Hong-Shiee Lai

High-frequency microsatellite instability predicts better chemosensitivity to high-dose 5-fluorouracil plus leucovorin chemotherapy for stage IV sporadic colorectal cancer after palliative bowel resection.

The influence of MSI on treatment outcome of colorectal cancers remains unclear and deserves further investigation. We recruited 244 patients with stage IV sporadic colorectal cancers for our study, based on appropriate eligibility criteria. Patients were nonrandomly allocated to 2 treatment groups of either with or without high‐dose 5‐FU plus leucovorin chemotherapy (HDFL, 5‐FU 2,600 mg/m2 leucovorin 300 mg/m2 maximum 500 mg). Each treatment group was further divided into 2 subgroups according to high‐frequency MSI (MSI‐H) status. MSI‐H was defined as the appearance of MSI in at least 2 of the 5 examined chromosomal loci (BAT‐25, BAT‐26, D5S346, D2S123, D17S250). We compared clinicopathologic parameters, p53 overexpression and overall survival between the groups. In addition, 4 subgroups were identified as follows: MSI‐H+HDFL+, n = 35; MSI‐H−HDFL+, n = 134; MSI‐H+HDFL−, n = 17; MSI‐H−HDFL−, n = 58. There was no significant difference of background clinicopathologic data between the HDFL+ and HDFL− treatment groups (p > 0.05). Survival analyses indicated that the patients of subgroup MSI‐H+HDFL+ survived significantly longer than those of subgroup MSI‐H−HDFL+, with median survival times of 24 (95% CI 20.2–27.9) and 13 (95% CI 11.6–14.4) months, respectively (p = 0.0001, log‐rank test). In contrast, in patients without chemotherapy, the prognosis was poor irrespective of MSI status, with median survival times of 7.0 (95% CI 4.6–9.4) and 7.0 (95% CI 6.1–7.9) months in the MSI‐H+HDFL− and MSI‐H−HDFL− subgroups, respectively (p = 0.8205, log‐rank test). MSI‐H cancers responded significantly better to HDFL (p = 0.001), with a mean response rate of 65.71% (95% CI 49.98–81.44%) in subgroup MSI‐H+HDFL+ compared to 35.07% (95% CI 26.99–43.15%) in subgroup MSI‐H−HDFL+. There appeared to be no preferential metastatic site where response to HDFL can be predicted based on the MSI status of the primary tumor. Toxicity to HDFL was similarly minimal between MSI‐H+ and MSI‐H− patients (p > 0.05). Multivariate analysis of all patients further indicated that MSI‐H and chemotherapy were independent favorable prognostic parameters (p < 0.05). Thus, the better prognosis of stage IV sporadic colorectal cancers with MSI‐H may be associated with better chemosensitivity, rather than lower aggressiveness in biologic behavior.

Long-term prognosis of patients with biliary atresia: a 25 year summary.

Objective: The purpose of this study was to delineate the long-term prognosis of biliary atresia (BA) in Taiwan. Study Design: From 1976 to 2000, 185 children were diagnosed with BA, 22 underwent exploratory laparotomy without Kasai operation, and 163 underwent Kasai operation, of which 141 cases had long-term follow-up and formed the basis of this study. The outcome was analyzed. Results: Among the 141 BA children studied who underwent Kasai operation, 115 (81.6%) had recoloration of stools, and 86 (61.0%) became jaundice-free (bilirubin <20 μmol/L). The resolution of jaundice and the absence of repeated cholangitis contributed to better outcome. Five and 10 year survival rates with native liver were 35% and 31%, respectively. Liver transplantation was performed in 19 patients (all but 2 with a living-related donor), and 15 (79%) survived. Five and 10 year overall survival rates for BA patients were 41.9% and 40.2%, respectively. Conclusions: The study delineated the long-term outcome of BA in an Asian country other than Japan. Survival with native liver after a Kasai operation in Taiwan was similar to that in the American and European series. Limited donors for liver transplantation in the years of the study accounted for the poor overall prognosis of BA patients in this series.

Free Radical Scavenging Activity of Fullerenol on the Ischemia-reperfusion Intestine in Dogs

Abstract. Fullerenol, a water-soluble C60-fullerene derivative, has been demonstrated to have the capability to scavenge free radicals in vitro and in vivo. The purpose of this study was to investigate whether fullerenol can scavenge the free radicals that are massively induced during ischemia-reperfusion (I/R) injury of the small intestine, either preventively or therapeutically. Clamping the superior mesenteric artery and vein for 60 minutes to induce I/R injury was performed on male mongrel dogs. Thirty dogs were divided into three groups (10 in each): The control (C) group received no medication; the preventive (P) group received fullerenol (1 mg/kg) intravenously 30 minutes before ischemia; the therapeutic (T) group received the same dose of fullerenol immediately after reperfusion. This study was an experimental randomized trial. Intestinal segments were obtained 10, 20, 30, and 60 minutes after reperfusion; and blood samples and specimens of major organs were taken 60 minutes after reperfusion. Concentrations of lipid peroxidation products, including conjugated diene (CD) and malondialdehyde (MDA), and the level of glutathione (GSH) in intestinal tissue were determined. Serum indicators of liver and renal function were measured. Histologic examination of the small intestine and major organs were also performed. A significant increase in intestinal MDA and CD contents was detected at 30 and 60 minutes after reperfusion. The tissue GSH content, in contrast, was decreased 60 minutes after reperfusion. Administration of fullerenol diminished these changes both preventively and therapeutically. Liver and renal functions were within normal limits in all groups. Moreover no obvious histopathologic additional damage could be found in either the P or the T group. It is suggested that fullerenol can be considered a powerful scavenger for the free radicals induced by I/R injury of the small intestine.

Hepatocellular carcinoma in children: Clinical review and comparison with adult cases

BACKGROUND Hepatocellular carcinoma (HCC) in children was rarely reported and usually included with hepatoblastoma in most studies of pediatric liver malignancies despite different clinical behaviors. The authors report their experience in pediatric HCC and discuss its differences from adult HCC. METHODS A retrospective review of radiographic, laboratory, pathological, and therapeutic data in 55 children with HCC was performed. The liver function was graded by modified Childs classification. Kaplan-Meier survival curves in various therapeutic and Childs groups were plotted, and log-rank test was used to detect differences among survival curves. RESULTS Although children with HCC mostly presented with advanced disease at diagnosis, disturbances of liver function were unremarkable. Sixty-eight percent of cases concurred with liver cirrhosis. The median survivals for resectable, chemotherapeutic, and untreated HCCs were 23, 3, and 2 months, respectively. Resectable HCC significantly posed a much better prognosis. However, the resectability was unsatisfactory (18.2%). Resection was limited because of anatomic unfeasibility including bilateral involvement (62.5%), portal vein thrombi (41.7%), distant metastasis (29.1%), para-aortic lymphadenopathy (18.8%), inferior vena cava thrombi (16.7%), and hilar invasion (6.3%). Distant metastasis was the most ominous for survival in children with unresectable HCC. CONCLUSIONS HCC behaved somewhat differently between children and adults. Surgical resection represented the best hope of long-term survival. The outcome in children could not keep up with that in adults because of a diagnostic delay. Hence, alpha-fetoprotein and sonography screening in carrier children should be worthwhile.

Bacterial cholangitis in patients with biliary atresia: impact on short-term outcome

Abstract Bacterial cholangitis (BC) is a common complication in patients with biliary atresia (BA) and is characterized by fever, acholic stools and positive blood cultures. The diagnosis is often empirical because the yield of blood cultures is low. It is difficult to differentiate BC from other febrile episodes. In order to characterize the clinical and laboratory features of BC in patients with BA, identify risk factors, and correlate cholangitis with outcome, 37 patients with BA from 1993 to 1998 who underwent a Kasai operation in our hospital were studied. The follow-up period ranged from 6 to 59 months. A total of 107 febrile episodes were documented in these patients. The diagnostic criteria for cholangitis were fever, increased jaundice, or acholic stools. The clinical features, laboratory data, results of bacterial cultures, and outcomes were analyzed retrospectively. A total of 107 febrile episodes, including 78 bouts of cholangitis and 29 non-cholangitis infections, were found in 34 patients. Patients with BC had higher postoperative bilirubin levels (P=0.02) and less frequent use of prophylactic antibiotics (P=0.05) than those with non-cholangitis infections. Abnormal white blood cell counts (>12,000 or <4,000 mm3) tended to be present in patients with BC (P=0.08). There were no statistical differences in the risk factors and laboratory data between culture-positive (n=16) and -negative (n=62) cholangitis cases. The occurrence of cholangitis significantly reduced survival in both patients with good (P=0.03) and inadequate bile flow (P=0.03). All 9 patients who had never had cholangitis survived during the follow-up period. Repeated attacks of BC further decreased survival probability. The responsive organisms were mainly enteric bacteria, including Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumanni, and Salmonella typhi. The sensitivity tests justified empirical therapy with ceftriaxone. The effectiveness of prophylactic trimethoprim-sulfamethoxazole or neomycin warrants further studies. BC was a highly prevalent postoperative complication in patients with BA, especially those with inadequate bile drainage. It significantly affected early mortality. Aggressive and complete treatment with empirical ceftriaxone was appropriate.

Viral etiology of intussusception in Taiwanese childhood.

BACKGROUND Adenovirus infection and lymphoid hyperplasia have been associated with childhood intussusception. However, the extent of other viruses involved in this condition remains unclear. This prospective study investigates the relationship between some lymphotropic viruses and current childhood intussusception. METHODS Patients with intussusception encountered in a pediatric emergency department in a recent 3-year period were studied. Healthy infants and toddlers of comparable age served as controls. Throat and rectal viral cultures were performed in patients and controls. Viral antibodies against adenovirus, cytomegalovirus, human herpesvirus (HHV)-6, HHV-7 and Epstein-Barr virus (EBV) were tested in paired sera from the patients. Acute stage serum from each patient and mesenteric lymph nodes from patients requiring surgery were studied for the presence of adenovirus genome by PCR. RESULTS Twenty-seven of 61 (44.3%) intussusception patients, but only 2 of 52 (3.8%) healthy controls shed nonenteric adenovirus in throat and rectal specimens (P < 0.001). Of the 27 (74.1%) patients who shed adenovirus, 20 were older than 1 year old, whereas only 1 of 15 (6.7%) similarly aged patients in a previous study from the same area three decades ago did so (P = 0.001). Among 43 patients with available paired sera, acute primary viral infection was found in 17 (39.5%) by adenovirus, 4 (9.3%) by HHV-6, 5 (11.6%) by HHV-7, 2 (4.7%) by EBV and none by cytomegalovirus. Multiple viral infections occurred in 6 patients. Adenovirus genome was detected in 4 of 9 mesenteric lymph nodes and in only 3 of 60 (5%) acute phase sera. CONCLUSIONS Primary nonenteric adenovirus infection contributes to current childhood intussusception. Acute primary HHV-6, HHV-7 and EBV infections also play etiologic roles.

Expression of Hepatocyte Transporters and Nuclear Receptors in Children With Early and Late-Stage Biliary Atresia

To investigate how the liver adapts to chronic obstructive cholestasis, liver samples from infants with early- and late-stage cholestasis were analyzed for changes in the levels of hepatocyte transporters and nuclear receptors. At early-stage cholestasis, most canalicular transporters and sinusoidal uptake transporters were downregulated, including bile salt export pump (BSEP, ABCB11), multidrug resistant protein 3 (MDR3, ABCB4), multidrug-resistant associated protein 2 (MRP2, ABCC2), sodium-dependent taurocholate cotransporting polypeptide (NTCP, SLC10A1), organic anion transporter (OATP, SLCO1A2), and nuclear receptor farnesoid X receptor (FXR, NR1H4). At late-stage cholestasis, FXR-BSEP levels returned to normal, MDR3 and MDR1 (ABCB1) were upregulated, and MRP-2 was downregulated. In addition, alternative sinusoidal efflux transporters, organic solute transporter alpha/beta (OSTα/β) and MRP4 were upregulated, and pregnane X receptor (PXR, NR1I2) levels decreased. Cytochrome enzyme P450 7A1 was markedly downregulated at both early and late-stage cholestasis. An analysis of the long-term prognosis of 18 patients revealed lower PXR and constitutive androstane receptor (CAR, NR1I3) levels in the poor prognosis group. In conclusion, at long-term cholestasis, hepatocyte bile efflux was through sinusoidal and canalicular transporters, with FXR-BSEP levels maintained and PXR downregulated. Low PXR and CAR levels were associated with poor prognosis.

Comparison of medial-to-lateral versus traditional lateral-to-medial laparoscopic dissection sequences for resection of rectosigmoid cancers: randomized controlled clinical trial.

This study aimed to compare medial-to-lateral versus lateral-to-medial laparoscopic dissection sequences for resecting rectosigmoid cancers. We hypothesized that the medial-to-lateral approach was a more efficient procedure and with potentially better oncologic results. Between January 1997 and June 1999, a total of 67 patients of rectosigmoid cancer treated by one surgeon using the laparoscopic approach were recruited for this prospective, randomized, double-blind clinical trial. Using the blocked randomization method, 36 patients were allocated to a medial-to-lateral (M) group and the other 31 to a lateral-to-medial (L) group; the groups were well matched in age, gender, symptoms, body mass index, American Society of Anesthesiology (ASA) class, tumor location, tumor distance above the anal verge, tumor gross morphology, TNM stage of the tumor, and accuracy of preoperative TNM staging (p > 0.05). All patients were followed up until June 2001. We found that the M group had a significantly shorter operating time and lower overall costs than the L group (p < 0.05). There was no significant difference between these two groups in terms of intraoperative complications, conversion rate, postoperative ileus, hospitalization, postoperative pain, postoperative complications, wound length, or disability (p > 0.05). The postoperative proinflammatory response, evaluated by the C-reactive protein level and the erythrocyte sedimentation rate, was significantly lower in the M group (p < 0.05). There was no significant difference between these two groups regarding postoperative immunosuppression, as evaluated by the alterations of total lymphocyte counts and the CD4+/CD8+ ratio (p > 0.05). The extent of dissection of these two dissection approaches was similar, as the harvested lymph nodes were equivalent (p > 0.05). During the whole follow-up period (median 32 months, range 24–54 months), the tumor recurrence rate was similar for these two groups of patients (5.6% in the M group vs. 6.5% in the L group; p > 0.05). These findings indicated that the medial-to-lateral approach was quicker, less expensive and possibly less invasive; moreover, it gave oncologic results similar to those achieved with the traditional lateral-to-medial dissection sequence. We thus concluded that the medial-to-lateral dissection sequence may currently be the most appropriate procedure for laparoscopic resection of rectosigmoid cancers.

Mucin glycosylating enzyme GALNT2 regulates the malignant character of hepatocellular carcinoma by modifying the EGF receptor.

Extracellular glycosylation is a critical determinant of malignant character. Here, we report that N-acetylgalactosaminyltransferase 2 (GALNT2), the enzyme that mediates the initial step of mucin type-O glycosylation, is a critical mediator of malignant character in hepatocellular carcinoma (HCC) that acts by modifying the activity of the epidermal growth factor receptor (EGFR). GALNT2 mRNA and protein were downregulated frequently in HCC tumors where these events were associated with vascular invasion and recurrence. Restoring GALNT2 expression in HCC cells suppressed EGF-induced cell growth, migration, and invasion in vitro and in vivo. Mechanistic investigations revealed that the status of the O-glycans attached to the EGFR was altered by GALNT2, changing EGFR responses after EGF binding. Inhibiting EGFR activity with erlotinib decreased the malignant characters caused by siRNA-mediated knockdown of GALNT2 in HCC cells, establishing the critical role of EGFR in mediating the effects of GALNT2 expression. Taken together, our results suggest that GALNT2 dysregulation contributes to the malignant behavior of HCC cells, and they provide novel insights into the significance of O-glycosylation in EGFR activity and HCC pathogenesis.

Microvessel density, cyclo‐oxygenase 2 expression, K‐ras mutation and p53 overexpression in colonic cancer

Tumour angiogenesis, cyclo‐oxygenase (COX) 2 expression, K‐ras mutation and p53 overexpression are commonly involved in colorectal tumorigenesis, but their interrelationship and clinicopathological effects remain inconclusive.