Clinical analysis of metaplastic breast carcinoma with distant metastases: A multi­centre experience.

Metaplastic breast cancer (BC-Mp), which includes a range of epithelial and mixed epithelial-mesenchymal tumours, are rare malignancies with an unfavourable prognosis. The limited literature on BC-Mp focuses mainly on retrospective data for radically treated patients. Notably absent are studies dedicated to the palliative treatment of BC-Mp with distant metastases. The present retrospective study investigated treatment modalities and prognosis in a multi-centre cohort of 31 female participants diagnosed with distant metastatic BC-Mp, including 7 patients with de novo metastatic disease. The median age of the patients was 61 years (range, 33-87 years), with 38.7% presenting local lymph node involvement. Lungs were the most common site for the metastatic disease (61.3%). Median Ki-67 index was 50% (range, 35-70%), and 80.7% of cases were classified as grade 3. Human epidermal growth factor receptor 2 (HER2)+ and estrogen receptor+ were detected in 12.9 and 6.5% of cases, respectively. A total of 62.4% of patients received first-line palliative systemic treatment. The 1- and 2-year overall survival (OS) were 38.5 and 19.2%, respectively. Receiving ≥1 line of palliative treatment was significantly associated with improved OS (P<0.001). Factors such as age, Ki-67 index, HER2 or hormonal status, presence of specific epithelial or mesenchymal components, location of metastases or chemotherapy regimen type did not influence OS. The present study provided insights into the clinicopathological profile, systemic treatment experience, prognostic factors and OS data of BC-Mp with distant metastases, emphasizing the imperative for clinical trials in this population.

Retrospective Observational Study to Determine the Epidemiology and Treatment Patterns of Patients with Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) poses a serious therapeutic challenge due to the occurrence of frequently aggressive, heterogenic, and metastatic tumours. The absence of therapeutic targets for traditional therapies is a hindrance to establishing a standardised therapy for TNBC. There is limited TNBCs epidemiological and real-world data about TNBC treatment regimens in Poland. We retrospectively analysed clinical data from our hospital registry from 2015 and 2020. A total of 8103 individuals with breast cancer were admitted to the MSCI, while 856 (10.6%) were diagnosed with TNBC. Most of the early-stage or locally advanced TNBC individuals had underlying conditions, presented mostly poorly differentiated (G3) stage II tumours and featured a bi-modal age distribution. On average, one-third of all tested TNBCs carried BRCA mutations and its identification impacted surgery preference. We observed a significant increase in the use of systemic therapy among TNBCs, whereas carboplatin and dose-dense regimens showed the most prominent upsurge in the neoadjuvant setting. Moreover, the use of neoadjuvants was positively correlated with less invasive breast and lymph node surgeries. The presented data align with general trends observed in other countries and will contribute to expanding knowledge in the planning of treatment regimens and their outcomes.

Does Alcohol Withdrawal Influence Arterial Stiffness and Classical Risk Factors for Cardiovascular Disease for Persons With Alcohol Use Disorder?

AIMS: The amount and pattern of cigarette and alcohol consumption are highly associated with cardiovascular risk. The aim of the present study was the assessment of changes in arterial stiffness and classical risk factors for cardiovascular disease after alcohol withdrawal and detoxification in persons with alcohol use disorder. METHODS: Two hundred and forty-one individuals (men and women) participated in the investigation. The photoplethysmographic method was applied to assess arterial stiffness in three stages within 6 weeks. Participants were divided into subgroups based on age and sex. Analyses were performed using analysis of variance with repeated measures. RESULTS: Different variations in time of stiffness index (SI) and reflection index (RI) values were recorded. Some increases in triglycerides, total cholesterol, low-density lipoprotein and a decrease in high-density lipoproteins were observed in all analyzed groups. Both systolic and diastolic blood pressure (DP) changed significantly during the 3 weeks of the study only in a group of younger men. The SI is correlated with age and gender. No correlation of RI with sex was found; however, RI was strongly correlated with age, pulse and DP. CONCLUSIONS: The presented study shows that some groups of patients (older women and younger men) after detoxification may be particularly vulnerable to vascular system disorders, i.e. arterial stiffness, making it suggested to include additional observation during therapy.

Discrepancy between Tumor Size Assessed by Full-Field Digital Mammography or Ultrasonography (cT) and Pathology (pT) in a Multicenter Series of Breast Metaplastic Carcinoma Patients.

Metaplastic breast cancer (BC-Mp) presents diagnostic and therapeutic complexities, with scant literature available. Correct assessment of tumor size by ultrasound (US) and full-field digital mammography (FFDM) is crucial for treatment planning. METHODS: A retrospective cohort study was conducted on databases encompassing records of BC patients (2012-2022) at the National Research Institutes of Oncology (Warsaw, Gliwice and Krakow Branches). Inclusion criteria comprised confirmed diagnosis in postsurgical pathology reports with tumor size details (pT) and availability of tumor size from preoperative US and/or FFDM. Patients subjected to neoadjuvant systemic treatment were excluded. Demographics and clinicopathological data were gathered. RESULTS: Forty-five females were included. A total of 86.7% were triple-negative. The median age was 66 years (range: 33-89). The median pT was 41.63 mm (6-130), and eight patients were N-positive. Median tumor size assessed by US and FFDM was 31.81 mm (9-100) and 34.14 mm (0-120), respectively. Neither technique demonstrated superiority (p > 0.05), but they both underestimated the tumor size (p = 0.002 for US and p = 0.018 for FFDM). Smaller tumors (pT1-2) were statistically more accurately assessed by any technique (p < 0.001). Only pT correlated with overall survival. CONCLUSION: The risk of underestimation in tumor size assessment with US and FFDM has to be taken into consideration while planning surgical procedures for BC-Mp.

[Recomendations on non-pharmacological interventions in women with PCOS to reduce body weight and improve metabolic disorders [Zalecenia dotyczace postepowania niefarmakologicznego u kobiet z PCOS celem zmniejszenia masy ciala i poprawy zaburzen metabolicznych]].

Women with PCOS are characterised by ovarian hyperandrogenism, which, apart from fertility problems, hirsutism, acne, and androgenic alopecia, also leads to the development of central (android) obesity and its adverse metabolic consequences. Additionally, women with PCOS have intrinsic insulin resistance (IR) with its consequent hyperinsulinaemia, which leads to the development of atherosclerosis, arterial hypertension, and type 2 diabetes mellitus (T2DM), which give rise to cardiovascular disease (CVD), being the main cause of death among women. Although there are several publications on the topic of life-style changes in women with PCOS to normalise body weight and thus to reduce the adverse metabolic consequences of obesity, such as T2DM and CVD, the number of randomised studies that would enable the formation of strong recommendations is very limited. Nevertheless, taking into consideration the pathophysiology, any intervention implementing healthy dietary habits leading to the reduction of body weigh should be the core of non-pharmacological treatment in women with PCOS. The aim of the given recommendations herein is to point out and systemise the interventions on lifestyle change in women with PCOS as well as to form a practical guideline for the health care specialists, dieticians, and mental-therapists (psychologist) who take care of women with this syndrome.

Identification of the metabolic fingerprints in women with polycystic ovary syndrome using the multiplatform metabolomics technique.

In addition to chronic anovulation and clinical signs of hyperandrogenism women with polycystic ovary syndrome (PCOS) are insulin resistant and therefore, develop central obesity with its long term consequences such as dyslipidaemia, hypertension, atherosclerosis and type 2 diabetes mellitus (T2DM), which all lead to the development of cardiovascular disease (CVD). Due to the polysymptomatic nature of this syndrome and lack of consensus on its diagnostic criteria there is a strong need of finding a reliable biochemical or molecular marker, which would facilitate making the accurate diagnosis of PCOS. Therefore, the aim of our study was to perform a metabolomics analysis with the use of two complementary techniques: gas chromatography and liquid chromatography coupled with mass spectrometry, of the serum samples from women with PCOS (n = 30) and to compare them with healthy age and BMI matched controls (n = 30). Obtained results were subjected to one-dimensional statistical analysis (student's t-test or its non-parametric equivalent U Mann-Whitney test) and multivariate statistical analysis (the principal component analysis [PCA], variable importance into projection [VIP] and selectivity ratio [SR]). The results of our study showed that women with PCOS are characterised by metabolic disorders of the amino acids, carbohydrates, steroid hormones, lipids and purines. Compared to control subjects, women with PCOS had increased serum levels of phospholipids, aromatic amino acids, organic acids, hormones and sphinganine and decreased total cholesterol. Among the identified compounds, total cholesterol, phenylalanine and dehydroepiandrosterone sulfate, uric and lactic acid were the compounds with the strongest discriminating power.

Serum bisphenol A concentrations correlate with serum testosterone levels in women with polycystic ovary syndrome.

The aim of this study was to determine serum bisphenol A (BPA) concentrations using high performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) in women with polycystic ovary syndrome (PCOS) (n = 106, age range 18-40 yrs) and to evaluate its potential impact on their hormonal and metabolic profile. The control group consisted of age- and BMI-matched 80 eumenorrheic women with no clinical or biochemical hyperandrogenism. Our results showed that women with PCOS had significantly higher serum BPA concentrations than healthy controls (geometric mean and [95% CI]: 0.202 ng/mL [0.150; 0.255] vs. 0.154 ng/mL [0.106; 0.201], P = 0.035), which correlated positively with serum total testosterone (TST) (R=0.285, P = 0.004) and the free androgen index (FAI) (R = 0.196, P = 0.049). There were no significant correlations between serum BPA and BMI, waist circumference, serum glucose, insulin and lipids. These results point to the potential role of BPA in the pathogenesis of the ovarian hyperandrogenism in women with PCOS.

Determination of trace levels of eleven bisphenol A analogues in human blood serum by high performance liquid chromatography-tandem mass spectrometry.

Chemicals showing structural or functional similarity to bisphenol A (BPA), commonly called BPA analogues, have recently drawn scientific attention due to their common industrial and commercial application as a substitute for BPA. In the European Union, the use of BPA has been severely restricted by law due to its endocrine disrupting properties. Unfortunately, it seems that all BPA analogues show comparable biological activity, including hormonal disruption, toxicity and genotoxicity. Until now, the knowledge about human exposure to BPA analogues is scarce, mainly due to the lack of the data concerning their occurrence in human derived biological samples. This study presents the development of an analytical method for determination of trace levels of eleven BPA analogues in human blood serum samples. The method involves fast and simple liquid-liquid extraction, using low sample and solvent volumes. Chromatographic separation of analytes was optimized using one-factor-at-a-time approach (mobile phase composition, gradient shape, chromatographic column selection, separation temperature, etc.). The method allows for effective separation of the analytes, even in the case of configurational isomers (bisphenol M and bisphenol P). The calibration curves for all analytes were linear in the range tested. The limits of detection and quantitation were in the range of 0.0079÷0.039ng/mL and 0.024÷0.12ng/mL respectively. Compound-dependent recovery values were in the rage of 88÷138%. Matrix effects were mitigated with the help of matrix-matched calibration curves prepared for every batch of samples. Results obtained after the analysis of 245 real human blood serum samples indicate that human beings are exposed to different BPA analogues, that are present in the environment and in common, daily use products.

Cessation of alcohol consumption decreases rate of nicotine metabolism in male alcohol-dependent smokers.

BACKGROUND: Rate of nicotine metabolism is an important factor influencing cigarette smoking behavior, dependence, and efficacy of nicotine replacement therapy. The current study examined the hypothesis that chronic alcohol abuse can accelerate the rate of nicotine metabolism. Nicotine metabolite ratio (NMR, a biomarker for rate of nicotine metabolism) and patterns of nicotine metabolites were assessed at three time points after alcohol cessation. METHODS: Participants were 22 Caucasian men randomly selected from a sample of 165 smokers entering a 7-week alcohol dependence treatment program in Poland. Data were collected at three time points: baseline (week 1, after acute alcohol detoxification), week 4, and week 7. Urine was analyzed for nicotine and metabolites and used to determine the nicotine metabolite ratio (NMR, a biomarker for rate of nicotine metabolism), and total nicotine equivalents (TNE, a biomarker for total daily nicotine exposure). RESULTS AND CONCLUSIONS: There was a significant decrease in urine NMR over the 7 weeks after alcohol abstinence (F(2,42)=18.83, p<0.001), indicating a decrease in rate of nicotine metabolism. On average NMR decreased 50.0% from baseline to week 7 (9.6±1.3 vs 4.1±0.6). There was no change in urine TNE across the three sessions, indicating no change daily nicotine intake. The results support the idea that chronic alcohol abuse may increase the rate of nicotine metabolism, which then decreases over time after alcohol cessation. This information may help to inform future smoking cessation interventions in this population.

Effects of partial silencing of genes coding for enzymes involved in glycolysis and tricarboxylic acid cycle on the enterance of human fibroblasts to the S phase.

BACKGROUND: Previously published reports indicated that some enzymes of the central carbon metabolism (CCM), particularly those involved in glycolysis and the tricarboxylic acid cycle, may contribute to regulation of DNA replication. However, vast majority of such works was performed with the use of cancer cells, in the light of carcinogenesis. On the other hand, recent experiments conducted on bacterial models provided evidence for the direct genetic link between CCM and DNA replication. Therefore, we asked if silencing of genes coding for glycolytic and/or Krebs cycle enzymes may affect the control of DNA replication in normal human fibroblasts. RESULTS: Particular genes coding for these enzymes were partially silenced with specific siRNAs. Such cells remained viable. We found that silencing of certain genes resulted in either less efficient or delayed enterance to the S phase. This concerned following genes: HK2, PFKM, TPI, GAPDH, ENO1, LDHA, CS1, ACO2, SUCLG2, SDHA, FH and MDH2. Decreased levels of expression of HK2, GADPH, CS1, ACO2, FH and MDH2 caused also a substantial impairment in DNA synthesis efficiency. CONCLUSIONS: The presented results illustrate the complexity of the influence of genes coding for enzymes of glycolysis and the tricarboxylic acid cycle on the control of DNA replication in human fibroblasts, and indicate which of them are especially important in this process.

Health risk of exposure to Bisphenol A (BPA).

Bisphenol A (BPA) belongs to chemicals that are produced in large quantities worldwide. It is commonly used as monomer in polycarbonate synthesis, plasticizer in the production of epoxy resins, as well as an additive for the elimination of surfeit of hydrochloric acid during the polyvinyl chloride (PVC) production. BPA is not only used in the production of plastics intended to a direct contact with food, including plastic packaging and kitchenware, but also in inner coatings of cans and jar caps. There are various routes of human exposure to this substance such as oral, by inhalation and transdermal. The main sources of exposure to BPA include food packaging and dust, dental materials, healthcare equipment, thermal paper, toys and articles for children and infants. BPA is metabolized in the liver to form bisphenol A glucuronide and mostly in this form is excreted with urine. Due to its phenolic structure BPA has been shown to interact with estrogen receptors and to act as agonist or antagonist via estrogen receptor (ER) dependent signalling pathways. Therefore, BPA has been shown to play a role in the pathogenesis of several endocrine disorders including female and male infertility, precocious puberty, hormone dependent tumours such as breast and prostate cancer and several metabolic disorders including polycystic ovary syndrome (PCOS). Because of the constant, daily exposure and its tendency to bio-accumulation, BPA seems to require special attention such as biomonitoring. This observation should include clinical tests of BPA concentration in the urine, which is not only one of the best methods of evaluation of the exposure to this compound, but also the dependence of the daily intake of BPA and the risk of some endocrine disorders.

Enzymes of the central carbon metabolism: are they linkers between transcription, DNA replication, and carcinogenesis?

Dependence of carcinogenesis on disruption of DNA replication regulation is a well-known fact. There are also many reports demonstrating the interplay between transcription and DNA replication processes, particularly underlying the importance of promoter activities in the control of replication initiation. Recent findings have shown direct links between central carbon metabolism and DNA replication regulation. Here, we summarize previously published reports which indicated that enzymes of the central carbon metabolism, particularly those involved in glycolysis and the tricarboxylic acid cycle, may contribute to regulation of transcription and DNA transactions (replication and repair). In this light, we propose a hypothesis that some of these enzymes might be linkers between transcription, DNA replication, and carcinogenesis. If true, it may have a consequence in our understanding of causes and mechanisms of carcinogenesis. Particularly, certain metabolic perturbations might directly (through central carbon metabolism enzymes) influence regulation of DNA transactions (replication control and fidelity), and thus facilitate carcinogenesis. To test this hypothesis, further studies will be necessary, which is discussed in the final part of this article.

[Links between glycolysis and DNA replication in eukaryotic cells]. / Powiazanie glikolizy z regulacja replikacji DNA w komórkach eukariotycznych.

Development of the eukaryotic cell proceeds through sequentional stages of the cell cycle, in which there are growth, replication of the genetic material, and cell division processes. Many environmental and intracellular factor decides if the cell proceeds throughout all stages of the cell cycle or enters the G0 silencing phase. The cell cycle depends also on metabolic processes, including central carbon metabolism and DNA replication. One cof major processes of the central carbon metabolism is glycolysis. This is the main pathway of glucose metabolism in cells, leading to conversion of this molecule to puryvare. Until recently, it was supposed that carbon metabolism and DNA replication are linked only indirectly, mostly through energy input, necessary for synthesis of nucleic acids, and production of precursors of deoxyribonucleotides. Nevertheless, recent studies, described and discussed in this article, suggested that there are much more complicated links, perhaps also direct, between these two processes.

[Plasma lipid concentration in smoking and nonsmoking male adults treated from alcohol addiction]. / Zmiany profilu lipidowego w osoczu mezczyzn o róznym statusie palenia tytoniu leczonych z powodu uzaleznienia od alkoholu.

Alcohol drinking and tobacco smoking affect plasma lipid levels and are both independent risk factors of cardiovascular diseases. Alcohol and nicotine addictions are more common among man than women in Poland. The aim of the study was to evaluate changes in plasma lipid levels after cessation of heavy drinking in smoking and nonsmoking Polish male adults. Subjects were recruited from individuals who participated in an inpatient addiction program following alcohol detoxification. We recruited 119 male adults: 48 non-smokers in age between 31 and 60 years (mean 48.7 +/- 8.8) and 71 smokers in age between 30 and 60 years (mean 46.1 +/- 7.8). Each subjects provided three blood samples: at baseline, after 3 weeks, and after 6 weeks of treatment. Plasma samples were analyzed for lipids by manual precipitation and automatic enzymatic methods. Changes in plasma lipid concentrations were analyzed using two-way analysis of variances with repeated measures with smoking status as between subjects factor and time post alcohol cessation as within-subject factors. All analyses were adjusted for age, and BMI. We found that plasma levels of HDL decreased in smoking and nonsmoking subjects by 30% and 24%, respectively (p < 0.001). In smoking subjects, plasma levels of triglycerides and LDL increased significantly after 6 weeks post cessation of heavy drinking cessation by 17% and 16%, respectively (p = 0.001). We also found that total cholesterol levels remained high in smoking subjects, but decreased significantly by 7% (p = 0.022) in nonsmoking subjects after 6 weeks post cessation of heavy drinking. We concluded that cigarette smoking increased LDL and inhibited the decline in plasma cholesterol among subjects addicted to alcohol following cessation of heavy drinking. Alcohol addiction therapy should be complemented with smoking cessation to prevent increase in cardiovascular risk.

Quantitative estimation of lysosomal storage in mucopolysaccharidoses by electron microscopy analysis.

Mucopolysaccharidoses (MPS) are severe inherited metabolic disorders caused by storage of glycosaminoglycans (GAGs). The level of accumulated GAGs is an important parameter in assessment of the severity of the disease and the efficacy of treatment; unfortunately, biochemical methods are often unreliable and only semi-quantitative. Therefore, finding other methods for estimation of GAG levels and/or assessment of the efficacy of applied therapy is very important. Although monitoring of GAG levels during therapy is crucial, in this work it is proposed that analysis of the ultrastructure of MPS cells by electron microscopic techniques can be considered as an alternative and reliable method for assessment of lysosomal storage. The number of complex lysosomal structures was found to be significantly higher in MPS cells relative to controls, while it decreased significantly in response to either enzyme replacement therapy or substrate reduction therapy. Thus, this parameter, easily assessed by electron microscopy, appears to correspond to the physiological state of MPS cells.

[Plasma fibrinogen concentration in smoking and nonsmoking patients treated from alcohol addiction]. / Zmiany stezenia fibrynogenu w osoczu pacjentów o róznym statusie palenia tytoniu leczonych z powodu uzaleznienia od alkoholu.

Cigarette smoking is common among persons addicted to alcohol. Both tobacco smoking and alcohol binge drinking are risk factors of many cardiovascular conditions. The risk of cardiovascular events decreases after alcohol cessation. However little is known about the effect of continues smoking on biomarkers of adverse cardiovascular events among patients treated from alcohol addiction. The aim of the study was to assess fibrinogen changes after alcohol drinking cessation among cigarette smokers and non-smokers. Total of 239 patients treated from alcohol addiction in Addiction Treatment Center (OTU) Parzymiechy, Poland were included in the study. There were total of 39 women: 11 non-smoking women, in the age range of between 31 and 59 years (mean age 47 +/- 9 years) and 28 smoking women in the age range of 31-60 years (mean age 43 +/- 8 years). Among 200 men, there were 150 smokers in the age range of between 30 and 60 years (mean age 44 +/- 8 years) and 50 non-smokers in the age range of 31 and 60 years (mean age 49 +/- 9 years). We found that among non-smoking patients fibrinogen levels remained unchanged three weeks post alcohol cessation (3.42 vs. 3.49 g/l) but after six weeks significantly decreased to the level of 3.09 g/l (p=0.00085). Among smoking patients fibrinogen levels increased after three weeks post alcohol cessation by 7.9% (z 3.41 do 3.68 g/l) and went back to a baseline level of 3.50 g/l. However those changes were not statistically significant. We found that alcohol cessation leads to decrease of fibrinogen levels only among non-smoking patients post alcohol cessation. A risk of cardiovascular diseases seemed to remain elevated among smokers treated from alcohol addiction. There is need for concomitant treatment of tobacco addiction among smoking alcoholics.