British Journal of Cancer

Saunders, MI; Dische, S; Barrett, A; Parmar, MKB; Harvey, A; Gibson, D

doi: 10.1038/bjc.1996.276pmid: 8664112

While radiotherapy is proceeding, tumour cells may proliferate. The use of small individual doses reduces late morbidity. Continuous hyperfractionated accelerated radiation therapy (CHART), which reduces overall treatment from 6-7 weeks to 12 days and gives 36 small fractions, has now been tested in multicentre randomised controlled clinical trials. The trial in non-small-cell lung cancer included 563 patients and showed improvement in survival; 30% of the CHART patients were alive at 2 years compared with 20% in the control group (P = 0.006). In the 918 head and neck cases, there was only a small, non-significant improvement in the disease-free interval. In this interim analysis there was a trend for those with more advanced disease (T3 and T4) to show advantage; this will be subject to further analysis when the data are more mature. The early mucosal reactions appeared sooner and were more troublesome with CHART, however they quickly settled; so far no difference in long-term morbidity has emerged. These results support the hypothesis that tumour cell repopulation can occur during a conventional course of radiotherapy and be a cause of treatment failure.

Vanderkerken, K; Goes, E; De Raeve, H; Radl, J; Van Camp, B

doi: 10.1038/bjc.1996.277pmid: 8664113

The evolution of bone lesions in transplantable C57BL/KaLwRjj 5T mouse myeloma (MM) has been followed in vivo. Mice were anaesthetised and a radiograph of the pelvis and hind legs was performed by a radiograph dedicated for mammography. This is the first description of an in vivo technique under experimental conditions whereby the development of bone lesions owing to the MM growth was demonstrated.

Oriuchi, N; Watanabe, N; Sugiyama, S; Higuchi, T; Imai, K; Yamanaka, H; Hashimoto, M; Kanda, H; Endo, K

doi: 10.1038/bjc.1996.278pmid: 8664114

Biodistribution of chimeric mouse/human monoclonal antibody against non-specific cross-reacting antigen (chNCA Ab) was studied in athymic mice and patients with metastatic bone disease. 99mTc-chNCA Ab showed a high labelling efficiency, stability and also a high binding ratio to human granulocytes. Since NCA showed cross-reactivity with carcinoembryonic antigen (CEA), animal experiments showed that 99mTc-chNCA Ab was accumulated in the xenografted tumour which expressed CEA, suggesting the preserved immunoreactivity of labelled materials. In the clinical study, injected 99mTc-chNCA Ab formed a high molecular weight complex immediately after intravenous administration and was trapped mainly in liver. The first-phase plasma half-life was 6.4 +/- 1.1 min. None of the patients showed adverse reaction or human antimurine or anti-chimeric antibody in their serum. 99mTc-chNCA Ab demonstrated remarkably different biodistribution between patients and the animal model and showed different pharmacokinetics from other murine and chimeric Abs reported previously. For safety HPLC analysis should be performed before clinical radioimmunodetection or radioimmunotherapy by incubating radiolabelled MAb with human serum under strict conditions.

Mlkvy, P; Messmann, H; Pauer, M; Stewart, JCM; Millson, CE; MacRobert, AJ; Bown, SG

doi: 10.1038/bjc.1996.279pmid: 8664115

Photodynamic therapy (PDT) has the potential to destroy small tumours with safe healing of adjacent normal tissue. This study looks at the effects of PDT on the normal pancreas and adjacent tissues in hamsters using the photosensitiser meso-tetrahydroxyphenylchlorin (mTHPC). Pharmacokinetic studies used fluorescence microscopy on sections of pancreas, stomach and duodenum 1 h to 6 days after mTHPC. Highest levels of sensitiser were seen in the gastric and duodenal mucosa and in the acinar pancreas after 2-4 days. For PDT, light at 652 nm was delivered by placing a 0.2 mm diameter bare-ended fibre against the tissue. An energy of 50 J was used 2 or 4 days after 0.1 or 0.3 mg kg-1 mTHPC and animals killed 1 to 7 days later. Maximum necrosis was seen 3 days after PDT with lesions up to 4 mm in pancreas, 4.5 mm in duodenum and 2.5 mm in stomach. By fractionating the light dose, the lesion size could be increased by 30%. The main complication was free or sealed duodenal perforation (avoided by shielding the duodenum). Partial, reversible bile duct obstruction was seen occasionally. There was no macroscopic damage to the bile ducts or major blood vessels. Apart from the duodenum, all lesions healed safely. In this animal model, only the duodenum was at risk of serious, irreversible damage. Treatment is likely to be safer in the much thicker human duodenum. mTHPC is a powerful photosensitiser and suitable for further study for tumours in the region of the pancreas although care is required near the duodenum.

Lartigau, E; Guichard, M

doi: 10.1038/bjc.1996.280pmid: 8664116

Recent data have shown that the in vitro and in vivo cytotoxicity of bioreductive drugs could be significantly increased when combined with chemotherapy drugs such as cisplatinum, depending on the timing of administration. The aim of this study was to define the toxicity (animal lethality) and the activity (growth delay assay, excision assay) of a bioreductive drug, tirapazamine, alone and combined with chemotherapy agents (5-FU, VP16, bleo, DTIC and c-DDP) on nude mice bearing xenografted human tumours: a rectal carcinoma (HRT18) and a melanoma (Na11+). Animal lethality was markedly increased when tirapazamine at the lethal dose 10% was combined with the other drugs. For the HRT18 tumour the combination of tirapazamine and bleomycin significantly increased the delay of regrowth compared with bleomycin alone (P = 0.04) and was more cytotoxic than tirapazamine alone (P = 0.04). For the Na11+ tumours the combination of tirapazamine with VP16 significantly increased tumour doubling time compared with the controls (P = 0.001) or VP16 alone. The combination of tirapazamine and VP16 was more cytotoxic than VP16 alone (P = 0.0001). When compared with c-DDP or tirapazamine alone, there was a significant decrease in plating efficiency when tirapazamine and c-DDP were given at the same time (P = 0.04), but not when tirapazamine was given 3 h before c-DDP. In conclusion, tirapazamine was shown to be cytotoxic against clonogenic human tumour cells. Its efficacy in vivo may depend on its combination with already active chemotherapy drugs on the tumour model used. The timing of administration may be less important than previously thought.

el-Ahmady, O; Halim, A-B; Mansour, O; Salman, T; el-Din, A Gamal; Walker, RP

doi: 10.1038/bjc.1996.281pmid: 8664117

Urinary gonadotropin peptide (UGP) levels were determined in urine samples from 450 Egyptian subjects to determine its relative level of expression in benign and malignant urological disease, and normal individuals. The mean UGP level in patients with bladder cancer was 44-fold higher than in patients with benign disease, and 81-fold higher than in normal individuals. At specificities of 95% and 100%, overall sensitivities of 73% and 60%, respectively, were observed for the detection of malignant disease. Mean UGP levels in patients with bladder cancer were significantly correlated with the stage and grade of malignant disease but did not vary significantly when stratified according to histological type of disease, nodal involvement or bilharzial association. UGP could be a potentially useful marker for the differentiation of benign from malignant urological disease.

Hiraki, A; Shinohara, M; Ikebe, T; Nakamura, S; Kurahara, S; Garrod, DR

doi: 10.1038/bjc.1996.282pmid: 8664118

Desmosomes are intercellular junctions that have been shown to be down-regulated in certain types of carcinomas and that may play a role in suppression of invasion and metastasis. We have shown previously that immunohistochemical staining for the major desmosomal glycoprotein, desmoglein (Dsg), is reduced in some cases of squamous cell carcinoma (SCC) of the head and neck, and that reduced staining correlates with lymph node involvement. Desmosomes are multicomponent organelles. We therefore sought to determine whether another major desmosomal molecule, desmoplakin (Dp), showed similar reduced expression to that shown by desmoglein. We have stained 65 specimens of primary SCC of the oral cavity (37 non-metastatic and 28 metatastic) with monoclonal antibodies to both desmoglein and desmoplakin. We show that reduction of Dp staining correlates with loss of differentiation of the primary tumour, degree of invasion and presence of lymph node metastases. Similar correlations were found with Dsg staining. There was also correlation between reduction in Dp staining and reduction in Dsg staining. It is concluded that down-regulation of desmosomal expression occurs in some cases of SCC of the oral cavity and is associated with invasion and metastasis. Desmosomes may have an invasion and metastasis suppressor function.

Tsai, JF; Jeng, JE; Ho, MS; Chang, WY; Hsieh, MY; Lin, ZY; Tsai, JH

doi: 10.1038/bjc.1996.283pmid: 8664119

To assess the role of hepatitis B e antigen (HBeAg) and its interaction with hepatitis B surface antigen (HBsAg) on the development of hepatocellular carcinoma (HCC), this case-control study included 361 age- and sex-matched pairs of patients with histologically proven HCC and healthy control subjects. HBsAg, HBeAg and antibody to HBeAg (anti-HBe) were detected by radioimmunoassay. Antibodies to hepatitis C virus (anti-HCV) were detected by second-generation enzyme immunoassay. The prevalences of HBeAg (20.2%), HBsAg (80.3%) and anti-HCV (29.5%) in cases were higher than in controls (1.9%, 20.7%, and 2.7% respectively; each P < 0.0001). Using patients negative for HBsAg, HBeAg and anti-HBe as a referent group, univariate analysis indicated that HBsAg alone or HBsAg and HBeAg were risk factors for HCC (P for trend < 0.0001). Calculation of incremental odds ratio indicated that there was additive interaction between HBsAg and HBeAg. Multivariate analysis indicated that HCC development was strongly associated with the presence of HBeAg (odds ratio, 8.1; 95% confidence interval, 2.4-27.1), HBsAg (odds ratio, 68.4; 95% confidence interval, 20.5-227.8) and anti-HCV (odds ratio, 59.3; 95% confidence interval, 13.6-258.4). In conclusion, HBsAg, HBeAg and anti-HCV are independent risk factors for HCC. There is additive and independent effect modification between HBsAg and HBeAg on the development of HCC.

Krajci, P; Meling, GI; Andersen, SN; Hofstad, B; Vatn, MH; Rognum, TO; Brandtzaeg, P

doi: 10.1038/bjc.1996.284pmid: 8664120

Secretary component (SC) is expressed basolaterally as a transmembrane protein (pIg receptor) on secretory epithelial cells. As pIg receptor it plays a central role in humoral immunity by mediating the external translocation of dimeric IgA and pentameric IgM. A few case reports have suggested that reduced or absent SC protein expression is associated with diarrhoeal disease, but there is no convincing evidence that a primary pIg receptor deficiency can occur. In this study the relative presence of SC mRNA was determined by Northern blot analysis and related to immunohistochemically determined SC protein expression in 33 colorectal adenomas (31 patients) with increased risk of developing sporadic colorectal cancer, as well as in 19 colorectal carcinomas from 19 patients with such sporadic tumours. In the adenomas, SC mRNA levels were positively related to SC protein expression; both mRNA and SC protein were negatively related to histological grade. Similarly, SC mRNA levels tended to be related to the SC protein expression in the carcinomas. SC mRNA was detected in all adenomas, and only two of ten carcinomas (10.5%) deemed to be SC deficient by immunohistochemistry also lacked SC mRNA expression, suggesting diallelic alterations in the SC-encoding gene (locus PIGR). This possibility agreed with Southern blot analysis performed on a separate sample of 32 other colonic carcinomas in which the diallelic loss of D1S58 (which exhibits a close linkage centromerically to PIGR) was calculated to be 6.4%. Together these findings suggested that reduced SC protein expression in colorectal adenomas might be a transcriptional defect reflecting the degree of cellular dysplasia, whereas absent SC protein expression in colorectal carcinomas might also involve post-transcriptional defects and occasional diallelic gene deletions representing late events in carcinogenesis.

Ohta, T; Numata, M; Yagishita, H; Futagami, F; Tsukioka, Y; Kitagawa, H; Kayahara, M; Nagakawa, T; Miyazaki, I; Yamamoto, M; Iseki, S; Ohkuma, S

doi: 10.1038/bjc.1996.285pmid: 8664121