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Breast cancer is one of the most frequent malignancies affecting women. The human breast cancer gene 1 (BRCA1) gene is mutated in a distinct proportion of hereditary breast and ovarian cancers. Tumourigenesis in individuals with germline BRCA1 mutations requires somatic inactivation of the remaining wild-type allelle. Although, this evidence supports a role for BRCA1 as a tumour suppressor, the mechanisms through which its loss leads to tumourigenesis remain to be determined. Neither the expression pattern nor the described functions of human BRCA1 and murine breast cancer gene 1 (Brca1) can explain the specific association of mutations in this gene with the development of breast and ovarian cancer. Investigation of the role of Brca1 in normal cell differentiation processes might provide the basis to understand the tissue-restricted properties.

Tissue remodeling is a key element in the local invasion and metastasis of malignant breast tumors. The degradation of extracellular matrix that is associated with this process is thought to be mediated by a number of Zn2+-dependent matrix metalloproteinases (MMPs). In most cases these enzymes are not produced by the malignant epithelium itself but by adjacent breast stroma, suggesting an important role for cell-cell interactions. We have analyzed Gelatinase A (MMP-2) and Gelatinase B (MMP-9) gene expression in a panel of six breast cancer cell lines and six primary cultures of stromal cells deriving from breast cancer biopsies. With one exception we did not detect MMP-2 or MMP-9 gene expression in any of the established tumor cell lines. Conversely, tumor stroma-derived fibroblasts expressed MMP-2 mRNA. although no MMP-9 mRNA was seen in RNase protection assays. When fibroblasts were cultured in the presence of media conditioned by MCF-7 tumor cells, MMP-2 enzyme production increased but MMP-9 activity remained undetectable. However, when fibroblasts and MCF-7 tumor cells were co-cultured together, MMP-9 was induced. These observations were confirmed by immunocytochemical analysis of co-cultures of MCF-7 and tumor-derived fibroblasts in which MMP-2 and MMP-9 protein expression was confined to stromal cells adjacent to MCF-7 tumor cells. No MMP-2 or MMP-9 staining was detected in monocultures of the two respective cell types. We conclude that MMP-2 expression is present in the stroma of malignant tumors and is increased by paracrine stimulation mediated by soluble factors. In contrast, MMP-9 expression tumor-derived fibroblasts requires direct contact with malignant tumor epithelium.

Background: The particular biomechanics of the upper cervical spine require, when trauma occurs, careful evaluation of the stability of the lesions, in order to guarantee the best possible therapeutic and prognostic approach. To date, there has been no uniformity of opinion in merit, especially with reference to treatment of odontoid fractures. It is necessary for this reason as much as for the opportune standardisation of the patients' classification parameters to establish what is meant by stability and which lesions are to be held as being unstable in the upper cervical spine., Methods: All the cases of upper cervical spine instability treated in our Unit from '94 to date have been reviewed. Four fractures to the first cervical vertebra, 29 to the odontoid process, 9 isolated fractures in the C2 body, 12 hangman fractures, 7 fractures of the articular processes, 2 to the occipital condyles and 4 C1-C2 dislocations without fractures were localised. Using precise prognostic indexes as our classification criteria, 56 of the 58 patients observed were addressed towards either conservative treatment or directly towards surgical treatment. In particular, 29 patients were conservatively treated with a collar or Halo-Vest. Twenty-seven surgical operations were carried out: 14 screw fixations, 6 anterior fixations using plates and screws, 4 rear ones using metal wire or wire with bone graft, 3 odontectomy operations associated with posterior fixation., Results: In the follow-up, using a range of between three months to six years, good fusion with spine stabilisation was achieved in all the patients treated. In particular, surgery was carried out as the first therapeutic indication in 25 cases, obtaining excellent results. Surgery was necessary in only 2 cases after the failure of external stabilisation., Conclusions: The judgement passed on instability in traumatic lesions in the upper cervical spine represents the decisive factor in the choice of the therapeutic option. Instead of always opting for conservative treatment, in the case of C1-C2 fractures-luxations, and going ahead with surgery only when there is instability or non-fusion of the segments resulting after successive monitoring, we believe that the definition and standardisation of the prognostic factors is opportune, in order to provide patients with a specific solution, in such a way as to reduce the failure percentage of the first treatment and optimise the healing time.

In a prospective survey clinical haematological and molecular biological data of 31 patients with chronic myelogenous leukaemia (chronic phase, CML) observed in their haematological outpatient department were analyzed. During 1996 and 1999 a regular follow-up of the Philadelphia chromosome level in treated patients was performed with molecular biological techniques, i.e. with reverse transcription polymerase chain reaction (RT-PCR) and with fluorescence in situ hybridization (FISH) methods. During the follow-up period of 33 months from the 31 patients with CML (16 males, 15 females) 25 ones were treated with human recombinant interferon-alpha (IFN), however, six others were getting only hydroxyurea (HU). During this period in three patients allogen bone marrow transplantation was performed and seven ones expired (six out of them of blastic crisis). The quality of therapeutic response at cytogenetical level was determined by decrease of the bcr-abl level due to the treatment (non-responders, major, minor and complete cytogenetic remission groups). In nine patients (five from the IFN-group, four from the HU-group) achieved no cytogenetic therapeutic response (non-responders, 29%). However, in 13 patients a minor (bcr-abl range of 60-30%), and in nine patients a maior/complete (bcr-abl of 30-10%) cytogenetic response (42% and 29%, respectively) were detected. Moreover, the quality of cytogenetic response correlated with the haematological remission. The maior/complete cytogenetic response was durable in eigth patients. The improvement of the overall survival of patients with CML, the postpone of the fatal accelerated-blastic phase could be expected only from the early introduced, in individually adjusted and given in maximally tolerated dosage of interferon (3-5 million UI/m2/day). The qualitative (RT-PCR) and quantitative (FISH) detections of the Philadelphia chromosome are reliably reproducible up-to-date molecular biological methods getting relevant results, which could be very helpful in the planning, monitoring, in setting of optimal dosage of the interferon therapy of patients with CML, in addition in the judgement of the effectiveness of the therapy, in the reduction of adverse effects, as well as in forecasting of the cytogenetic progression.

Case history of a seventy year old man with myelodysplastic syndrome is presented. The disease terminated into acute leukaemia in 22 months. The pure, B lymphoid stem cell nature of the leukaemic cells has been proved, beside morphology and cytochemistry, by detailed flow cytometric phenotyping and PCR amplification as well as sequencing of the immunoglobulin heavy chain gene CDR3 region.

CD30(Ki-1) positive anaplastic large cell lymphoma (ALCL) is a distinct entity, in which the monoclonal antibody-positivity against the CD30(Ki-1) antigen of tumour cells has a diagnostic value. The histological subtypes of ALCL show also certain clinical differences. Except for some pediatric cases and cutaneous forms clinical outcome is very unfavourable despite of the various treatment methods. In this prospective study (follow-up of 11-60, median 16 months) clinicopathological data and treatment results of fifteen adult patients with ALCL were analysed, Mean age was 46 (16-69) ys with a bimodal tendency and a distinct female: male ratio (3:2) was observed. Early clinical stages (I-II/A-B, eight patients) dominated, and two main groups could be distinguished histologically (Hodgkin-related, ALCL-HR and common type, -CT in eight and seven patients), respectively. In all histological specimens CD30 antigen expression was detected. Additional immunophenotyping was performed in five cases (two 0-variant, two of B-cell and one of T-cell origin), respectively. A bulky disease, mainly in the mediastinum was observed in six cases, and a primary gastrointestinal localization in two other patients. In the treatment of these high grade malignant lymphomas a combination of cobalt irradiation and aggressive chemotherapy was applied (in elder the CHOP-regimen, in younger patients mainly the Pro-MACE-Cyta-BOM-protocol). In one relapsed younger patient autologous bone marrow transplantation was also performed. A complete or partial remission was achieved in thirteen patients (86.6%) but six patients expired after only a short response period to therapy. Overall survival was 19, whilst disease-free survival revealed to be 15 months. Eight of their living nine patients have a durable complete remission. Due to residual mediastinal mass after radiotherapy in three cases a permanent radiological follow-up is needed. Advanced age and clinical stages are considered to be unfavourable, whilst histological subtypes were indifferent prognostic factors, as well. Favourable results in therapy and durable complete remission in younger patients are probably caused by the their better tolerance of third-line aggressive chemotherapy.

The authors present a case in which a patient, treated with Myleran for chronic myeloid leukaemia showed tumour like changes in the lung. They stress the differential diagnostic difficulties and the importance of histological diagnosis. This case proves that with discontinuation of the therapy the lung change may be reversible.

The authors reviewed 70 cases of Streptococcus pneumoniae meningitis occurring over a 5-years period (1985-1989). Clinical features, outcome and laboratory findings in elderly patients (> 60 years of age, 21 patients) were compared with those in younger patients (< 59 years of age, 49 patients). Mortality rate was 57% in elderly group vs. 20% in younger. Admission to the hospital was delayed in the elderly. Only 67.6% of them were admitted on the first two days of the illness vs. 81.6% of younger patients. Nearly 62% of them were deeply soporous or comatose on admission (Mathew-Lawson grade 3 and 4), while in the control group only 31% of patients had such severely altered mental status. Although glucose cerebrospinal fluid (CSF)/blood ratio tended to be lower in the elderly (0.09 vs 0.17) the difference did not reach statistical significance. Thrombocytes in the peripheral blood were lower in the elderly (113 x 10(9)/L vs. 148 x 10(9)/L, p < 0.05). When we compared laboratory findings in survivors and nonsurvivors from both groups, nonsurvivors had significantly lower glucose CSF/blood ratio (0.054 vs. 0.174, p = 0.008), and higher bilirubin levels in serum (27.9 vs 14.7, p = 0.003), but differences were more obvious in younger group of patients. Our results suggest that there is increased risk of death among elderly patients. It can be at least partially attributed to their later admittance to the hospital and because of that delayed start of the appropriate therapy and more severe conscious disturbances. All these factors contribute to the greater case-fatality ratio observed in elderly patients with pneumococcal meningitis.

The results of hospital infection surveillance over an eight-month period in the Intensive Care Unit (ICU) of the University Hospital of Infectious Diseases "Dr Fran Mihaljević", Zagreb, are presented together with the results of the antibiotic resistance of isolated gram-negative bacteria in relation to the clinical material taken for culture. Of 110 strains of gram-negative bacteria isolated, 103 (93.6%) were resistant to ampicillin, 80 (72%) to gentamicin, 74 (67%) to cefotaxime, 50 (45.5%) to pefloxacin. Imipenem, ciprofloxacin, ceftazidime and amikacin were the most active representatives of their respective groups with 5, 25, 49 and 50% of resistant strains. Strains isolated in urinary tract infections were significantly less resistant to amikacin and ceftazidime (p < 0.05) than strains isolated from other sources. Our findings stress the need for close surveillance of antibiotic resistance in these selected groups of patients, and are particularly relevant for planning empirical anmtibiotic therapy of hospital infection in the ICU.

An eight-year-old boy developed rabies 31 days after having been scratched by a dog and died 9 day later. Intensive supportive medical treatment was complicated by apnea, cardiac arrest, hypotension, increased secretion of antidiuretic hormone and severe hypoproteinemia. The treatment with intramuscular human antirabies immunoglobulin (HRIG) 2400 I.U. and intrathecal 1200 I.U. in combination with intramuscular interferon alpha 4 million I.U. was given every second day. The diagnosis of rabies was confirmed before death, on the third day of the disease, by direct fluorescent antibody staining of the saliva and cerebrospinal fluid for viral antigen. At the autopsy, the brain tissue specimens were tested for the presence of the virus by inoculation into the suckling mice brain and for the viral antigen by direct fluorescent antibody method. The brain tissue specimens collected at autopsy were also tested for virus by direct fluorescent antibody method.

We studied the entry of ciprofloxacin into the cerebrospinal fluid (CSF) in 37 patients with various types of meningitis (bacterial meningitis 10 patients, viral 12 patients, tuberculous 7 patients). Eight patients were in the control group with normal CSF finding. Mean ciprofloxacin concentrations in the CSF 50-60 minutes after 200 mg of ciprofloxacin was given in infusion were 0.20 +/- 0.12 mg/L in patients with bacterial meningitis, which was significantly higher than in other tested groups (p = 0.0325). Ciprofloxacin achieved concentrations in the CSF 6.5-39% of serum (mean value 15% +/- 9%) in the bacterial meningitis group, while in the groups with viral and tuberculous meningitis the levels were significantly lower (approximately 9% of serum) but still higher than in the control group (approximately 5% of serum). Our data suggest that ciprofloxacin should be very cautiously used in selected patients with bacterial meningitis caused by multiple resistant strains of gram negative bacteria.

Between 1983 and 1987, we treated 16 patients with Hodgkin's disease, according to a post-COPP and a post-ABVD protocol, respectively. All patients had received previous treatment, including megavoltage cobalt radiotherapy, and were in advanced stages of disease, mostly with immunosuppression/immune deficiency. The protocol of lomustine, etoposide, adriamycin, methotrexate and prednisolone was commenced after the above therapy had failed or was not tolerated. Compared to the previously used chemotherapy, the 3 new cytotoxic agents were well tolerated. A complete remission was obtained in 4 patients and a partial remission in 9. In 2 patients, there was a temporary partial remission only. In more than half the patients, a positive effect on the clinical course was recorded. Viewed as a whole, a favourable objective and subjective result ensued. This LEAMP second-line protocol was found to be effective and well tolerated.

Between 1983-1987 16 patients with advanced stage Hodgkin disease, most of whom in an immunsuppressed, immundeficient state, were treated with a new "post-COPP", or "post-ABVD" reserve-protocol. In all cases megavoltage Co radiotherapy and COPP (CVPP) or ABVD polychemotherapy had previously been. Compared with the previously administered polychemotherapy the new 3-component cytostatic agent was well tolerated by the patients. The LEAMP-protocol therapy is therefore recommended in cases of ineffective combined radiochemotherapy (chemoresistance) or intolerance to chemotherapy. In four cases prolonged, complete, in nine cases partial remission was achieved and in more than a half of the patients favourable clinical effects and changes were experienced. In two cases temporary, partial remission was seen. One cases, because of the short period of treatment could not be evaluated. On the basis of the longitudinal observations the results achieved seemed subjectively and objectively favourable. The LEAMP-protocol was found to be well tolerated and satisfactorily effective.

In a 34-year-old woman a non-Hodgkin malignant lymphoma with extreme splenomegaly and monoclonal IgM paraproteinaemia was seen. The removed spleen and splenic hilar lymph glands showed a nodular centroblastic-centrocytic malignant lymphoma with large numbers of plasmocytoid cells containing monotypical (monoclonal) IgM-kappa type immunoglobulin. The case represents a borderline non-Hodgkin malignant lymphoma with features of a follicular tumour and an immunocytoma. The appearance of peculiar intracytoplasmic inclusions would support this assumption. Therapeutic measures (splenectomy and/or cytostatic treatment) and prognostic features (nodularity of the tumour) are discussed.

As a 3rd generation cephalosporin Cefobid monotherapy was applied during 1985-1986 with 16 hematological patients in immunodeficient, immunosuppressive states where the available aimed and combined antibiotic therapy failed to be effective for the treatment of bacterial infections of grave course and septic character. 4 g/day was the average I.V. dose of Cefobid, higher doses were applied only in especially grave septic states. The hematological patients tolerated well the Cefobid in monotherapy. Recovery form the septic state and excellent clinical effect was found with 9 patients, good effect with 4 and satisfactory effect with 1 patient. In 1 case the therapy had to be stopped owing to drug hypersensitivity. Cefobid is regarded as an antibiotic drug that is effective if used in monotherapy for treating grave, septic infections of hematological patients in immunodeficient--immunosuppressive--myelodepressive states having received earlier antineoplasmic polychemotherapy.