Low-dose ipilimumab plus nivolumab combined with IL-2 and hyperthermia in cancer patients with advanced disease: exploratory findings of a case series of 131 stage IV cancers - a retrospective study of a single institution.

The 3-year overall survival (OS) rate of patients with previously treated or untreated stage III or IV melanoma has by now reached 63% using ipilimumab and nivolumab therapy. However, immune-related adverse events (irAEs) of grade 3 or 4 occurred in 59% of patients leading to discontinuation of therapy in 24.5% of patients and one death. Therapy with checkpoint inhibitors could be safer and more effective in combination with hyperthermia and fever inducing therapies. We conducted a retrospective analysis to test the safety and efficacy of a new combination immune therapy in 131 unselected stage IV solid cancer patients with 23 different histological types of cancer who exhausted all conventional treatments. Treatment consisted of locoregional- and whole-body hyperthermia, individually dose adapted interleukin 2 (IL-2) combined with low-dose ipilimumab (0.3 mg/kg) plus nivolumab (0.5 mg/kg). The objective response rate (ORR) was 31.3%, progression-free survival (PFS) was 10 months, survival probabilities at 6 months was 86.7% (95% CI, 81.0-92.8%), at 9 months was 73.5% (95% CI, 66.2-81.7%), at 12 months was 66.5% (95% CI, 58.6-75.4%), while at 24 months survival was 36.6% (95% CI:28.2%; 47.3%). irAEs of World Health Organization (WHO) Toxicity Scale grade 1, 2, 3, and 4 were observed in 23.66%, 16.03%, 6.11%, and 2.29% of patients, respectively. Our results suggest that the irAEs profile of the combined treatment is safer than that of the established protocols without compromising efficacy.

Nottingham prognostic index plus (NPI+) predicts risk of distant metastases in primary breast cancer.

The Nottingham prognostic index plus (NPI+) is based on the assessment of biological class combined with established clinicopathologic prognostic variables providing improved patient outcome stratification for breast cancer superior to the traditional NPI. This study aimed to determine prognostic capability of the NPI+ in predicting risk of development of distant disease. A well-characterised series of 1073 primary early-stage BC cases treated in Nottingham and 251 cases from Budapest were immunohistochemically assessed for cytokeratin (Ck)5/6, Ck18, EGFR, oestrogen receptor (ER), progesterone receptor, HER2, HER3, HER4, Mucin 1 and p53 expression. NPI+ biological class and prognostic scores were assigned using individual algorithms for each biological class incorporating clinicopathologic parameters and investigated in terms of prediction of distant metastases-free survival (MFS). The NPI+ identified distinct prognostic groups (PG) within each molecular class which were predictive of MFS providing improved patient outcome stratification superior to the traditional NPI. NPI+ PGs, between series, were comparable in predicting patient outcome between series in luminal A, basal p53 altered and HER2+/ER+ (p > 0.01) tumours. The low-risk groups were similarly validated in luminal B, luminal N, basal p53 normal tumours (p > 0.01). Due to small patient numbers the remaining PGs could not be validated. NPI+ was additionally able to predict a higher risk of metastases at certain distant sites. This study may indicate the NPI+ as a useful tool in predicting the risk of metastases. The NPI+ provides accurate risk stratification allowing improved individualised clinical decision making for breast cancer.

In vitro activity of clarithromycin in combination with other antimicrobial agents against biofilm-forming Pseudomonas aeruginosa strains.

The aim of the study was to investigate the biofilm-production of 60 Pseudomonas aeruginosa strains isolated from clinical samples and to examine the effect of different antimicrobials and their combinations with clarithromycin on biofilm-formation. The minimal inhibitory concentrations (MICs), minimal biofilm inhibitory concentrations (MBICs), and antibiotic synergy by calculating the fractional inhibitory concentration (FIC) index were determined for the following antibiotics: ceftazidime, cefepime, piperacillin/tazobactam, imipenem, meropenem, levofloxacin, ciprofloxacin, gentamicin, amikacin, tobramycin, netilmicin and clarithromycin. A total of 14 (23.3%) isolates out of 60 isolates of P. aeruginosa were biofilm positive. Cefepime, imipenem and meropenem had the lowest MIC 90 values. Piperacillin/tazobactam and clarithromycin had the highest MIC 90 values. Imipenem, meropenem, piperacillin/tazobactam and clarithromycin had the lowest MBIC 90 values. For biofilm-forming P. aeruginosa strains 2-fold to 128-fold higher MBIC values than MIC values were obtained for ceftazidime, cefepime, imipenem, amikacin and netilmicin. The MBIC was 2-fold to 512-fold lower then the MIC values in the case of piperacillin/tazobactam, ciprofloxacin, levofloxacin and clarithromycin. Synergy was generally demonstrated for clarithromycin in combination with aminoglycosides, fluoroquinolones or ceftazidime. However, surprisingly it was found that combinations of clarithromycin with carbapenems or cefepime led to an antagonistic interaction: combination of clarithromycin with imipenem, meropenem or ertapenem showed antagonism in 37.5%, 50% and 62.5% of the strains tested whereas its combination with cefepime expressed antagonism in 75% of the strains, respectively. To the best of our knowledge no one has previously described this phenomenon so far.

Prevalence and antimicrobial resistance of uropathogens in different inpatient wards.

The predominant causative agent of urinary tract infections in children and adults is Escherichia coli , but it is necessary to appreciate the importance of other Gram-negative rods, especially in newborns. Antibiotic resistance rates are also different in children and in adult care units due to many factors and therapeutical guidelines.The aim of this retrospective study was to show the local prevalence and resistance patterns of uropathogens in certain clinics of university and present the distribution of uropathogens in different age groups. Therefore, 4833 positive samples were analysed. E. coli was found to be the highest prevalent causative agent in every adult care unit, but some differences in other causative agents could have been detected. Three types of antimicrobial agents showed decreasing susceptibility rates: trimethoprim/sulfamethoxasole, cephalosporins and quinolones; but there were differences in resistance among the 8 investigated inpatient wards.

[Transport of newborn infants who need intensive care]. / Intenzív ellátást igényló újszülöttek szállítása.

A 4-year-long experience is reported on mobile neonatal emergency transport service for pathological newborn babies from referral hospitals to the NICU level III. The area covered by the NICU consists of three counties with a total population of 1 million. Distance of the hospitals from the NICU ranges 0.5-115 km, transport time varies from 0.5-5.0 hours. In the transport staff are dedicated neonatal team from the NICU III, the driver and the emergency medical technician are the employee of the National Ambulance Service. During the study period 385 patients were transported. Clinical condition and characteristic laboratory parameters of the babies at departure and arrival are analysed and compared to evaluate the efficacy and quality of the system. Furthermore, some questions regarding organisation, transit time and response time and legal aspects are discussed.

[Effect of long-chain polyunsaturated fatty acids on arachidonate and docosahexaeonic acid in healthy infants in the first four months of life]. / Hosszú szénláncú, többszörösen telítetlen zsírsavak hatása egészséges csecsemók arachidonsav-és dokozahexénsav-ellátottságára 92 eletelsonegy honapjaban.

Fatty acid compositions of plasma phospholipids (PL), triglycerides (TG) and sterol esters (STE) were measured by high resolution capillary gas-liquid chromatography in formula fed healthy infants at the ages of 5 days and 1, 2, 3 and 4 months. The infants were randomly assigned to receive either conventional infant formula (F, n = 10) without long-chain polyunsaturates (LCP) or the same formula supplemented with LCP (LCP-F, n = 12) in amounts and ratios similar to those characteristic to human milk. From the age of 1 month onwards, percentage contributions of the principal omega-6 LCP, arachidonic acid were significantly higher in plasma lipids of infants fed LCP-F than in those receiving conventional formula without dietary LCP. Values of the principal omega-3 LCP, docosahexaenoic acid were also significantly lower in the infants fed conventional formula than in those receiving LCP-F throughout the study. The data obtained indicate that from the formula supplemented with LCP both arachidonic and docosahexaenoic acids were effectively absorbed and incorporated into infantile plasma lipids. Recent data of the literature suggest that supplementation of infant formula with LCP may beneficially influence visual and psychomotor development also in healthy, term infants.

Plasma amino acid concentrations in healthy, full-term infants fed hydrolysate infant formula.

The effect of feeding hydrolysate infant formula (HF) on protein and amino acid metabolism was investigated in healthy, full-term infants who were either breast-fed (BF, n = 10) or received conventional formula (CF, n = 10) or HF based on soy and beef collagen (n = 10) with equal total protein equivalent contents. There were no differences between groups for gain in weight, length, and head and chest circumferences throughout the study. Plasma concentrations of total proteins, albumin, urea nitrogen, uric acid, and creatinine as well as total amino acid and total essential amino acid concentrations did not differ at the ages of 2, 4, and 8 weeks. In contrast, significant differences were seen in concentrations of five free amino acids. Arginine concentrations were significantly higher at the age of 4 weeks in the infants fed HF than in the other groups (71 +/- 12 versus 27 +/- 6 and 30 +/- 4, mumol/L, mean +/- SEM, HF versus BF and CF, p < 0.01). Plasma histidine concentrations were also higher in infants receiving HF (4 weeks: 217 +/- 33 versus 91 +/- 18, HF versus BF, p < 0.01; 8 weeks: 218 +/- 33 versus 105 +/- 20, HF versus CF, p < 0.01). The most pronounced feeding-related differences were seen in plasma glycine concentrations (2 weeks: 653 +/- 89 versus 345 +/- 55, HF versus BF, p < 0.01; 8 weeks: 613 +/- 74 versus 385 +/- 56 and 312 +/- 46, HF versus BF and CF, p < 0.01), with the mean value exceeding the upper limit of the normal range in infants fed HF. Although the biological importance of the differences observed remains to be clarified, further investigations on amino acid metabolism are needed to establish the final nutritional safety of feeding hydrolysate infant formulae.

[Long-chain polyunsaturated fatty acids in breast-fed and formula fed healthy infants]. / Szoptatott és tápszerrel táplált egészséges csecsemök ellátottsága hosszú szénláncú, többszörösen telítetlen zsírsavakkal.

While human milk contains considerable amounts of long-chain polyunsaturated fatty acids (LCP), most formulae contain only the precursors of LCP synthesis (linoleic and alpha-linolenic acids) but are devoid of preformed dietary LCP such as are arachidonic and docosahexaenoic acids. LCP contents in plasma phospholipids (PL), triglycerides (TG) and sterol esters (STE) were measured by high resolution capillary gas-liquid chromatography in healthy, term infants fed human milk of formula. Percentage contributions of the precursor fatty acids were similar or higher in plasma lipids in formula fed than in breast-fed infants, meanwhile values of the intermediary metabolites of LCP synthesis did not differ between the two groups. Percentage contributions of arachidonic acid were higher in breast-fed than in formula fed infants at the ages of 2 weeks (PL: 9.39 +/- 1.00 vs. 6.91 +/- 0.38, TG: 0.61 +/- 0.03 vs. 0.41 +/- 0.05, %weight/weight, mean +/- SEM), 1 month (PL: 9.06 +/- 1.04 vs. 6.16 +/- 0.35, TG: 0.62 +/- 0.10 vs. 0.32 +/- 0.04, STE: 4.50 +/- 0.45 vs. 2.84 +/- 0.39) and 2 months (PL: 8.41 +/- 1.19 vs. 5.74 +/- 0.37). Similarly, docosahexaenoic acid values were at the ages of 1 month (PL: 1.94 +/- 0.21 vs. 1.19 +/- 0.21, TG: 0.12 +/- 0.03 vs. 0.04 +/- 0.02) and 2 months (PL: 2.02 +/- 0.36 vs. 0.99 +/- 0.07) significantly higher in breast-fed infants than in those receiving formula.(ABSTRACT TRUNCATED AT 250 WORDS)

Lipid and apolipoprotein levels and enteral nutrition in very low-birth-weight preterm infants.

Lipid, lipoprotein cholesterol and apolipoprotein A-I, A-II and B levels were determined in 10 very low-birth-weight (birth weight 1279 +/- 144 g; gestational age 29.2 +/- 1.2 weeks, mean +/- SD) preterm infants on postnatal days 3, 10 and 21. Feeding with pooled human milk began on day 3 +/- 1 and by day 10 all infants were exclusively enterally fed. Both triglyceride and total cholesterol levels increased significantly from day 3 to day 10 (0.84 +/- 0.28 versus 1.53 +/- 0.72 and 2.42 +/- 0.47 versus 3.24 +/- 0.80, mmol/l, respectively) (p < 0.01); thereafter no further increase was observed. The increase in total cholesterol level was primarily due to a significant enhancement of very low-density lipoprotein and low-density lipoprotein cholesterol (1.52 +/- 0.34 versus 2.29 +/- 0.73 mmol/l, p < 0.01). Apo A-I, A-II and B levels did not change between day 3 and day 10. From day 10 to day 21, however, a significant increase in apo A-I concentration was noted (0.57 +/- 0.20 versus 0.87 +/- 0.17 g/l, p < 0.01), whereas apo A-II levels increased significantly from day 3 to 21 (0.15 +/- 0.03 versus 0.27 +/- 0.08 g/l, p < 0.01). No change in apo B level was seen.

[Mortality among mature neonates requiring intensive care]. / Intenzív ellátást igénylö érett újszülöttek halálozása.

Causes of mortality among term infants hospitalized in a Neonatal Intensive Care Unit during a period of five years were investigated. Among the 107 fatal cases analyzed, congenital malformation was the cause of death in 63 and hypoxia/asphyxia in 35 cases, whereas 9 newborns died primarily of infection. Though congenital malformation is the leading cause of mortality, nevertheless, also perinatal asphyxia and primary and secondary infections play an important role. The utmost importance of prevention and proper medical care is emphasized.

[Comparison of human milk with 3 different types of infant food in the nutrition of full-term neonates]. / Az anyatej és három különbözö tápszer összehasonlító vizsgálata érett újszülöttek táplálásában.

Healthy, term infants who were either breast-fed, or received conventional formula (Mildibé, EGIS; Pre-Aptamil, Milupa), or a formula containing hydrolyzed proteins (Aptamil H. A., Milupa) were investigated. Each group consisted of 10 infants who were fed ad libitum. Somatic development (gain in weight, length and head- and chest circumferences), serum Ca and P levels, alkaline phosphatase activities and basic biochemical parameters of protein metabolism (serum total protein, albumin, uric acid, creatinine and urea nitrogen levels) were determined at the ages of 2, 4 and 8 weeks. Anthropometric measurements did not reveal considerable differences between the groups investigated. At the age of four weeks, serum calcium levels were significantly higher in the breast-fed infants than in those receiving formula. Both at the ages of four and eight weeks, serum total protein levels were significantly lower in the infants receiving the formula consisting of hydrolyzed proteins than in the breast-fed controls. No difference of considerable extent was seen in the other biochemical parameters measured. The results obtained indicate that, in the lack of the possibility of breast-feeding, all the three formulae investigated can be used as substitute of breast milk.

Electrolyte and glucose concentration in plasma and cerebrospinal fluid measured parallel in pathologic newborn infants.

Cerebrospinal fluid and plasma sodium, potassium, chloride, calcium and glucose concentration were measured parallel in 14 pathological newborn babies of gestational age and birthweight of 36.3 +/- 4.3 wks and 2410 +/- 890 g, respectively, at the age of 37.8 +/- 4.4 wks postconceptionally. Whilst potassium, calcium and glucose level is much lower in the cerebrospinal fluid than in the plasma, similar sodium and higher chloride concentration was found in the cerebrospinal fluid. The significant positive correlation between plasma and cerebrospinal fluid glucose and sodium levels proves the lack of a functioning barrier for these compounds. On the other hand, cerebrospinal potassium level varied within a narrow range, independently of the plasma-concentration and the maturity of the studied babies. Pathophysiological implications of the results are further discussed in short.

Evaluating the sport scuba diver.

When evaluating an individual planning to scuba-dive, search for conditions that increase the risk of a diving accident. These risks can be categorized as absolute, relative or temporary. An understanding of barotrauma and decompression sickness is essential. The psychologic examination is as important as the determination of physical fitness.