Tumour location influences local cytokine production and host metabolism.

To determine whether the location of tumour growth influences host cytokine and metabolic responses, experimental subcutaneous (SQ) and liver (LIV) tumours were compared in Buffalo rats. An LIV tumour that was only 1 +/- 1% (P < 0.05 versus SQ) of body weight produced similar anorexia, weight loss, acute phase response, and systemic cytokine responses as are SQ tumour that was 10 +/- 2% of body weight. Neither tumour-bearing group had abnormal liver function tests or evidence of obstructive biliary pathology. Tumour necrosis factor (TNF) was detected by western analysis in both tumour as well as histologically normal liver remote from the tumour in the LIV group but not in livers of animals in freely fed and SQ groups. The proximity of the tumour to competent tissue macrophage populations, such as hepatic Kupffer cells, may be sufficient to induce cachexia. Hence, tumour location may be as important as tumour burden in determining the host's response to cancer.     

Tumour colony growth in the irradiated mouse lung

The effect of irradiation of recipient mouse lung on tumour colony growth after intravenous injection of C3H mammary adenocarcinoma cells or aggregates was tested in C3H male mice irradiated with 14 MeV electrons to the whole or half of the thorax. Injections were made 3 h, 48 h, 3½ months or 9½ months after irradiation.     

Tumour growth rates and RECIST criteria in early drug development

Purpose

The evaluation of treatment efficacy with RECIST criteria does not take into account tumour growth dynamics. We notably investigated the impact of the pre-treatment tumour growth rate (GR) on the evaluation of treatment response.

Patients and methods

Seventy-six patients included in phase I clinical trials had scanographic evaluations before and after starting an experimental treatment. The GR was calculated for the pre-treatment period and for the experimental period (i.e. during the new treatment). Tumour response was evaluated per protocol at week 12 and at week 24 of the experimental period according to RECIST criteria. We studied the relation between pre-treatment and experimental GRs and RECIST tumour response.

Results

On average the tumour GR was decreased by 40% during the experimental period; compared to the pretreatment period (p = 0.03). An increased growth rate (acceleration of GR during experimental treatment compared to pretreatment) was observed in 20 (38%) of the 53 patients considered as non-progressive at week 12 according to RECIST. Conversely a decreased GR was observed in 12 out of 23 (53%) patients classified as progressive according to RECIST. The variation in the GR between the pre-treatment and experimental period was not significantly correlated with response evaluated according to RECIST at week 12 or at week 24 (p = 0.45 and 0.44, respectively).

Conclusions

RECIST evaluation of tumour response depends on the natural history of the tumours and poorly measures the impact of treatment on the kinetics of tumour growth. Integrating pre-treatment GR evaluations could substantially improve the assessment of treatment efficacy in drug development.     

Tumour angiogenesis factor (TAF) in human and animal tumours.

Extracts were made from Walker 256 carcinoma, spontaneous rat mammary adenocarcinoma, Wilms' tumour, human neuroblastoma and human haemangioma. Chromatography of the extracts on Sephadex G-100 yielded four fractions, A, B, C and D. Injection of fractions B and C resulted in the growth of new capillaries in the subcutaneous fascia or rats. Controls, e.g. similar extracts of rat liver or human kidney, did not induce neovascularisation. The endothelium of newly-formed blood vessels contained many mitotic figures. A limitation of this method is that it is qualitative only. In order to develop a quantitative in vitro assay for a tumour angiogenesis factor (TAF), short-term primary cultures were initiated from adult rat brain white matter, as cells from such cultures were shown to be vascular in origin. Addition of fractions containing TAF (B and C) which were active in vivo failed to stimulate thymidine uptake by the cells. The possible reasons for this failure and the therapeutic potential of TAF in cancer control are discussed.     

Tumour sublines with different metastatic capacity induce similar blood coagulation changes in the host.

This paper is aimed at investigating how metastatic tumour growth influenced the haemostatic system of the host. Blood platelet count, blood fibrinogen level, the activated partial thromboplastin time (APTT) and the prothrombin time (PT) were determined at various intervals during growth and metastasis of a murine fibrosarcoma (mFS6) or one of its sublines with different metastatic capacity. Progressive thrombocytopenia and increase in fibrinogen level were observed during development of the tumour in all the animal groups studied, irrespective of the metastatic potential of the various sublines. No significant changes were observed in the PT or APTT values. These data support the concept that primary rather than metastatic growth influences the haemostatic system of tumour-bearing animals.     

Tumour markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines for clinical use

The aim of this article is to present updated guidelines for the use of serum, tissue and faecal markers in colorectal cancer (CRC). Lack of specificity and sensitivity preclude the use of all existing serum markers for the early detection of CRC. For patients with stage II or stage III CRC who may be candidates for either liver resection or systemic treatment should recurrence develop, CEA should be measured every 2-3 months for at least 3 years after diagnosis. Insufficient evidence exists to recommend routine use of tissue factors such as thymidylate synthase, microsatellite instability (MSI), p53, K-ras and deleted in colon cancer (DCC) for either determining prognosis or predicting response to therapy in patients with CRC. Microsatellite instability, however, may be used as a pre-screen for patients with suspected hereditary non-polyposis colorectal cancer. Faecal occult blood testing but not faecal DNA markers may be used to screen asymptomatic subjects 50 years or older for early CRC.     

A Guideline for the Management of Gastrointestinal Stromal Tumour (GIST)

Gastrointestinal stromal tumour (GIST) is the commonest mesenchymal tumour to affect the gastrointestinal tract. Appropriate management requires accurate diagnosis and the skills of a multidisciplinary team. Surgery is the only curative treatment option and should be performed whenever feasible, by experienced personnel. For patients with advanced unresectable or metastatic disease, the receptor tyrosine kinase inhibitor imatinib offers effective therapy and can provide effective palliation for the majority of patients with this disease. The background to this recent development and a guideline for the management of GIST is proposed.     

Radiation Treatment of Giant-Cell Tumour of Bone (Osteoclastoma)

Ten patients with giant cell tumours of the bone were treated by radiation therapy. Indications were non-radical primary surgery in 8 cases and recurring lesions in 2. Tumour doses ranged from 23 to 75 Gy delivered with supervoltage equipment in 8 cases. There were 3 recurrences after radiation therapy, all occurring in patients with tumour doses less than 39 Gy; 2 of these had received orthovoltage therapy and 2 died later from lung metastases. Modern supervoltage irradiation is probably as effective as surgery which is nevertheless recommended in operable cases.     

Neuroendocrine Tumour of the Cystic Duct: A Case Report and Literature Review

This is a case report of a neuroendocrine tumour of the cystic duct which is extremely rare and was an incidental finding during laparoscopic surgery. A literature review of similar cases is also provided.     

Correlation of Tumour Response with Starting Tumour Size and Dose of Tamoxifen in an N-Methyl-N-Nitrosourea (NMU)-Induced Rat Mammary Cancer Model

Background: The aim of this preliminary study was to address variations of responses observed with different starting tumor sizes of 10 and 15 mm, and the effects of different doses of tamoxifen (TAM) on experimental rat mammary tumors. Materials and Methods: Thirty-five inbred female Sprague Dawley rats aged 43 days were administered with three weekly doses of N-methyl-N-nitrosourea (NMU) intraperitoneally (ip) at 50 mg/kg body weight. Animals were randomized (beginning from 10 mm tumor size) into four TAM-treated (50, 100, 200 and 500 μg/day) groups of six animals each, and another group (n=6) treated with TAM 100 μg/day at starting tumour size of 15 mm. The animals were treated by oral gavage daily for 8 weeks before sacrifice. Results: Serum urea and creatinine, and overall physical tumor burden were significantly modulated in animals treated with variable doses of TAM compared to the untreated controls (n=5). Final body weight and tumor number were significantly different in the 10 mm-treated animals compared to those treated at 15 mm. There were no significant differences in histopathological features among all the groups. Conclusions: Our findings suggest the importance of standardizing tumour size and drug doses before initiation of treatment, particularly in the direct comparison of basic end-tumour physical parameters.     

Biochemical modulation of tumor-growth, metastasis and host metabolism

Exogenous nutrients, hormones and metabolites can significantly alter tumor growth, metastasis, and host nutritional status. Arginine, serine and methionine are critical amino acids required for protein, DNA and RNA synthesis and, thus, for cellular proliferation. To determine the effect of these specific amino acids on host metabolism, primary tumor growth and metastasis, 48 Lewis rats bearing the mammary adenocarcinoma MAC-33 were randomized to receive similar diets with 3% supplements of serine, arginine, methionine or glycine (control). After 25 days on each diet, animals were sacrificed to determine primary tumor biochemical composition and growth kinetics, number of lung metastases and carcass weight. A significant reduction in lung metastases occurred with serine and methionine supplementation (p<0.01) with no significant change in primary tumor size. However, increased mortality (p<0.001) and low carcass weight (p<0.05) were found in the methionine group indicating significant host toxicity. Serine-supplemented animals had a mortality rate and carcass weight comparable to the control group. Arginine supplementation had no effect on primary tumor growth, metastasis or carcass weight; however, increased mortality was observed in this group compared to controls. These results suggest that serine supplementation selectively supports host growth and inhibits metastasis in tumor-bearing animals. This study demonstrates the potential to differentially effect host and tumor growth with exogenous amino acid supplements.     

Detection of Circulating Tumour DNA in the Blood (Plasma/Serum) of Cancer Patients

Small amounts of free DNA circulate in both healthy and diseased human plasma/serum, and increased concentrations of DNA are present in the plasma of cancer patients. Characteristics of tumour DNA have been found in genetic material extracted from the plasma of cancer patients. These features include decreased strand stability and the presence of specific oncogene, tumour suppressor gene and microsatellite alterations. Point mutations of the ras genes have been detected in the plasma DNA of patients suffering from haematopoetic malignancies, colorectal and pancreatic cancer, sometimes prior to clinical diagnosis. Rearranged immunoglobulin heavy chain DNA has been found in the plasma of patients with non-Hodgkins lymphoma and acute B cell leukaemia. Microsatellite instability, expressed either as a new allele or a loss of one allele (LOH) occurs in the plasma and serum DNA of patients suffering from head and neck, lung and renal cell cancer. The results obtained in many different cancers have opened a new research area indicating that plasma DNA might eventually be a suitable target for the development of non-invasive diagnostic, prognostic and follow-up tests for cancer.