[Prognostic markers of advanced non-small cell lung carcinoma -  assessing the significance of oncomarkers using data-mining techiques RPA]. / Prognostické markery pokrocilého nemalobunkového karcinómu plúc -  hodnotenie významu onkomarkerov pomocou data-miningovej metódy RPA.

INTRODUCTION: Identification of new prognostic factors can help in designing future clinical studies. In the case of advanced non-small cell lung cancer, there might be good candidates - tumor markers CYFRA 21-1, CEA or NSE [1-8]. It is possible to evaluate the relationship between their expression and prognosis by data mining technique recursive partitioning and amalgamation. PATIENTS AND METHODS: We analyzed retrospective data of 162 patients of Oncology clinics in Trnava. All of these patients were admitted between 2008 and 2012 for the administration of first-line chemotherapy according to current recommendations. We evaluated the impact of known pretreatment prognostic markers - performance status, weight loss, smoking, age, sex, stage, histologic subtype, comorbidity and oncomarkers CYFRA 21-1, CEA or NSE, as well as combinations of these factors on survival. RESULTS: Our analyses showed that there are three subgroups of patients with good, intermediate and unfavorable prognosis. Oncomarkers played an important role in formation of a subgroup of 49 patients with good prognosis - including patients with no pretreatment weight loss and low levels of CEA ( 4.1 ng/ml) or NSE ( 11.1 ng/ml). In this subgroup, the median survival time was at least 16 months (not achieved) and the difference in survival compared to the rest of the group was highly statistically significant (risk ratio 5.21, 95% CI 1.41-19.28; p < 0.0001). CONCLUSION: We showed the prognostic significance of low levels of NSE and CEA oncomarkers in the group of patients with no pretreatment weight loss. Recursive partitioning and amalgamation is a useful data mining method, but the generated hypothesis needs to be confirmed by further clinical study designed for this purpose

Breakthrough fungaemia in neonates and infants caused by Candida albicans and Candida parapsilosis susceptible to fluconazole in vitro.

Breakthrough fungaemias due to Candida albicans and Candida parapsilosis appearing during fluconazole therapy in neonates and infants were assessed for risk factors and outcome. Forty fungaemias occurred during therapy with fluconazole within a 12 year national survey and were compared with 161 cases of non-breakthrough paediatric fungaemias. The agar disc diffusion test method was used for antifungal susceptibility testing and the Vitek system for species identification. Univariate and multivariate analysis for risk factors for breakthrough fungaemia were carried out. All the fungaemias were a result of strains susceptible to fluconazole at 0.25-4 mg/L in vitro [C. albicans (85%) and C. parapsilosis (15%)]. The mean number of positive blood cultures per episode was 2.2. Sixteen children had 'early' breakthrough fungaemias (within 4-5 days) and 24 fungaemias appeared on day 6 and later. Mean fluconazole MICs in the 'early' group were 1.2, and 2.8 mg/L in the 'late' group (P < 0.03, t-test). However, no difference was observed in the average dose of fluconazole used in the two groups. Neonatal age, total parenteral nutrition, very low birth weight, before surgery, central or umbilical venous catheterization and artificial ventilation were all significantly related to breakthrough fungaemia in univariate analysis but only central or umbilical venous catheterization were significant in multivariate analysis. The outcome of breakthrough fungaemia was better overall and attributable mortalities in non-breakthrough fungaemia was significantly higher in comparison with breakthrough fungaemia.

Prospective study of fungaemia in a single cancer institution over a 10-y period: aetiology, risk factors, consumption of antifungals and outcome in 140 patients.

Over a 10-y period (1989-99) we prospectively evaluated all patients with fungaemia among 16,555 admissions (21,004 blood cultures) at a national cancer referral institution in the Slovak Republic. A prospective protocol was completed on 140 patients with fungaemia, which was then analysed in terms of aetiology, clinical characteristics, potential risk factors and outcome. The most frequently isolated organism was C. albicans, in 75 patients (52.9%), followed by non-albicans Candida spp. in 45 patients (32.1%). Non-Candida spp. yeasts represented 16 episodes in 16 patients (11.4%). Moulds caused 4 episodes in 4 patients (3.6% of all fungaemias) and all were caused by Fusarium spp. Mucositis (p = 0.025), > or = 3 positive blood cultures (p = 0.02), acute leukaemia (p = 0.00001), neutropenia (p = 0.0015), quinolone prophylaxis (p < 0.000005) and breakthrough fungaemia (p = 0.004) during prophylaxis with fluconazole (p = 0.03) and itraconazole (p = 0.005) were significantly more associated with non-Candida than C. albicans spp. Furthermore, attributable mortality was higher in the subgroup of non-Candida than C. albicans spp. (50.0 vs. 18.7%, p < 0.02). The only independent risk factor for inferior outcome was antifungal therapy of < 10 d duration (odds ratio 2.1, 95% confidence interval, p < 0.001). Aetiology, neutropenia and mucositis were not independent risk factors for higher mortality in multivariate analysis; however, they were risk factors for inferior outcome in univariate analysis (p < 0.05-0.005).

Antibiotic use and development of resistance in blood culture isolates: 8 years of experience from a cancer referral center.

The consumption of antimicrobial agents in a Slovakian national cancer institute from 1989-1996 was compared with resistance rates in clinically significant blood culture isolates. We observed an increase in resistance of viridans streptococci to penicillin and of enterococci to ampicillin. Resistance to vancomycin and teicoplanin was stable over the entire period despite a 20-fold increase in vancomycin consumption. Nor did we observe increased resistance to ofloxacin despite a 10-fold increase in consumption. Consumption of aminoglycosides and resistance levels were both stable. A different situation was observed with third-generation cephalosporins, where resistance of Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Acinetobacter spp. to ceftazidime and cefotaxime increased with increasing consumption. Resistance of Enterobacteriaceae to cefotaxime and ceftazidime was stable. Resistance to imipenem did not change significantly. However, the number of Stenotrophomonas maltophilia bacteremias increased significantly after imipenem was introduced in 1991. Because of improved outcome in bacteremia, an increased incidence of both gram-negative and gram-positive bacteremia led to only a slight increase in associated mortality.

Prospective study on fungemia in children with cancer: analysis of 35 cases and comparison with 130 fungemias in adults.

The aim of this prospective study on fungemia in children with cancer compared with adults with cancer appearing during the last 10 years in a pediatric hospital and in national cancer institutions was to investigate risk factors, etiology, therapy, complications and outcome. Univariate analysis showed significant differences in 35 children with cancer and fungemia in comparison with 130 cases of fungemias in adults with cancer. It was found that (1) therapy with corticosteroids (40 vs 18.5%, P<0.03), (2) breakthrough fungemia during ketoconazole prophylaxis (20 vs 7.7%, P<0.025), and (3) meningitis as a complication of fungemia (11.4 vs 0.8%, P< 0.001) occurred more frequently in the pediatric subgroup with fungemia. Candida albicans was more common as the causative agent of fungemia among adults (58.5 vs 37.1, P<0.02) than in children. However, mortality was similar in children with cancer and in adults with cancer and fungemia (31.4 vs 23.1%, NS). Comparison of risk factors revealed no differences between adults and children with cancer and fungemia except in etiology, breakthrough fungemia during prophylaxis with ketoconazole, prior therapy with corticosteroids and meningitis as a complication. The outcome was also similar in pediatric and adult cancer patients with fungal bloodstream infection.

Nosocomial candidaemias due to species other than Candida albicans in cancer patients. Aetiology, risk factors, and outcome of 45 episodes within 10 years in a single cancer institution.

Forty-five cases of fungaemia due non-albicans Candida spp. (NAC) in a single National Cancer Institution within 10 years were analysed for aetiology, risk factors and outcome. There had been 12 cases of fungaemia that were due to C. krusei, 14 due to C. parapsilosis, 7 due to C. (T.) glabrata, 6 to C. tropicalis, 2 to C. guillermondii, 2 to C. lusitaniae, 1 to C. stellatoidea, and 1 to C. rugosa. Comparison of 45 NAC fungaemia with 75 episodes of C. albicans fungaemia revealed differences only in two risk factors: previous empiric therapy with amphotericin B (16.0 vs 2.2%, P<0.01) appeared more frequently in cases of C. albicans fungaemia, and prior prophylaxis with fluconazole (8.9 vs 0%, P<0.02) was conversely more frequently observed with NAC. The incidence of other risk factors, such as underlying disease, chemotherapy, antibiotic prophylaxis or therapy, treatment with corticosteroids, catheter insertion, mucositis, cytotoxic chemotherapy, and neutropenia, was similar in both groups. There was no difference either in attributable or in overall mortality between NAC and C. albicans fungaemia in our cancer patients.

Ciprofloxacin in treatment of nosocomial meningitis in neonates and in infants: report of 12 cases and review.

Twelve cases of neonatal and infant nosocomial meningitis treated with intravenous ciprofloxacin in doses of 10 to 60 mg/kg/day are described. Four neonates were 21 to 28 days old and eight infants were 2 to 6 months old. Six presented with Gram-negative meningitis: Escherichia coli (2), Salmonella enteritidis (1), Acinetobacter calcoaceticus (1), two with two organisms, and (H. influenzae plus Staphylococcus epidermidis, Acinetobacter spp. plus S. epidermidis), and six were attributable to Gram-positive cocci (four S. aureus and two Enterococcus faecalis). Ten cases were cured. In two cases, reversible hydrocephalus appeared that responded to intraventricular punctures. In seven children, no neurologic sequellae appeared after a 2- to 4-year follow-up. One neonate had relapse of meningitis 3 months later and was ultimately cured, but developed a sequellae of psychomotoric retardation. Follow-up varied from 27 months to 10 years. Current published case reports from Medline on quinolone use in meningitis in neonates and infants are reviewed.

Documented fungal infections after prophylaxis or therapy with wide spectrum antibiotics: relationship between certain fungal pathogens and particular antimicrobials?

Antibiotics are known to be one of the major risk factors for fungal infection. We investigated whether there was a relationship between particular documented fungal infections and therapeutically or prophylactically administered antimicrobials in 105 patients with fungemia or histologically proven invasive aspergillosis or fusariosis. Out of 105 patients, 82.9% received antimicrobials affecting anaerobic microbial gut flora such as: imipenem, vancomycin, ceftazidime, metronidazole, clindamycin or ampicillin-sulbactam. In addition, 44.5% of patients had received prophylaxis with ofloxacin. 31.5% of Candida albicans fungemias occurred despite empiric therapy with amphotericin B and 21.1% during prophylaxis with azoles. The incidence of C. albicans infections (fungemias) was significantly higher (58.9% vs 33.7%, p<0.04) in patients receiving antibiotics not affecting anaerobic gut flora such as ofloxacin, an aminoglycoside or azithromycin. On the other hand, patients treated with third generation cephalosporins, carbapenems, glycopeptides, and broad spectrum penicillins were more likely to develop proven invasive Aspergillus spp. infection (27.9% vs 5.3%, p<0.001) in comparison to those treated with antimicrobials which preserve anaerobic gut flora.

The role of cisplatin in chemotherapy of advanced breast cancer.

Cisplatin containing regimens as first-line, second-line or as a third-line chemotherapy were administered in 26 and 36 patients, respectively. The overall response rate in patients on first-line chemotherapy was 53.9%, in patients on second or third-line chemotherapy 30.6%. The differences both in overall and disease-free survival between patients on first-line and on second/third-line chemotherapy were statistically significant in favor of women treated with first-line chemotherapy (p = 0.05). Hematologic and nonhematologic toxicities were mild to moderate and were more pronounced in patients on second and third-line chemotherapy. The overall response rate, DFS and OS were significantly better and longer in the group of patients treated with "bolus" CDDP in comparison to the group of patients treated with CVI CDDP. Our results confirm the activity of cisplatin-containing regimens (mainly CAP schedules) in patients with advanced breast cancer not only as a first-line therapy but also in heavily pretreated patients by chemotherapy and/or radiation therapy and endocrine manipulation.

Combined chemotherapy (cisplatin, cyclophosphamide, lomustine and vincristine) and multifractionation radiotherapy in inoperable nonmetastatic squamous cell lung cancer.

A modified protocol was used in the treatment of inoperable nonmetastatic squamous cell lung cancer which consisted of three courses of induction chemotherapy with cisplatin, cyclophosphamide, lomustine and vincristine. Radiotherapy was delivered in multifractionated regime, daily two fractions of 1.5 Gy, 4 hours apart up to the total dose of 51 Gy. During 1985-1989, 77 patients were entered into the study. Twenty-six patients did not complete treatment, but were evaluated for the response rate and in survival analysis. There were 29 patients with Stage I and II, and 48 patients with Stage III lung cancer. After combined treatment CR was 15%, PR 39% and RR 54%. One- to four-year overall survival of 48 evaluable patients with Stage III were: 58%, 30%, 17% and 7%, respectively. The overall survival of the whole treatment group was significantly better than the survival of historical control group of 65 patients treated by radiotherapy only.

Non-Hodgkin's lymphomas of Waldeyer's ring.

The following data have been achieved in investigation of 40 patients with non-Hodgkin's lymphoma involvement of the Waldeyer's ring (WR): a) Palatinal tonsils and nasopharynx are the parts of WR most frequently involved. b) Involvement of WR warrants a careful X-ray, and/or endoscopic examination of the gastrointestinal tract. c) WR is most frequently involved in patients with diffuse histiocytic and lymphohistiocytic NHL. d) The basic treatment in patients of clinical Stage I and II is local-regional radiotherapy, in those of Stage III and IV, it is combined chemotherapy. Of key importance in the choice of the strategy and tactics of treatment is the determination of histological subgroup. e) Prognosis in patients with NHL probably does not depend on the origin of the disease but rather on basic stratification criteria (clinical stage, histological subgroup, occurrence or absence of systemic symptoms, presence or absence of bulky tumors). The results are significantly influenced by the degree of radicality of treatment. Methods of a "local-regional" treatment appear to be inadequate in the majority of patients with NHL of high and intermediate grade malignancy. Consequently, the involvement of WR does not seem to represent a distinct clinical-pathological entity.

Non-invasive methods for detection of cardiomyopathy in the course of antineoplastic treatment.

In our group of patients suffering from cancer and treated by polychemotherapy and monitored in a complex non-invasive way we obtained data as follows: A normal physical, sensoric and biochemical cardiac finding prior to treatment has been observed in 47 patients out of 68 (69.1%). A pathological cardiac finding prior to treatment has been found in 18 patients out of 68 (26.5%). Pathological changes evidencing for cardiomyopathy (CMP) induced by chemotherapy have been detected in 19 patients out of 68 (27.6%). Out of 18 patients with a pathological report prior to treatment in 8 of them the polycardiographic, echocardiographic, and biochemical alterations deteriorated during the chemotherapy. CMP induced by polychemotherapy has been found altogether in 27 patients out of 68 (39.6%). In this group of patients with clinically and biochemically detected CMP due to antineoplastic treatment, we found a significant decrease of ejection fraction (EF) (values less than 50%) and a marked increase Weisler's index (WI) (values greater than 0.520) approximately in 30% of patients. Our preliminary results show that polycardiographic examinations of systolic time interval (STI), the EF detected echocardiographically, as well as determination of myocardial isoenzyme creatine phosphokinase (CK-MB) activity represent useful non-invasive methods of early detection of any myocardial damage in the course of actinochemotherapy. A systematic monitoring of patients reduces the uncertainty with antitumor chemotherapy so that it enables--in a majority of cases--to bring the planned antineoplastic treatment to a successful end.