Property of a new Prussian blue-bounded iron complex able to peroxidate non-saturated fatty acids with a tendency to create conditions that may encourage ferroptosis.

Ferroptosis is a cell death process caused by redox imbalance in the cell environment. However, the cell death pathway proves beneficial in anticancer therapy, so compounds inducing ferroptosis are sought. The paper presents a newly synthesized iron complex named FeT, composed of ferricyanide and tartrate, which seems to meet these expectations. It is relatively stable, easily soluble in water and capable of peroxidating unsaturated fatty acids. T24 bladder cells were used as model cells. Preliminary studies demonstrated a strong inhibitory effect of this compound on cell proliferation. The cytotoxicity of FeT was assessed. Independently, it initiates caspase activity, indicating the complex cellular impact of this compound. This effect is compellingly the result of FeT penetration into the cell's interior with possible direct damage to mitochondria, thus explaining the involvement of apoptosis in cell death. At the same time, after penetrating into the cell, it causes an increase in reactive oxygen species (ROS), lipid peroxidation and a decrease in reduced glutathione, which is interpreted as to cause ferroptosis. In turn, reducing mitochondrial potential may indicate both ferroptosis and an internal pathway to apoptosis.

Simultaneous detection of melatonin and six metabolites of L-tryptophan pathway in rat gastric mucosa.

Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine synthesized in vertebrates mainly in the pineal gland, and is known to be involved mainly in thermoregulation and control of the circadian rhythm. That indoleamine can affect the auto-, para- and endocrine pathways, regulating body functions and affecting the metabolism of animals and humans. In addition to the pineal gland, melatonin can be synthesized in many extra-pineal tissues, mainly in the gastrointestinal tract. Previous studies have shown that melatonin plays an important role in the defense system of the gastrointestinal mucosa, demonstrating a protective effect on the gastrointestinal tract and the acceleration of healing of chronic ulcers through the scavenging of reactive oxygen metabolites (ROS) and the activation of protective nitric oxide (NO) and vasodilator neuropeptides released from the sensory afferent neurons. The process of converting the melatonin precursor L-tryptophan into melatonin is already known, but not all aspects of this process for the synthesis of other metabolites of this pathway have been fully elucidated and this issue remains poorly understood. In this study, the conversion of L-tryptophan to melatonin and other metabolites was determined in gastric mucosa collected from rats with or without intragastric (i.g.) melatonin or L-tryptophan administration, both administered at a single dose of 50 mg/kg. For the determination of five metabolites of L-tryptophan: kynurenine, 5-hydroxytryptamine, 5-hydroxytryptophan, anthranilic acid, indole-3-acetic acid together with melatonin, we have modified the previously developed high-performance liquid chromatography (HPLC) method using a native fluorescence detection system and UV-VIS. The obtained results show that: 1) L-tryptophan is converted into melatonin in the gastric mucosa during the day, e.g. after eating a meal containing L-tryptophan, as it was imitated and confirmed by our study, in which this amino acid was administered directly to the stomach, 2) the gastric mucosa is capable of producing melatonin in much greater amounts than those recorded in the blood serum of rats given a single dose of L-tryptophan, and 3) apart from melatonin, the only serum levels of these five metabolites of the L-tryptophan metabolic pathway are detectable, while their level in the gastric mucosa is low and barely detectable under physiological conditions. Our present observations support the notion that the gastric mucosa is one of the main sources of melatonin production from L-tryptophan outside the pineal gland.

Small-molecule inhibitor - tyrphostin AG1296 regulates proliferation, survival and migration of rhabdomyosarcoma cells.

Rhabdomyosarcoma (RMS) is the most commonly occurring malignant soft tissue tumor in children. Despite improving its treatment methods, the current outcome in the advanced stages of this tumor is not satisfactory. RMS cells are characterized by abnormal cellular signaling due to the changes in the activity of the tyrosine kinases. Thus, substances blocking the mitogenic signal transmitted by receptors with tyrosine kinase activity raise hopes for inhibition of the uncontrolled cell growth. In this study, we examined the anticancer activity of tyrphostin AG1296, a tyrosine kinase inhibitor that binds to the intracellular domain of the PDGF (platelet-derived growth factor) receptor in human RMS alveolar and embryonal cell lines. We have discovered that tyrphostin AG1296 completely inhibited cell proliferation and effectively inhibited cell viability. Tyrphostin AG1296 induced apoptosis of the RMS cells and significantly inhibited their migration. Additionally, investigated inhibitor slightly inhibited expression of AKT and phosphorylation of ERK in alveolar RMS cells. Importantly, the inhibitor exerted also potent effects on the nanomechanical properties and cytoskeleton organization of RMS cells. To conclude, tyrphostin AG1296 is a promising compound in the treatment of alveolar RMS. Undoubtedly, a better knowledge of receptor pathomechanism of tyrosine kinases may contribute to developing new, more effective ways of RMS treatment.

Hypersensitivity to hydrolyzed cow's milk protein formula in infants and young children with atopic eczema/dermatitis syndrome with cow's milk protein allergy.

PURPOSE: Atopic eczema/dermatitis syndrome (AEDS) is often the first manifestation of atopic disease in children. Food hypersensitivity should be considered in approximately 40% of these patients. AEDS children with cow's milk allergy are commonly prescribed a hydrolyzed formulas or amino acid-based formulas for an alternative protein source. The aim of this study was to investigate hypersensitivity to extensive hydrolyzed casein and whey proteins in AEDS children with cow's milk protein allergy (CMA). MATERIAL AND METHODS: The study included 67 hospitalized children with AEDS (m/f--43/24), aged 1-28 months (mean 11.34 +/- 8.52) and CMA confirmed by oral food challenge. All patients were treated with extensively hydrolyzed formulas: 48/67 children with casein hydrolysates and 19/67 children with whey hydrolysates. RESULTS: In most of studied children we recognized severe AEDS (SCORAD Index: mean 55.41 +/- 17.4; 95% CI 51.17-59.66) with elevated total IgE (mean 432.98 +/- 1030.46; 95% CI 181.63-684.33). In 22/67 children (32.8%) we established diagnosis of hypersensitivities to hydrolyzed formula (HHF): in 17/22 to casein hydrolysates, in 4/22 to whey hydrolysates and in 1/22 to amino-acid based formula. Children with HHF did not differ in the severity of AEDS evaluated by SCORAD (57.18 +/- 16.59 vs 54.56 +/- 17.90), the serum level of total IgE (603.9 +/- 1253 vs 349.4 +/- 906.1) and the time of breast-feeding (4.4 +/- 4.0 months vs 6.8 +/- 7.28). They differ in the number of plasma eosinophils and positive correlation between number of eosinophils and serum level of total IgE (p<0.05, r=0.46 vs r=0.07). CONCLUSIONS: Children with moderate or severe atopic eczema/dermatitis syndrome can demonstrate hypersensitivity to hydrolyzed formula recommended for therapeutic indications.

An international prospective study of the EORTC cancer in-patient satisfaction with care measure (EORTC IN-PATSAT32).

Little is known about patients' satisfaction with care in oncology hospitals across cultural contexts. Within the EORTC, we developed a 32-item satisfaction with care questionnaire to measure patients' appraisal of hospital doctors and nurses, as well as aspects of care organisation and services. This study assessed the psychometric characteristics of the questionnaire, the EORTC IN-PATSAT32, in a large, international sample of patients with cancer. Patients discharged from a surgery or medical oncology ward in nine countries were invited to complete at home the EORTC IN-PATSAT32 as well as other instruments for psychometric testing. Of 762 eligible patients recruited, 15% failed to return the questionnaire. Of the 647 compliant patients, 63% completed the questionnaires within 15 min and 82% required no help in its completion. Multitrait scaling analysis revealed excellent internal consistency and convergent validity, although some scales within the IN-PATSAT32 were relatively highly correlated. Test-retest data on 113 patients showed high reliability for most scales. Scales of the IN-PATSAT32 and of the QLQ-C30 were not significantly correlated, suggesting that the two questionnaires are assessing quite distinct concepts. The scales of the IN-PATSAT32 were able to discriminate clearly between patients with differing care expectations and differing intentions to recommend their hospital to others. This study supports the acceptability to patients, and the psychometric robustness of the EORTC IN-PATSAT32 questionnaire. Further studies are needed to assess the responsiveness of the questionnaire to changes in the structure and process of care over time.

European health systems and cancer care.

INTRODUCTION: Data on the survival of all incident cases collected by population-based cancer registries make it possible to evaluate the overall performance of diagnostic and therapeutic actions on cancer in those populations. EUROCARE-3 is the third round of the EUROCARE project, the largest cancer registry population based collaborative study on survival in European cancer patients. The EUROCARE-3 study analysed the survival of cancer patients diagnosed from 1990 to 1994 and followed-up to 1999. Sixty-seven cancer registries of 22 European countries characterised by differing health systems participated in the study. This paper includes essays providing brief overviews of the state and evolution of the health systems of the considered countries and comments on the relation between cancer survival in Europe and some European macro-economic and health system indicators, in the 1990s. OVERVIEW OF THE EUROPEAN HEALTH SYSTEMS: The European health systems underwent a great deal of reorganisation in the last decade; a general tendency being to facilitate expanding involvement of the private sector in health care, a process which occurred mainly in the eastern countries (i.e. the Czech Republic, Estonia, Poland, Slovakia and Slovenia). In contrast, organisational changes in the northern European countries (i.e. Denmark, Iceland, Finland and Sweden) tended to confirm the established public sector systems. Other countries, including the UK and some southern European countries (i.e. England, Scotland, Wales, Malta and Italy) have reduced the public role while the systems remain basically public, at least at present. Our findings clearly suggest that cancer survival (all cancer combined) is related to macro-economic variables such as the gross domestic product (GDP), the total national (public and private) expenditure on health (TNEH) and the total public expenditure on health (TPEH). We found, however, that survival is related to wealth (GDP), but only up to a certain level, after which survival continues to be related to the level of health investment (both TNEH and TPEH). According to the Organisation for Economic Co-operation and Development (OECD), the TNEH increased during the 1990s in all EUROCARE-3 countries, while the ratio of TPEH to TNEH reduced in all countries except Portugal. CONCLUSIONS: Cancer survival depends on the widespread application of effective diagnosis and treatment modalities, but our enquiry suggests that the availability of these depends on macro-economic determinants, including health and public health investment. Analysis of the relationship between health system organisation and cancer outcome is complicated and requires more information than is at present available. To describe cancer and cancer management in Europe, the European Cancer Health Indicator Project (EUROCHIP) has proposed a list of indicators that have to be adopted to evaluate the effects on outcome of proposed health system modifications.

EUROCARE-3: survival of cancer patients diagnosed 1990-94--results and commentary.

EUROCARE-3 analysed the survival of 1815584 adult cancer patients diagnosed from 1990 to 1994 in 22 European countries. The results are reported in tables, one per cancer site, coded according to the International Classification of Diseases (ICD)-9 classification. The main findings of the tables are summarised and commented on in this article. For most solid cancers, wide differences in survival between different European populations were found, as also reported by EUROCARE-1 and EUROCARE-2, despite a remarkable (10%) overall increase in cancer survival from 1985 to 1994. Survival was highest in northern Europe (Sweden, Norway, Finland and Iceland), and fairly good in central-southern Europe (France, Switzerland, Austria and Spain). Survival was particularly low in eastern Europe, low in Denmark and the UK, and fairly low in Portugal and Malta. The mix of tumour stage at diagnosis explains much of the survival differences for cancers of the digestive tract, female reproductive system, breast, thyroid, and also skin melanoma. For tumours of the urinary tract and prostate, the differences were explained mainly by differences in diagnostic criteria and procedures. The case mix by anatomic subsite largely explains differences in survival for head and neck cancers. For oesophagus, pancreas, liver and brain cancer, with poor prognoses, survival differences were limited. Tumours, for which highly effective treatments are available, such as testicular cancer, Hodgkin's lymphoma and some haematological malignancies, had fairly uniform survival across Europe. Survival for all tumours combined (an indicator of the overall cancer care performance of a nation's health system) was better in young than old patients, and better in women than men. The affluence of countries influenced overall cancer survival through the availability of adequate diagnostic and treatment procedures, and screening programmes.

Cancer prevalence in Central Europe: the EUROPREVAL Study.

BACKGROUND: Information on cancer prevalence is either absent or largely unavailable for central European countries. MATERIALS AND METHODS: Austria, Germany, The Netherlands, Poland, Slovakia, Slovenia and Switzerland cover a population of 13 million inhabitants. Cancer registries in these countries supplied incidence and survival data for 465 000 cases of cancer. The prevalence of stomach, colon, rectum, lung, breast, cervix uteri, corpus uteri and prostate cancer, as well as skin melanoma, Hodgkin's disease, leukaemia and all malignant neoplasms combined was estimated for the end of 1992. RESULTS: A large heterogeneity was observed within central European countries. For all cancers combined, estimates ranged from 730 per 100 000 in Poland (men) to 3350 per 100 000 in Germany (women). Overall cancer prevalence was the highest in Germany and Switzerland, and the lowest in Poland and Slovenia. In Slovakia, prevalence was higher than average for men and lower than average for women. This was observed for almost all ages. As shown by incidence data, breast cancer was the most frequent malignancy among women in all countries. Among men, prostate cancer was the leading malignancy in Germany, Austria and Switzerland, and lung cancer was the major cancer in Slovenia, Slovakia and Poland. The Netherlands had a high prevalence of both prostate and lung cancer. Time-related magnitude of prevalence within each country and the variability of such proportions across the countries has been estimated and cancer prevalence is given by time since diagnosis (1 year, 1-5 years, 5-10 years, >10 years) for each site. The weight of 1-year prevalence (248 per 100 000 among men and 253 per 100 000 among women) was <15% of total prevalence. Prevalent cases between 1 and 5 years since diagnosis represented between 22% and 34% of the total prevalence. Prevalent cases diagnosed from 5 to 10 years before (335 per 100 000 for men and 505 per 100 000 for women) represented between 17% and 23% of prevalent cancers. Finally, long-term cancer prevalence (diagnosed >10 years before), reflecting long-term survival, and number of people considered as cured from cancer were 490 per 100 000 for men and 1028 per 100 000 for women, with a range between 26% (The Netherlands, men) and 50% (Slovakia, women). CONCLUSION: It is clear from observing countries in Central Europe, that high cancer prevalence is associated with well-developed economies. This burden of cancer could be interpreted as a paradoxical effect of better treatments and thereby survival. It could also be taken as a sign for not being satisfied with the advances in treating patients diagnosed with cancer, and for supporting more primary prevention.

[Cervical cancer prevention - awareness and health behavior changes of women in 1976, 1986, 1990 and 1998]. / Zmiany uswiadomienia i zachowan zdrowotnych kobiet dotyczace profilaktyki raka szyjki macicy w latach 1976, 1986, 1990 i 1998.

AIM: To find the changes in the proportion of women who declared knowledge about cytological tests and underwent that test in the years 1976, 1986, 1990 and 1998, as well as in the proportion of those who declared showing up at the gynaecologist during the last year. To assess the number of women taking part in the secondary prevention of cervical cancer. To correct health education intervention targeted at women. METHODS: The results of four cervical prevention surveys on representative samples of Polish women aged over 18 years were compared. RESULTS: The substantial (58%) increase in the proportion of women who declared awareness of cytological tests was shown. As expected, smaller favourable changes were found in the field of women's health related to secondary prevention. The percent of women who declared yearly visits at the gynaecologists increased by 12% and those who declared having cytological tests done during last three years by 7%. The lowest level of awareness and the lowest frequency of using prevention services were declared among women aged over 60, represented the lowest education level and resided in rural areas. CONCLUSIONS: It is important to continue educational work and intervention measures concerning cervical cancer prevention, with special attention to the most neglected groups of women.

Survival of European women with gynaecological tumours, during the period 1978-1989. EUROCARE Working Group.

This study concerns the survival of European patients diagnosed between 1978 and 1989 with cancer of corpus and cervix uteri and ovary. Variations in survival in relation to age, country and period of diagnosis were examined. Data from the EUROCARE study were supplied by population-based cancer registries in 17 countries to a common protocol. Five years after diagnosis, relative survival rates were 75, 62 and 35% for cancers of the endometrium, cervix and ovary, respectively. Survival decreased markedly with age. The decrease was especially evident for ovarian cancer, which declined from 65% (15-45 years) to 18% (75+ years). In 1985-1989 there were important inter-country differences in survival for European women with gynaecological cancers: Eastern European countries were characterised by low 5-year relative survival whilst in Sweden, Austria, The Netherlands and Switzerland survival was generally higher than for other European countries. From 1978-1989, 5-year relative survival improved slightly for cervical cancer and improved more among the oldest patients. Prognosis also improved slightly for patients with ovarian tumours and this increase (around 20%) was concentrated among patients between 15 and 64 years of age. Intercountry differences in survival did not in general reduce over time, although for ovarian cancer survival differences narrowed probably in relation to the more widespread use of more effective chemotherapy. Intercountry and time differences in survival for cervical cancer are almost certainly related to variations in the effectiveness of cervical screening programmes. For corpus uteri cancer there was no improvement in survival over the period of this study and intercountry survival differences for this cancer are probably related to differences in patient management.

History of 400 years of struggle against cancer in Poland.

The over 400-year history of struggle against cancer in Poland is presented in this work, from its beginning, marked by the establishment of the first hospital for cancer patients in Warsaw in 1592, up to the achievement of the main aim of the National Cancer Programme, i.e., the recent construction of a large modern cancer centre in Warsaw. In the meantime, a number of significant events have taken place in Poland for example, studies on cancer conducted in the 17th-19th centuries, a report on cancer mortality data which was published in 1888, and the Warsaw Committee on Cancer Research and Control, established in 1906. As regards the 20th century, the National Cancer Research and Control programmes were carried out (in 1924, 1952 and 1975), among other activities. An oncological network was built up in Poland based on 11 comprehensive cancer control centres and provincial outpatient clinics. At present, out of each 100,000 new cancer cases more than 70,000 die every year in Poland. The leading localizations in males are: lung (30.5%), stomach (9.8%), larynx (5.5%), prostate (5.1%) and urinary bladder (5.0%); in females: breast (17.5%), cervix uteri (9.8%), lung (6.6%), stomach (6.2%) and ovary (6.2%). Cancer patients' estimated probability of surviving 5 years is 26.4% (males) and 39.8% (females).

Changes in the incidence and survivals of ovarian cancer in Poland.

The incidence and mortality trends, as well as survivals, are presented according to the Warsaw Cancer Registry data concerning 4,112 ovarian cancer cases registered in the years 1963-1988, in two populations, the urban of Warsaw City and the rural of the Warsaw Rural Areas (WRA). The standardized incidence rate in Warsaw in 1988 was 13.44/100,000 and it has not changed significantly in relation to the 1963 figure, but statistical significance characterized the increase of incidence in WRA population and the general population of Poland. The standardized incidence rates were as follows: WRA 1963 6.8, 1988 11.7; in Poland as a whole respectively, 6.5 in 1960 and 11.7 in 1988. The most rapid increase of incidence occurred in the 1960s, then the trend stabilized, and another increase began in 1984. The incidence growth was accompanied by similar trends in mortality. The mortality rates in 1988 were: 8.3 in Warsaw; 6.9 in Poland, and 6.9 in WRA. The mortality increase was statistically significant in WRA and in the total population of Poland. The analysis of mortality and incidence trends in Warsaw City and in Poland as a whole justifies the identification of Warsaw as a high-risk population, while Poland appears to be a population of rapidly growing ovarian cancer risk. Despite a statistically insignificant growth of ovarian cancer incidence and mortality in Warsaw, the risk keeps increasing as can be seen in the permanent increase of incidence and mortality rates which began in 1973, in increasingly age-specific incidence and mortality rates in almost all age groups, and in a shift of top incidence and mortality rates towards younger age groups. The risk of this cancer is higher in Warsaw City than in rural areas, but the urban/rural ratio was declining from 2.5 to 1.3 during the study period. The relative 5 years survival rates in Warsaw are similar to those observed world wide, and they are 37.3% against 38.5% in WRA. Compared with the previous period between the years 1963 and 1968, there has been an improvement in the 5-year survival rates in both populations and in all age groups, except the oldest, resident in Warsaw.

Striking differences in the epidemiological picture of breast cancer in urban and rural areas in Poland.

Poland is a European country of medium female breast cancer risk but a steady, mean incidence growth of 3.5% per year makes this cancer the most frequent malignancy and a leading cause of cancer-related deaths among the women of the 1980s. Our analysis is based on data collected by the Warsaw Cancer Registry in the years 1963-1987. The crude incidence rate in Poland doubled against 1963 and was nearly 40/100,000 in 1988. In 1988 eight thousand women developed breast cancer. In Poland, the incidence of 37.7 was higher in Warsaw than the rate of 16.6 obtained for Warsaw Rural Areas (WRA) in 1963. The trend continued until 1988 to reach 59.7 and 33.5 in the respective areas. Incidence rapidly grew with age, starting in the group of 30 to reach its peak of 149.2 at 65 and over in Warsaw and 86.6 in WRA. Mortality rates in Warsaw grew from 16.6 in 1963 to 30.7 in 1988 and, from 10.8 to 17.4 in WRA in the respective years. The urban/rural ratio declined from 1.7 to 1.5 during this period. The unfavourable proportion (patient distribution according to clinical staging in Warsaw was: 0 + I-17.2%; II-34.1%; III-29.1%; IV-23.6%. The relative 5-year survivals in Warsaw were 58.7% and they improved little compared to the former periods. These figures were even lower in WRA and they showed a downward trend for women aged over 65. A steady increase in breast cancer risk observed after 1963 and the large proportion of advanced breast cancers diagnosed, were followed by poor results of treatment causing about 5,000 breast cancer deaths in Poland annually.

Epidemiology of breast and gynaecological cancers in Poland.

The epidemiological data on breast cancer and cancer of the female reproductive organs are presented in the light of data provided by the National Cancer Registry and the Warsaw Cancer Registry. Estimates say that cancer of the breast and the reproductive organs attacked 19,764 women in Poland, 1989, of whom 9,436 died. This number represents 41.2% of the total cancer incidence in women. The standardized incidence rates calculated for these cancers per 100,000 and arranged according to localization, were as follows: breast 34.4; cervix 19.5; ovary 12.4; corpus uteri 10.6. Mortality: breast 15.5; cervix 8.0; ovary 6.8; corpus uteri 2.5. Comparing with the average rates in EC countries, the risk in Poland of breast cancer was lower but was higher in cervical and uterine cancers. The risk of ovarian cancer was similar in Poland and the E.C. The relative 5-year survivals estimated for the years 1978-1982 in Poland were as follows: breast 49.3%; cervix 50.7%; and corpus uteri 66.1%, which was lower than in Switzerland, Finland, Australia, and USA (Caucasians); and similar in patients with ovarian cancer (35.1%). Particularly unfavourable 5-year survival rates were given for cancer of the breast and cervix in the rural areas. Unfavourable trends are observed in the control of the breast and cervical cancer in Poland which confirms inadequacy of the existing preventive programmes based on screening. According to estimates, the introduction of preventive measures could reduce cervical cancer mortality by 60% during 10 years and breast cancer mortality by 40% within 7 years, which means saving about 3,000 lives yearly.