTLA4, CD28, and ICOS genes are located on chromosome 2q33 and their polymorphisms confer susceptibility to infectious and immune diseases through deregulation of T-cell stimulation. We aimed to determine the role of CTLA4, CD28, and ICOS polymorphisms in gastric MALT lymphoma. PATIENTS AND METHODS Genotyping for CTLA4 (49 A/G, -318 C/T, and CT60 A/G), CD28 (IVS3+ 17T/C), and ICOS (c.602 A/C and c.1624C/T) was performed for 62 patients with gastric MALT lymphoma and compared with 250 unrelated healthy controls. RESULTS H pylori infection was significantly higher in patients with gastric MALT lymphoma (90.3%) compared with controls (66.4%; P < .001). The CTLA4 -318 C/T genotype was associated with a lower risk of developing gastric MALT lymphoma (odds ratio [OR] = 0.3; P = .022), whereas CTLA4 49 G/G genotype was linked to a higher risk (OR = 4.1; P = .044). In patients with H pylori infection, CTLA4 49 G/G genotype was associated with an even higher risk (OR = 6.4; P = .047). Carriage of the tightly linked -318C -49G haplotype conferred a four-fold higher susceptibility to MALT lymphoma (OR = 4.2; P = .042). Complete remission after H pylori eradication was related to tumor stage but not to genotypes or haplotypes. CONCLUSION These results indicate a genetic link of CTLA4 gene polymorphisms to development of gastric MALT lymphoma and indirectly support the crucial role of host activated T cells in the MALT lymphomagenesis.

Caffeic acid phenethyl ester induces apoptosis of human pancreatic cancer cells involving caspase and mitochondrial dysfunction.

Aims: This study aimed to investigate the effect of caffeic acid phenethyl ester (CAPE), an active component isolated from honeybee propolis, in inducing apoptosis in human pancreatic cancer cells. Methods: Inhibition of viability of BxPC-3 and PANC-1 cell lines induced by CAPE was estimated by a trypan blue dye exclusion test. The type of cell death in BxPC-3 after CAPE treatment was characterized by observation of morphology, sub-G1 DNA content, annexin-V/PI staining, caspase-3 and caspase-7 assay, and DNA agarose gel electrophoresis. Results: CAPE (10 µg/ml) resulted in marked inhibition of viability of BxPC-3 (80.4 ± 4.1%) and PANC-1 (74.3 ± 2.9%) cells. CAPE induced a time-dependent increase in hypodiploid percentage and a significant decrease in mitochondrial transmembrane potential in BxPC-3 cells. It induced morphological changes of typical apoptosis, but no DNA fragmentation was noted by DNA electrophoresis. The inhibition of growth and increased in the proportion of sub-G1 cells was partially blocked by pretreatment with the pan-caspase inhibitor Z-VAD-fmk (50 µM) in BxPC-3 cells indicating a caspase-related mechanism in CAPE-induced apoptosis. Caspase-3/caspase-7 activity was approximately 2 times greater in CAPE-treated BxPC-3 cells compared with control cells. Conclusions: These results suggest that CAPE is a potent apoptosis-inducing agent. Its action is accompanied by mitochondrial dysfunction and activation of caspase-3/caspase-7.

Molecular analysis of secondary kinase mutations in imatinib-resistant gastrointestinal stromal tumors

Most gastrointestinal stromal tumors (GISTs) are associated with activating kinase mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene, and imatinib has revolutionized the care of advanced GISTs. However, most patients gradually developed resistance to imatinib. We intend to identify the secondary kinase mutations in imatinib-resistant GISTs and to study the relationship between secondary kinase mutations and the clinical response to imatinib. Twelve advanced GIST patients, who have developed resistance to imatinib were included in this study. Paraffin-embedded pretreatment GIST specimens and progression lesions of the tumors after resistance to imatinib were analyzed for kinase mutations in exons 9, 11, 13, and 17 of KIT gene and exons of 10, 12, 14, and 18 of PDGFRA gene. Primary KIT mutations have been found in all but one of the primary tumors including one case harboring de novo double KIT exon 11 mutations. Secondary kinase mutations in KIT and PDGFRA were found in seven and 1 of 12 patients, respectively. Two patients harbored more than one secondary KIT mutations in different progression sites, and there are four types of clonal or polyclonal evolution being observed. The secondary PDGFRA exon 14 mutation H687Y is a novel mutation that has never been reported before. Acquired secondary kinase mutations are the most important cause of secondary imatinib resistance in advanced GISTs. The identification of secondary kinase mutations is important in the development of new therapeutic strategies.

Rabeprazole- versus Esomeprazole-Based Eradication Regimens for H. pylori Infection

Background:  Different kinds of proton pump inhibitor‐based triple therapies could result in different Helicobacter pylori eradication rates.

Comparison of coplanar and noncoplanar intensity-modulated radiation therapy and helical tomotherapy for hepatocellular carcinoma

BackgroundTo compare the differences in dose-volume data among coplanar intensity modulated radiotherapy (IMRT), noncoplanar IMRT, and helical tomotherapy (HT) among patients with hepatocellular carcinoma (HCC) and portal vein thrombosis (PVT).MethodsNine patients with unresectable HCC and PVT underwent step and shoot coplanar IMRT with intent to deliver 46 - 54 Gy to the tumor and portal vein. The volume of liver received 30Gy was set to keep less than 30% of whole normal liver (V30 < 30%). The mean dose to at least one side of kidney was kept below 23 Gy, and 50 Gy as for stomach. The maximum dose was kept below 47 Gy for spinal cord. Several parameters including mean hepatic dose, percent volume of normal liver with radiation dose at X Gy (Vx), uniformity index, conformal index, and doses to organs at risk were evaluated from the dose-volume histogram.ResultsHT provided better uniformity for the planning-target volume dose coverage than both IMRT techniques. The noncoplanar IMRT technique reduces the V10 to normal liver with a statistically significant level as compared to HT. The constraints for the liver in the V30 for coplanar IMRT vs. noncoplanar IMRT vs. HT could be reconsidered as 21% vs. 17% vs. 17%, respectively. When delivering 50 Gy and 60-66 Gy to the tumor bed, the constraints of mean dose to the normal liver could be less than 20 Gy and 25 Gy, respectively.ConclusionNoncoplanar IMRT and HT are potential techniques of radiation therapy for HCC patients with PVT. Constraints for the liver in IMRT and HT could be stricter than for 3DCRT.

Spontaneous Clearance of Helicobacter pylori Colonization in Patients with Partial Gastrectomy: Correlates with Operative Procedures and Duration After Operation

BACKGROUND/PURPOSE For patients undergoing gastric surgery because of complications of peptic ulcers, such as bleeding or perforation in the pre-Helicobacter pylori eradication era, their infection status was not surveyed or it was neglected altogether. Previous reports have shown spontaneous clearance of H. pylori in these patients but the determining factors remain ill-defined. METHODS Seventy-six patients with previous partial gastrectomy for complicated peptic ulcers were enrolled prospectively. Patients with peptic ulcers but without gastrectomy were selected as a control group. Gastric biopsy specimens were obtained from each patient for histological H. pylori staining and rapid urease test on endoscopic evaluation. Spontaneous clearance of H. pylori colonization was defined when patients who were positive for H. pylori prior to operation became negative, without eradication treatment. RESULTS The prevalence of H. pylori colonization was significantly lower in patients with partial gastrectomy (22.4%, 17/76 vs. 67.1%, 51/76, p < 0.001). There was a trend towards decreasing prevalence of H. pylori colonization as time after operation increased: 1-15 years, 29.5% (13/44); 16-30 years, 13.6% (3/22); and > 31 years, 10% (1/10). The spontaneous clearance rate of H. pylori after partial gastrectomy was 43% (13/30). The time after operation in the spontaneous clearance group was longer than that in those without (20.8 +/- 11.7 vs. 12.1 +/- 11.0 years, p = 0.048). Billroth-II procedure had a higher bile reflux rate and a lower H. pylori infection prevalence than the Billroth-I procedure. CONCLUSION Spontaneous clearance of H. pylori develops in a certain number of patients who undergo distal gastrectomy. The clearance rate is related to operative procedures and time after operation.

Scurvy in a Patient with Depression

Scurvy is a nearly-forgotten disease in developed countries where adequate nutrition is easily available. It still may occur, however, when, for a variety of reasons, people fail to eat a diet containing adequate vitamin C. We report the case of a 52-year-old patient with depression who developed scurvy.

Insulinoma Causing Hypoglycemia in a Patient with Type 2 Diabetes

Insulinoma in a patient with pre-existing diabetes is extremely rare. A 74-year-old woman with type 2 diabetes mellitus who had been treated with a sulfonylurea for 6 years began experiencing frequent episodes of hypoglycemia. Endogenous hyperinsulinism was found 9 months after the sulfonylurea was discontinued, and transabdominal ultrasonography and magnetic resonance imaging identified a pancreatic tumor. Pathology examination of the resected tumor demonstrated an insulinoma. Postoperatively, the patient had no further episodes of hypoglycemia. Thereafter, she required insulin to control her hyperglycemia. Although hypoglycemic agents are the commonest cause of hypoglycemia in type 2 diabetes, insulinomas may occur in these patients. This possibility should be considered if the hypoglycemia persists despite dose adjustment or cessation of the drugs.

Proposed Scoring System to Determine Small Bowel Mass Lesions Using Capsule Endoscopy

BACKGROUND/PURPOSE Capsule endoscopy is a highly sensitive method for the detection of small bowel lesions. False-positive findings are important confounding factors. This study reports on a scoring system for evaluating the role of capsule endoscopy in small bowel tumors. METHODS Ten men and two women (age, 23-79 years) with suspected small bowel tumors were included from 120 patients referred for capsule endoscopy between March 2004 and March 2008. The indications were gastrointestinal bleeding (n = 9), melanoma workup (n = 1), physical checkup (n = 1), and iron deficiency anemia (n = 1). The proposed tumor score was composed of five components: bleeding, mucosal disruption, an irregular surface, color, and white villi. These can be scored for probability of mass lesions seen at capsule endoscopy. Small bowel mass lesions were probably present in those with a score of >or= 4, and a score of <or= 2 indicated a low probability of a small bowel mass lesion. RESULTS Capsule endoscopy showed probable small bowel mass lesions in six patients, and a low lesion probability in the other six. Capsule endoscopy showed that new lesions were not detected by esophagogastroduodenoscopy or colonoscopy. All six patients with probable small bowel tumors were found to have pathological findings upon capsule endoscopy: two with lymphangioma, and one each with ileal ectopic pancreas, with melanoma metastasis, gastrointestinal lymphoma, and gastrointestinal stromal tumor. CONCLUSION Capsule endoscopy may detect small bowel tumors more reliably by using the scoring system outlined. It should be considered in suspected cases of small bowel tumor.