Primary Radiotherapy of Stage IIA/B–IIIB Cervical Carcinoma

BACKGROUND: Comprehensive literature on cervical cancer demonstrates, even today, the need for optimization of the timing of external-beam radiotherapy (EBRT) and high-dose-rate brachytherapy (HDR-BT) in the treatment of stage IIA/B-IIIB cervical carcinoma. PATIENTS AND METHODS: 210 patients with carcinoma of the cervix were treated in the Municipal Center of Oncoradiology between January 1991 and December 1996 (FIGO IIA: n = 10, FIGO IIB: n = 113, and FIGO IIIB: n = 87). Two regimens were compared: sequential radiation therapy (SRT) with 4 x 8 Gy HDR-BT to point A followed by EBRT, and continuous radiation therapy (CRT) in which 5 x 6 Gy HDR-BT to point A, one session per week, was integrated into the EBRT. A total dose of 68-70 Gy to point A and 52-54 Gy to point B was given in EBRT with SRT, five fractions per week were applied. Four fractions per week were applied in CRT, i. e., no EBRT was performed on the day of HDR-BT. Total doses to points A and B were identical in both regimens. Overall treatment time (OTT) amounted to 56 days for SRT and 35 days for CRT. Median follow-up time was 3.4 (2.5-4.2) years. RESULTS: Progression-free 5-year-survival (PFS) was 71% in the CRT and 56% in the SRT group. Nevertheless, this difference was not statistically significant (p = 1.00), and the same was found in a subgroup analysis of the different tumor stages, showing, however, an unequivocal trend. Late bladder and rectal injuries occurred in 13% and 25%, respectively. Late rectal injuries were significantly more frequent with SRT than CRT (35 patients in the SRT and 18 patients in the CRT group; p = 0.037). This was due to the higher doses per fraction of HDR-BT in the SRT group. No difference was found regarding late bladder injuries (p = 0.837). CONCLUSION: For the patients included in this study, no advantage has been found so far in using CRT, i. e., shortening the OTT by weekly integration of HDR-BT into EBRT. Nevertheless, an obvious trend exists. The dose of 8 Gy per fraction of HDR-BT in the SRT regimen was obviously too high. To achieve a significant improvement in local control and disease-free survival (DFS) as well as overall survival (OS), the combination with modern chemotherapy regimens and regional deep hyperthermia may rather be the treatment option.     

Behavior of the Common Bile Duct Diameter Before and 12 Years after Choledochostomy for Cholecystolithiasis and Choledocholithiasis. A Prospective Study

INTRODUCTION : In patients with common bile duct (CBD) stones, the diameter of the CBD is usually dilated. After surgery, the behavior of CBD diameter is not clearly known. OBJECTIVE : To determine at a late follow-up the width of CBD before and after choledochostomy for CBD stones. MATERIAL AND METHODS : In this prospective study, 39 patients with gallstones and CBD stones were included. They were 30 women and 9 men with a mean age of 52.6 years. In all ultrasound, determination of the CBD caliber before and 12 years after surgery was performed. RESULTS : The mean value of the inner diameter of the CBD before surgery was 11.6 and 12.3 mm in patients below or above 60 years, respectively. Measurement 12 years after surgery showed a mean decrease of nearly 50% of preoperative values, which was highly significant (p < 0.0001). However, either below or above 60 years, only 75% of the patients showed this decrease, whereas 25% remained unchanged. CONCLUSION : The dilated preoperative CBD returns to normal or near normal values in 3/4 of the patients after surgical exploration of the CBD and extraction of the stones.     

Phenoxyacetic acid induces glutathione-dependent detoxification and depletes the glutathione pool in Penicillium chrysogenum

Enzymes of the glutathione-dependent detoxification pathway (glutathione S-transferase and γ-glutamyl-transpeptidase)¹) were induced, and the glutathione pool was completely depleted by phenoxyacetic acid in Penicillium chrysogenum mycelia incubated for 15 h in a culture medium containing lactose as a carbon source and sodium glutamate as a nitrogen source. A significant increase in both the oxidised glutathione concentrations and the glutathione reductase activities were also observed. 1-Chloro-2,4-dinitrobenzene - a potent substrate and inducer of glutathione S-transferase - initiated very similar physiological changes but no β-lactam production could be detected in this case. When (NH₄)₂HPO₄ was used as a nitrogen source the penicillin biosynthesis was repressed and the induction of γ-glutamyltranspeptidase by phenoxyacetic acid was hindered considerably.     

Repair of DNA lesion O 6-methylguanine in hepatocellular carcinogenesis

Evidence from both experimental carcinogenesis and studies in human cirrhotic liver suggest that defective repair of the promutagenic DNA base lesion, O ⁶-methylguanine, is a factor in the multistep process of hepatocellular carcinogenesis. Ubiquitous environmental alkylating agents such as N-nitroso compounds can produce O ⁶-methylguanine in cellular DNA. Unrepaired, O ⁶-methylguanine can lead to the formation of G ? A transition mutations, a known mechanism of human oncogene activation and tumour suppressor gene inactivation. Combined treatment of rodents with an agent producing O ⁶-methylguanine in DNA, and an agent promoting cell proliferation, leads to development of hepatic nodules and hepatocellular carcinoma (HCC), cell division, hence DNA replication, being required for the propagation of tumorigenic mutation(s) in hepatocyte DNA. The paramount importance of O ⁶-methylguanine in hepatocellular carcinogenesis is indicated by the observation that transgenic mice engineered to have increased hepatic levels of repair enzyme O ⁶-methylguanine-DNA methyltransferase (MGMT) are significantly less prone to hepatocellular carcinogenesis following alkylating agent treatment. Cirrhosis is a universal risk factor for development of human HCC, and a condition that is characterized by increased hepatocyte proliferation as a result of tissue regeneration. Levels of the human repairing enzyme for O ⁶-methylguanine were found to be significantly lower in cirrhotic liver than in normal tissue. In accord with findings from animal models, this suggested a mechanism in which persistence of O ⁶-methylguanine due to defective DNA repair by MGMT, together with increased hepatocyte proliferation, might lead to specific gene mutation(s) and hepatocellular carcinogenesis. Screening for the presence and persistence of O ⁶-methylguanine in human DNA presently involves formidable technical difficulty. Indications are that such limitations might be overcome by the use of an ultrasensitive method such as immuno-polymerase chain reaction (PCR). This approach should allow parallel measurement of DNA adduct and repair enzyme in routine liver biopsy samples. It might also enable investigation of O ⁶-methylguanine in human genes specifically associated with hepatocellular carcinogenesis. Given the wide variation in human MGMT levels observed between individuals, tissues, and cells, this technology should be adapted to permit the ultrasensitive localisation and measurement of adducts and repairing enzyme in liver biopsy tissue sections. Ability to ultrasensitively measure O ⁶-methylguanine, and its repair enzyme, should prove valuable in the risk assessment of cirrhotic patients for developing hepatocellular carcinoma. Received for publication on July 6, 1998; accepted on Aug. 12, 1998     

Role of nitric oxide in modulating neurotransmitter release from rat striatum

The effect of the nitric oxide synthase inhibitor N-nitro- -arginine methyl ester (L-NAME) on the basal and stimulation-evoked release of dopamine (DA) and acetylcholine (ACh) was investigated in rat striatum. The experiments were carried out in isolated superfused striatal slices, loaded with either [³H]-dopamine or [³H]-choline.We have found that L-NAME reduced the elecrical field stimulation-evoked release of DA, while its enantiomer N-nitro-D-arginine methyl ester (D-NAME) was ineffective. In the presence of the nitric oxide (NO) precursor -arginine L-NAME failed to influence DA release. Furthermore, treatment with the N-methyl- -aspartate (NMDA) receptor antagonist MK-801 completely reversed the effect of L-NAME on striatal DA release. In contrast, L-NAME had no effect on either the basal or the stimulation-evoked ACh release in any experimental conditions studied.Our data indicate that endogenously produced NO is involved in the modulation of striatal DA, but not in ACh release. Furthermore, it seems likely that the modulatory effect of NO is linked to activation of presynaptic NMDA receptors located on the striatal dopaminergic nerve terminals.