Morgagni-Larrey hernia (2 personal cases)

Morgagni-Larrey hernia is a rare diaphragmatic form whose time of onset is almost impossible to determine. Its symptoms, if any, are not easy to interpret. A standing X-ray of the chest is the only way in which its presence may be suspected and diagnosis must be confirmed by the use of contrast media. Abdominal or thoracic surgery is mandatory, even in symptom-free cases. The choice of route will be determined by the facts of the case and the patient's age. The clinical picture observed in two personal cases and their treatment are described.     

Delayed cerebrovascular consequences of radiation to the neck. A clinicopathologic study of a case

A man had a stroke 27 years after radiation therapy to the neck for treatment of laryngeal papillomas. There were premonitory symptoms suggesting cerebral ischemia. In contrast to many previously reported cases, in our patient there is a strong relationship between radiation therapy and stroke. Pathoanatomic study of the surgical vascular specimen strongly suggests that radiation is a potentially modifiable cause of delayed stroke.     

Myelodysplastic syndromes in children: Observations on five cases

Five paediatric patients with a myelodysplastic syndrome (MDS) (age range 4-12 years) are described. The frequency of MDS in our institution in the last 13 years is 1.12% of all leukaemic syndromes. Diagnosis and classification were made according to the recent proposals of the FAB Co-operative Group: four refractory anaemia with excess of blasts in transformation (RAEB-T) and one refractory anaemia with excess of blasts (RAEB). The haematqlogical picture at onset is presented with morphological, cytochemical, immunological and cytogenetic data. Two patients had trisomy 8 and one had monosomy 7. In three patients an evolution towards acute myeloid leukaemia was observed. Multiple drug treatment used in the chronic phase and/or during transformation in acute leukaemia did not produce complete remission. Low-dose Ara-C was employed in one case in the chronic phase without improvement. Four patients died 3-17 months after diagnosis. One is alive with persistent leukaemia 8 months after diagnosis.     

Pharmacokinetic model for procaine in humans during and following intravenous infusion.

A multicompartment pharmacokinetic model is presented to describe procaine distribution in humans during and following intravenous infusion. The model, based on a general perfusion model, relates individual characteristics such as sex, age, weight, height, infusion rate and duration, and hematocrit to general parameters such as drug metabolism, protein binding, ion-trapping effects, and tissue-plasma distribution coefficients to provide an individualized distribution prediction. Experimentally observed kinetics of blood procaine levels collected during intravenous procaine infusion as an adjunct to surgical anesthesia and blood lidocaine levels obtained from the literature compared very well with the model simulation.     

Differences in radiation sensitivity in subpopulations of mammalian multicellular systems.

A partial review of new and existing data on the radiation sensitivity of complex cellular systems of mammals is reported. The experimental evidence suggests that a unique sensitivity can always be associated with each subpopulation in a complex system, provided that such a subpopulation can be adequately identified and monitored. The analysis of the survival curves of normal tissues confirms the variations in radiation sensitivity between different renewing tissues. In particular, the hemopoietic system is most responsive to radiation and, at the same time, represents a good example of how the radiation sensitivity of an overall population can be resolved for subpopulations of varying degrees of commitment to proliferate and differentiate. Moreover, variations in radiation response depending on the redistribution of cells along the cycle phases have been taken into consideration, mainly by analyzing the results in different tissues of fractionation experiments at relatively high and low doses. These phenomena are discussed for both normal and malignant systems.     

Grade of chemotherapy-induced necrosis as a predictor of local and systemic control in 881 patients with non-metastatic osteosarcoma of the extremities treated with neoadjuvant chemotherapy in a single institution

To determine whether necrosis induced by pre-operative chemotherapy correlates with the rate of systemic and local relapse, may change the pattern of relapse and/or may modify the chance of success of post-relapse treatments, we evaluated 881 patients with non-metastatic osteosarcoma of the extremities treated with five different protocols of neoadjuvant chemotherapy and surgery at the same institution between 1983 and 1999. The 5-year disease-free survival (DFS) and overall survival (OS) correlated significantly with the histological response to chemotherapy. Five-year DFS and OS in good and poor responders were 67.9% versus 51.3% (P < 0.0001) and 78.4% versus 63.7% (P < 0.0001), respectively. The prognostic value of the histological response was valid only for osteoblastic and telangiectatic osteosarcoma subtypes. Nonetheless, since they represent more than 70% of all osteosarcomas, we conclude that chemotherapy-induced necrosis has a significant prognostic value, regardless of the type of chemotherapy performed after surgery.     

VEGF and VEGFR-2 immunohistochemistry in human melanocytic naevi and cutaneous melanomas

Vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2) play a key role in vasculogenesis and angiogenic sprouting, which are crucial for tumour development and metastasis. In order to determine their possible role in the acquisition of metastatic potential throughout melanocytic tumour progression, VEGF and VEGFR-2 immunohistochemical expression were evaluated in 36 human melanocytic tumours of the skin (24 malignant melanomas and 12 common naevi). Different VEGFR-2 immunostaining patterns were detected in the vast majority of melanomas (21/24; 88%). A nuclear membrane-like pattern was mainly associated with in situ and microinvasive melanomas, whereas a combined cytoplasmic membrane and nuclear membrane-like pattern was seen in invasive melanomas. A nuclear membrane-like pattern was also observed in 83% (10/12) of common naevi. Cytoplasmic immunostaining for VEGF was observed in 72% (8/11) of in situ/microinvasive melanomas, 84% (11/13) of invasive melanomas and 91% (11/12) of naevi. CD31 was also investigated as an immunohistochemical marker for microvessel density (MVD) evaluation. No associations were found between MVD and VEGF/VEGFR-2 expression. Taken together, these data indicate that VEGF production is a common event in benign melanocytic tumours, whereas VEGFR-2 expression, co-localized in the cytoplasmic and nuclear membrane, is associated with progression towards invasive melanoma. The role exerted by VEGF/VEGFR-2, however, seems to be independent of the development of a tumour-related capillary network.     

In vitro inhibition of promyelocytic leukemia/retinoic acid receptor-alpha (PML/RARalpha) expression and leukemogenic activity by DNA/LNA chimeric antisense oligos

Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by the chromosomal translocation t(15:17) that leads to the expression of promyelocytic leukemia/retinoic acid receptor-alpha (PML/ RARalpha) oncofusion protein. The block of differentiation at the promyelocytic stage of the blasts and their increased survival induced by PML/RARalpha are the principal biological features of the disease. Therapies based on pharmacological doses of retinoic acid (RA, 10(-6) M) are able to restore APL cell differentiation in most cases, but not to achieve complete hematological remission because retinoic acid resistance occurs in many patients. In order to elaborate alternative therapeutic approaches, we focused our attention on the use of antisense oligonucleotides as gene-specific drug directed to PML/RARalpha mRNA target. We used antisense molecules containing multiple locked nucleic acid (LNA) modifications. The LNAs are nucleotide analogues that are able to form duplexes with complementary DNA or RNA sequences with highly increased thermal stability and are resistant to 3'-exonuclease degradation in vitro. The DNA/LNA chimeric molecules were designed on the fusion sequence of PML and RARalpha genes to specifically target the oncofusion protein. Cell-free and in vitro experiments using U937-PR9-inducible cell line showed that DNA/LNA oligonucleotides were able to interfere with PML/RARalpha expression more efficiently than the corresponding unmodified DNA oligo. Moreover, the treatment of U937-PR9 cells with these chimeric antisense molecules was able to abrogate the block of differentiation induced by PML/RARalpha oncoprotein. These data suggest a possible application of oligonucleotides containing LNA in an antisense therapeutic strategy for APL.