Genetic dissection of melanoma pathways in the mouse.

The frequent loss of the INK4a/ARF locus, encoding for both p16(INK4a)and p19(ARF)in human melanoma, raises the question as to which INK4a/ARF gene product functions to suppress melanoma-genesis in vivo. Studies in the mouse have shown that activated RAS mutation can cooperate with INK4a(Delta 2/3)deficiency (null for both p16(INK4a)and p19(ARF)) to promote development of melanoma, and these melanomas retain wild-type p53. Given the functional link between p19(ARF)and p53, we have now shown that activated RAS can also cooperate with p53 deficiency to produce melanoma in the mouse. Moreover, genome-wide analysis of RAS-induced p53 mutant melanomas reveals alterations of key components governing RB-regulated G1/S transition, such as c-Myc. These experimental findings suggest that both RB and p53 pathways function to suppress melanocyte transformation in vivo in the mouse.     

Overexpression of transforming growth factor-alpha causes liver enlargement and increased hepatocyte proliferation in transgenic mice.

Transforming growth factor-alpha (TGF-alpha) expression is associated with hepatocyte DNA replication both in vivo and in culture. Our previous work using TGF-alpha transgenic mice showed that constitutive overexpression of this growth factor in the liver causes hepatic tumors in 75 to 80% of the animals at 12 to 15 months of age. To understand the cellular events by which TGF-alpha overexpression leads to abnormal liver growth, we examined hepatocyte proliferative activity in young and old TGF-alpha transgenic mice and hepatocyte ploidy in normal, dysplastic, and neoplastic livers of these animals. At 4 weeks of age, transgenic mice had higher liver weights and liver weight/body weight ratios than non-transgenic mice of the same age and hepatocyte proliferative activity, measured by 3H-thymidine incorporation after 3- and 7-day infusion, proliferating cell nuclear antigen staining, and mitotic index determination, was 2 to 3 times higher than in controls. In both transgenic and non-transgenic mice hepatocyte proliferation declined with age but the decrease was much more pronounced in control animals, so that at 8 months of age, hepatocyte replication was 8 to 10 times higher in transgenic animals. Surprisingly, however, transgenic and non-transgenic mice at this age had similar liver weight/body weight ratios. Labeling studies done in 3-month-old animals revealed that hepatocyte turnover was much faster in transgenic than in control animals, suggesting that a homeostatic compensatory mechanism involving cell death tended to restore normal liver weight/body weight ratios in older transgenic mice. Ploidy analyses showed that at 4 weeks of age transgenic mice had a higher proportion of diploid and tetraploid hepatocytes and that the hepatocellular tumors which developed in TGF-alpha transgenic mice at 13 months of age contained a higher fraction of diploid hepatocytes than that present in adjacent tissue or in dysplastic livers. The results demonstrate that constitutive overexpression of TGF-alpha causes increased hepatocyte proliferation and liver enlargement in young animals and is associated with a delay in the establishment of hepatic polyploidy. These findings as well as the response of transgenic mice to partial hepatectomy show that constitutive overexpression of TGF-alpha initially caused increased but regulated hepatocyte proliferation which in older animals was compensated in part by a faster cell turnover. At 8 to 10 months of age, proliferative activity may become constitutive in some TGF-alpha expressing hepatocytes.(ABSTRACT TRUNCATED AT 400 WORDS)     

Gastric wall thickness in normal and neoplastic subjects: A prospective study performed by abdominal ultrasound

Gastric wall thickness (body-antrum) was blind measured prospectively by real-time ultrasound in 58 patients (30 with gastric cancer and 28 healthy) who had previously undergone endoscopy.Gastric wall thickness on the average measured 15.933±4.471 mm in the neoplastic patients and 5.107±1.100 mm in the normal subjects. Seven millimeters was the highest value found in the normal subjects (4 cases) and the minimum value found in the neoplastic patients (1 case).Knowing the normal gastric wall thickness value on a standard ultrasound examination of the upper abdomen is useful, as ultrasound is often performed as a screening or first-step procedure, in order to address the patients with higher values toward more specific techniques.This paper was presented in part as a free communication at EUROSON '87, Helsinki, June 1987.     

Surgical management of extensive gnathophyma

Rhinophyma is an uncommon disease of the nose characterized by irregular skin thickening and nodular deformation. The extensive growth causing 'whisky nose' is due to hyperplasia of the sebaceous glands and the surrounding connective tissue. Other facial regions may concomitantly be affected. We present a case of extensive gnathophyma accompanying minor lesions of the nose. Surgical treatment led to an excellent cosmetic result.     

Staging of thoracic lymphoma by radiological imaging

Thoracic lymphomas, which are very common especially in Hodgkin's disease patients, are characterised by enlargement of mediastinal lymph nodes, parenchymal abnormalities, and pleural, pericardial and chest wall involvement. The use of several imaging techniques has been proposed in order to assess the extent of the disease correctly and to plan therapy. The most relevant results in this field, especially those using computed tomography (CT), magnetic resonance imaging (MRI) and gallium scanning, are summarised in this review. Presently CT is widely and successfully used in staging patients, whereas MRI seems to be preferable, as a second-step technique, if pericardial, pleural and chest wall involvement are suspected. The role of gallium scanning is limited in the staging, although it could be relevant in the follow-up of treated patients. Received 4 April 1996; Revision received 7 November 1996; Accepted 7 November 1996     

Is growth hormone a radioprotective agent?

There is currently substantial clinical interest in growth hormone (GH) as a protective agent against radiation-related normal tissue injury. To further assess the potential radiation injury-preventive effects of GH, these effects were studied in rats by using a radiation-induced skin injury model. Group 1 received neither GH nor irradiation (control group). Group 2 received 30 Gy of gamma irradiation as a single dose to the right hind legs of the rats (radiation group). Group 3 and 4 received the same irradiation plus either 0.01 U/kg/day GH (RT + 0.01 GH group) or 0.02 U/kg/day GH (RT + 0.02 GH group) subcutaneously. Clinically and histopathologically, acute skin reactions were assessed by two independent experts in radiation oncology and pathology, respectively. Irradiation increased dermatitis in rats when compared with the control group. The severity of radiodermatitis in the rats in the RT + 0.01 GH and RT + 0.02 GH groups was significantly lower than that in the RT group; radiodermatitis developed earlier in the RT group than in the other groups. GH was efficacious in preventing epidermal atrophy, dermal degeneration such as oedema and collagen fibre loss, and hair follicle atrophy, but not better than in the control group. These results are preliminary to studies that will be performed with higher doses of GH in radiation-treated cancer patients, with the aim of reducing radiation-induced toxicity.     

Magnetic resonance angiography and colour-Doppler sonography in the evaluation of abdominal aortic aneurysms

This prospective study was aimed at comparing the diagnostic accuracy of magnetic resonance angiography (MRA) with colour-Doppler ultrasonography (colour-Doppler US) in the assessment of abdominal aortic aneurysms (AAA). Twenty patients with abdominal aortic aneurysms underwent MRA, colour-Doppler US, digital subtraction angiography (DSA) and CT. The MRA technique and colour-Doppler findings were compared with DSA as well as surgical and pathological findings, which were considered as the gold standard. In 6 patients who refused surgery, CT and DSA were considered as the gold standard. The MRA technique always correctly assessed the size and site of the aneurysms, the involvement of the renal and common iliac arteries, the course of the left renal vein, the thrombotic component and the calcifications. Colour-Doppler US always correctly assessed the size and site of the aneurysms, the thrombotic component and calcifications and the involvement of the iliac arteries. Our preliminary results suggest that MRA together with colour-Doppler US represents a valid alternative to invasive imaging in the assessment of AAA. Received 18 July 1996; Revision received 4 December 1996; Accepted 11 February 1997     

Rapid development of hepatic tumors in transforming growth factor {alpha} transgenic mice associated with increased cell proliferation in precancerous hepatocellular lesions initiated by N-nitrosodiethylamine and promoted by phenobarbital

The carcinogenic and tumor-promoting effects of human transforminggrowth factor