O6-Methylguanine-DNA methyltransferase status in neuroendocrine tumours: prognostic relevance and association with response to alkylating agents

Background:

O⁶-Methylguanine-DNA methyltransferase (MGMT) loss of expression has been suggested to be predictive of response to temozolomide in neuroendocrine tumours (NETs), but so far, only limited data are available. We evaluated the prognostic and predictive value of MGMT status, assessed by two molecular methods and immunohistochemistry, in a large series of NETs of different origins.

Methods:

A total of 107 patients, including 53 treated by alkylants (temozolomide, dacarbazine or streptozotocin), were retrospectively studied. In each case, we used methyl-specific PCR (MS-PCR) and pyrosequencing for evaluation of promoter methylation and immunohistochemistry for evaluation of protein status.

Results:

MGMT promoter methylation was detected in 12 out of 99 (12%) interpretable cases by MS-PCR and in 24 out of 99 (24%) by pyrosequencing. O⁶-Methylguanine-DNA methyltransferase loss of expression was observed in 29 out of 89 (33%) interpretable cases. Status of MGMT was not correlated with overall survival (OS) from diagnosis. Progression-free survival and OS from first alkylant use (temozolomide, dacarbazine and streptozotocin) were higher in patients with MGMT protein loss (respectively, 20.2 vs 7.6 months, P<0.001 and 105 vs 34 months, P=0.006) or MGMT promoter methylation assessed by pyrosequencing (respectively, 26.4 vs 10.8 months, P=0.002 and 77 vs 43 months, P=0.026).

Conclusions:

Our results suggest that MGMT status is associated with response to alkylant-based chemotherapy in NETs.     

Relationship between body-mass index and serum folate concentrations in pregnant women

The concentration of micronutrients impacts fetal development and pregnancy outcome and has been suggested to be negatively correlated with the body-mass index (BMI). We evaluated the relationship between BMI and the serum folate concentration in 802 and 660 Korean pregnant women in mid- and late pregnancy, respectively, who participated in a multicenter prospective study. There was a significant negative correlation between BMI value and the serum folate concentration at mid- and late pregnancy (P for trend 0.001 and 0.024, respectively). A general linear model confirmed this correlation at both time points after adjusting for gestational age and total folate intake. These findings are important as the serum folate concentration is a rate-limiting factor for placental folate transport to the fetus, and an inadequate folate supply may cause various malformations.     

Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma

BACKGROUND: Identification of risk factors for the development of hepatocellular carcinoma (HCC) is important for HCC surveillance in chronic hepatitis B virus (HBV) infection. Our aim was to study the independent risk factors and effect of HBV genotypes on HCC development in a prospective longitudinal cohort of chronic hepatitis B patients. PATIENTS AND METHODS: Chronic hepatitis B patients recruited since 1997 were prospectively followed up for the development of HCC. HCC was diagnosed by a combination of alpha fetoprotein, imaging, and histology. Liver cirrhosis was defined as ultrasonic features of cirrhosis together with hypersplenism, ascites, varices, and/or encephalopathy. RESULTS: In total, 426 patients were followed up for 1664 person years; median 225 (range 12-295) weeks. Forty nine (11%) patients had underlying clinical liver cirrhosis. A total of 242 (57%) and 179 (42%) patients had HBV genotypes C and B, respectively. Twenty five patients developed HCC in a median follow up of 121 (range 14-236) weeks. The overall incidence of HCC was 1502 cases per 100 000 person years. On multivariate analysis, clinical liver cirrhosis and HBV genotype C infection were independently associated with HCC development, with an adjusted relative risk of 10.24 (95% confidence interval (CI) 4.39-23.89; p<0.001) and 2.84 (95% CI 1.05-7.72; p = 0.040), respectively. Patient age, sex, hepatitis B e antigen (HBeAg) status, alanine aminotransferase (ALT) levels, and basal core promoter mutations did not predict HCC development. Patients infected with HBV genotype C tended to have persistently positive HBeAg or fluctuating HBeAg status and higher ALT levels during the follow up period. CONCLUSION: Genotype C HBV infection is an independent risk factor for HCC development in addition to liver cirrhosis.     

Value of quantitative radionuclide bone scanning in the diagnosis of sacroiliac joint syndrome in 32 patients with low back pain

A prospective study was performed to compare the results of quantitative radionuclide bone scanning with those of sacroiliac joint anesthetic block in patients with unilateral low back pain. Thirty-four subjects, forming the control group, underwent quantitative radionuclide bone scanning of the sacroiliac joints. The normal values in sacroiliac uptake difference were taken to be between –1.7% and +6.2%. Thirty-two patients with chronic unilateral low back pain underwent sacroiliac bone scanning and sacroiliac joint block. Six of the seven patients with increased uptake > 6.2% on the painful side had at least 75% pain reduction in response to the block. The sensitivity, specificity, and positive and negative predictive values of the quantitative bone scanning in the unilateral mechanical sacroiliac joint syndrome were 46.1%, 89.5%, 85.7%, and 72%, respectively. Received: 21 July 1997 Revised: 17 November 1997 Accepted: 22 January 1998     

Non-surgical treatment for afferent loop syndrome in recurrent gastric cancer complicated by peritoneal carcinomatosis: percutaneous transhepatic duodenal drainage followed by 24-hour infusion of high-dose fluorouracil and leucovorin.

Afferent loop syndrome (ALS) is a debilitating complication of recurrent gastric cancer. Surgical intervention is usually not feasible in the face of poor general performance, presence of advanced peritoneal carcinomatosis and limited survival of the patients. Non-surgical approaches include internal drainage by stenting at the stenotic or anastomotic site and external drainage via the percutaneous routes. Percutaneous transhepatic duodenal drainage (PTDD) has been shown to provide effective palliation for ALS, but long-term catheterization is usually inevitable. We hereby present two cases of recurrent gastric cancer whose ALS was successfully treated with PTDD followed by weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin (HDFL). PTDD rapidly ameliorated the incapacitating symptoms of ALS, and the effective, low-toxicity chemotherapy subsequently led to tumor regression, restoration of bowel patency and removal of the drainage tube. At present, both patients have remained ALS-free and drainage-free for 16 and 17 months, respectively. Our results indicate that this non-surgical approach with PTDD followed by weekly HDFL could serve as a safe and effective treatment for ALS in recurrent gastric cancer complicated by peritoneal carcinomatosis.     

Down regulation of bcl-2 by p53 in nasopharyngeal carcinoma and lack of detection of its specific t(14;18) chromosomal translocation in fixed tissues

High levels of bcl-2 protein have been found in a wide variety of human cancers. Since p53 gene inactivation occurs in over half of human cancers, it is possible that loss of p53-mediated repression of bcl-2 gene expression accounts, at least in part, for the frequent abnormalities in bcl-2 protein production seen in tumours. By using immunohistochemical methods, we have analysed thirty-three nasopharyngeal carcinomas for p53 and bcl-2 expression. We found an inverse correlation between the expression of these two proteins ( P  < 0.001). Moreover, we utilized universal oligonucelotide primers of a region 5' to the bcl-2 MBR and at the 3' end of J_H segments to initiate a DNA polymerase chain reaction that amplified these bcl-2-J_H junctures. Of the twelve nasopharyngeal carcinomas expressing bcl-2, none showed a t(14;18) chromosome translocation. These findings may indicate potential mechanisms by which bcl-2 regulates apoptosis.     

Associations of FcɛRIβ E237G polymorphism with wheezing in Taiwanese schoolchildren

Background The β‐chain of a high‐affinity IgE receptor (Fc?RIβ) has been proposed as a candidate gene for atopic diseases, but previous studies have come to inconsistent conclusions. Because some air pollutants would produce oxidative stress, increase serum IgE, and trigger T‐helper type 2 (Th2)‐type airway inflammation, the associations of Fc?RIβ polymorphism with wheezing illness may vary by their exposures and variants of oxidant defence genes. The purpose of this study was to investigate the association of Fc?RIβ E237G polymorphism with wheezing illness and to determine whether these associations vary with air pollution and glutathione S‐transferase (GST) P1‐105 and M1 genotypes. Methods In 2001, we conducted a case–control study comprised of 214 children with any history of wheezing and 185 non‐wheezing controls, all of whom were selected from 2558 fourth‐ to ninth‐grade schoolchildren in southern Taiwan. We examined differences in associations with ambient air pollution and by GST genotypes. Results Compared with the Fc?RIβ EE genotype, children with the G allele had a significantly reduced risk of lifetime wheezing with low‐ozone exposure [adjusted odds ratio (aOR)=0.25, 95% confidence interval (CI) 0.08–0.69]. The risk was not reduced in children living in high‐ozone communities (aOR=0.98, 95% CI 0.57–1.67). This difference in genotypic effects between low‐ and high‐pollution environments was statistically significant. The reduction of the protective effect from the G allele with higher air pollution was most marked in the GSTP1‐105 Ile/Val or Val/Val and GSTM1 null groups. Conclusion The Fc?RIβ E237G allele may have a protective role in wheezing illness among Taiwanese schoolchildren, depending on airway oxidative stress levels.