The role of oncogenes, tumour suppressor genes and growth factors in oral squamous cell carcinoma: a case of apoptosis versus proliferation

Mutation, deactivation and disregulated expression of oncogenes and tumour-suppressor genes may be involved in the pathogenesis of oral squamous cell carcinoma (SCC). Deactivation of the p53 tumour-suppressor gene allows cell proliferation and blocks apoptosis of malignant oral keratinocytes. Mutation in the ras oncog-ene results in persistent mitogenic signalling. Upregul-ated c-Myc expression, in the presence of growth factors, provides an additional proliferative signal. Loss of retino-blastoma tumour-suppressor gene (Rb) function may contribute to oral keratinocyte hyperproliferation and recent evidence suggests that simultaneous deactivation of both p53 and Rb is required for tumourigenesis. Enhanced Bcl-2 and reduced Fas expression inhibit tumour cell apoptosis and may convey resistance to cyto-toxic drugs and T cell-mediated cytotoxicity, respectively. Exogenous mutagens such as tobacco, alcohol and viral oncogenes may cause altered expression of oncogenes and tumour-suppressor genes in some cases of oral SCC. The impact of these mechanisms on future therapies for oral SCC is highlighted.     

The relationship between ligation of the ductus arteriosus and intracranial hemorrhage in preterm infants

Surgical closure of patent ductus arteriosus (PDA) and perioperative time have been proposed as conditions of increased risk of peri-intraventricular hemorrhage (PVH-IVH) in preterm infants. We examined by pre- and postoperative ultrasound (US) scan 15 low birth-weight neonates who underwent PDA ligation within the first two weeks of life. They were assessed with regard to clinical state, perioperative management and development of PVH-IVH. Fourteen did not show onset or extension of intracranial hemorrhage in the immediate postoperative period. One patient developed a wide III grade IVH in the 24 perioperative hours. His conditions were particularly severe, suggesting that many factors such as acidosis, hypoxia, hypercapnia and hypotension might have combined to lead to hemorrhage. We conclude that PDA ligation is not likely to increase the risk of PVH-IVH per se.     

Leprosy and HIV coinfection: a critical approach

An increase in leprosy among HIV patients, similar to that observed in patients with TB, was expected approximately 20 years ago. Studies conducted in the 1990s together with those reported recently seemed to indicate that a coinfection with HIV did not alter the incidence and the clinical spectrum of leprosy and that each disease progressed as a single infection. By contrast, in countries with a high seroprevalence of HIV, TB was noted to increase. Explanations may be provided by the differences in the incubation time, the biology and toxicity of Mycobacterium leprae and Mycobacterium tuberculosis. After the introduction of HAART the leprosy-HIV coinfection manifested itself as an immune reconstitution inflammatory syndrome (IRIS), typically as paucibacillary leprosy with type 1 leprosy reaction. The incidence of leprosy in HIV-infected patients has never been properly investigated. IRIS-leprosy is probably underestimated and recent data showed that the incidence of leprosy in HIV patients under HAART was higher than previously thought.     

Reaching the target dose with one single 131I-mIBG administration in high-risk neuroblastoma: The determinant impact of the primary tumour

Background : ¹³¹I-metaiodobenzylguanidine (¹³¹I-mIBG) effectiveness in children with metastasised neuroblastoma (NB) is linked to the effective dose absorbed by the target; a target of 4 Gy whole-body dose threshold has been proposed. Achieving this dose often requires administering ¹³¹I-mIBG twice back-to-back, which may cause haematological toxicity. In this study, we tried identifying the factors predicting the achievement of 4 Gy whole-body dose with a single radiopharmaceutical administration. Materials and methods : Children affected by metastatic NB and treated with a high ¹³¹I-mIBG activity (>450 MBq (megabecquerel)/kg) were evaluated retrospectively. Kinetics measurements were carried out at multiple time points to estimate the whole-body dose, which was compared with clinical and activity-related parameters. Results : Seventeen children (12 females, median age 3 years, age range: 1.5–6.9 years) were included. Eleven of them still bore the primary tumour. The median whole-body dose was 2.88 Gy (range: 1.63–4.22 Gy). Children with a ‘bulky’ primary (>30 mL) received a higher whole-body dose than those with smaller or surgically removed primaries (3.42 ± 0.74 vs. 2.48 ± 0.65 Gy, respectively, p = .016). Conversely, the correlation between activity/kg and the whole-body dose was moderate (R: 0.42, p = .093). In the multivariate analysis, the volume of the primary tumour was the most relevant predictor of the whole-body dose (p = .002). Conclusions : These data suggest that the presence of a bulky primary tumour can significantly prolong the ¹³¹I-mIBG biological half-life, effectively increasing the absorbed whole-body dose. This information could be used to model the administered activity, allowing to attain the target dose without needing a two-step radiopharmaceutical administration.     

T regulatory cells (TREG)(TCD4+CD25+FOXP3+) distribution in the different clinical forms of leprosy and reactional states

BACKGROUND

Leprosy is characterized histologically by a spectrum of different granulomatous skin lesions, reflecting patients'' immune responses to Mycobacterium leprae. Although CD4+CD25+ FoxP3+ T regulatory cells are pivotal in the immuneregulation, presence, frequency, and distribution of Tregs in leprosy, its reactional states have been investigated in few studies.

OBJECTIVES

This study aimed to verify the frequency and distribution of regulatory T cells in different clinical forms and reactional states of leprosy.

METHODS

We performed an immunohistochemical study on 96 leprosy cases [Indeterminate (I): 9 patients; tuberculoid tuberculoid: 13 patients; borderline tuberculoid: 26 patients; borderline borderline: 3 patients; borderline lepromatous: 8 patients; lepromatous lepromatous: 27 patients; reversal reaction: 8 patients; and erythema nodosum leprosum: 2 patients].

RESULTS

FoxP3-positive cells were present in 100% of the cases with an average density of 2.82% of the infiltrate. Their distribution was not related to granulomatous structures or special locations. There was a statistically significant increment of FoxP3 expression in patients with leprosy reversal reactions when compared with patients presenting with type I leprosy (P= 0.0228); borderline tuberculoid leprosy (P = 0.0351) and lepromatous leprosy (P = 0.0344).

CONCLUSIONS

These findings suggest that Tregs play a relevant role in the etiopathogenesis of leprosy, mainly in type I leprosy reaction.     

Imiquimod and lymphatic field clearance: a new hypothesis based on a remote immune action on skin cancer

Basal cell carcinoma and actinic keratosis are frequent neoplasms. Topical treatments include the recently approved imiquimod cream. We describe here the case of a 68-year-old man with multiple actinic keratosis on the forehead, upper trunk and on the left cheek. In addition, an exulcerated basal cell carcinoma was observed. The patient was advised only to treat lesions on the forehead with imiquimod cream. This resulted in complete clearance of actinic keratosis within 6 weeks. At follow-up, a planned surgical excision of the basal cell carcinoma and actinic keratosis on the cheek was carried out. Histopathologically, both excision specimens no longer showed features of basal cell carcinoma or actinic keratosis, despite the fact that the imiquimod treatment was not applied to the cheek. Imiquimod cream is a topical immune response modifier, which has shown antiviral and anti-tumorous properties by inducing the production of cytokines as well as by stimulating dendritic cells and lymphocytes. Our observation supports the concept of lymphatic transport of immune cells and factors with subsequent immunological curing of tumours, not only in the treated area, but also those in the area between the imiquimod application site and the regional lymph nodes (the "lymphatic field clearance").