Circulating tumor cells and their clinical significance

Metastases to other organs and the formation of secondary tumors are responsible for 90% of cancer-related deaths. However, even in the early stages of cancer, about 30–40% of patients with localized disease may have latent metastasis, which are likely derived from circulating tumor cells (CTCs) involved in disease progression. Therefore, detection and analysis of CTCs can play an important role in the diagnosis and decision-making of adjuvant treat­ment that aims to prevent metastasis. At present, patients’ selection of treatment is based on the statistical risk of recurrence of metastatic disease, without considering whether the tumor cells have spread from the primary tumor. This may lead to unnecessary treatment of non-metastatic disease patients. Therefore, early detection of CTCs in the blood is critically important, and should allow for a more accurate assessment of disease severity. Here, we provide an overview of CTC phenotypes, including plasticity of CTCs, and their clinical significance

Circulating tumor cells and their clinical significance

Metastases to other organs and the formation of secondary tumors are responsible for 90% of cancer-related deaths. However, even in the early stages of cancer, about 30–40% of patients with localized disease may have latent metastasis, which are likely derived from circulating tumor cells (CTCs) involved in disease progression. Therefore, detection and analysis of CTCs can play an important role in the diagnosis and decision-making of adjuvant treat­ment that aims to prevent metastasis. At present, patients’ selection of treatment is based on the statistical risk of recurrence of metastatic disease, without considering whether the tumor cells have spread from the primary tumor. This may lead to unnecessary treatment of non-metastatic disease patients. Therefore, early detection of CTCs in the blood is critically important, and should allow for a more accurate assessment of disease severity. Here, we provide an overview of CTC phenotypes, including plasticity of CTCs, and their clinical significance

Migracja i inwazyjność komórek nowotworowych; rola plastyczności komórek i udział macierzy zewnątrzkomórkowej w tworzeniu przerzutów

Migratory and invasive potential of the cell is determined by the type of a tissue from which the cell derives. However, in case of neoplastic cells they display some plasticity of a phenotype which enables changes in the mode of migration. These transitions may influence the metastatic potential of the tumour. Processes described vitally depend on the tumour microenvironment and may be regulated by the dynamic of the extracellular matrix alterations.Zdolność komórek do migracji jest determinowana przez rodzaj tkanki, z jakiej się wywodzą. W przypadku komórek nowotworowych możliwa jest jednak pewna plastyczność fenotypu, umożliwiająca zmianę typu migracji. Zmiany te mogą mieć wpływ na poziom inwazyjności nowotworu. Opisywane procesy pozostają w ścisłej zależności od mikrośrodowiska, w jakim znajdują się komórki i mogą być regulowane przez zmiany zachodzące w macierzy zewnątrzkomórkowej, która w dynamiczny sposób wpływa na potencjał migracyjny i inwazyjny

Hairpin structure within the 3′UTR of DNA polymerase β mRNA acts as a post-transcriptional regulatory element and interacts with Hax-1

Aberrant expression of DNA polymerase β, a key enzyme involved in base excision repair, leads to genetic instability and carcinogenesis. Pol β expression has been previously shown to be regulated at the level of transcription, but there is also evidence of post-transcriptional regulation, since rat transcripts undergo alternative polyadenylation, and the resulting 3′UTR contain at least one regulatory element. Data presented here indicate that RNA of the short 3′UTR folds to form a strong secondary structure (hairpin). Its regulatory role was established utilizing a luciferase-based reporter system. Further studies led to the identification of a protein factor, which binds to this element—the anti-apoptotic, cytoskeleton-related protein Hax-1. The results of in vitro binding analysis indicate that the formation of the RNA–protein complex is significantly impaired by disruption of the hairpin motif. We demonstrate that Hax-1 binds to Pol β mRNA exclusively in the form of a dimer. Biochemical analysis revealed the presence of Hax-1 in mitochondria, but also in the nuclear matrix, which, along with its transcript-binding properties, suggests that Hax-1 plays a role in post-transcriptional regulation of expression of Pol β

Wtórna ostra białaczka szpikowa u chorej po skutecznym leczeniu ostrej białaczki promielocytowej

Clonal aberrations, leading to development of therapy-related myelodysplastic syndromes and secondary acute myeloid leukemias (s-AML), are present in 10% of patients treated previously for acute promyelocytic leukemia (APL). Most of them, especially monosomy 7, are associated with extremely poor prognosis. We present a case of 22-years-old female patient with APL diagnosed in 2008 who achieved complete cytogenetic and molecular remission after treatment according to PETHEMA protocol. Two years after the treatment was completed, s-AML with complex monosomal karyotype including monosomy 7 and t(3;21)(q26.2;q22) was diagnosed. Complete cytogenetic remission was achieved after 2 induction cycles and finally the allogeneic hematopoietic stem cell transplantation from HLA-matched related donor was performed. In the posttransplant period moderate chronic graft versus host disease was observed. Now, 15 months after transplantation, the patient is still in complete cytogenetic remission with 100% of donor chimerism. Presented case demonstrates diagnostic and therapeutic dilemma of s-AML in a patient with complete remission of APL.Klonalne aberracje chromosomalne, prowadzące do powstawania zespołów mielodysplastycznych rozwijających się po leczeniu lub wtórnych ostrych białaczek szpikowych (s-AML), występują u około 10% chorych leczonych w przeszłości z powodu ostrej białaczki promielocytowej (APL). Większość z nich, a w szczególności monosomia chromosomu 7, wiąże się z wybitnie niekorzystnym rokowaniem. W pracy przedstawiono przypadek 22-letniej chorej na APL rozpoznaną w 2008 roku, w całkowitej remisji cytogenetycznej i molekularnej po terapii według protokołu PETHEMA, u której 2 lata po zakończeniu leczenia APL rozpoznano s-AML ze złożonym kariotypem monoso­malnym, z obecnością między innymi monosomii chromosomu 7 i translokacji t(3;21)(q26.2;q22). Po 2 cyklach leczenia indukującego uzyskano całkowitą remisję cytogenetyczną i zakwalifikowano chorą do allogenicznego przeszczepienia krwiotwórczych komórek macierzystych od zgodnego dawcy rodzinnego. Okres okołoprzeszczepowy był powikłany przewlekłą chorobą przeszczep przeciw gospo­darzowi w stopniu umiarkowanym. Obecnie, 15 miesięcy po transplantacji, chora nadal pozostaje w całkowitej remisji cytogenetycznej ze 100-procentowym chimeryzmem donorowym. Opisany przypadek ilustruje złożony problem diagnostyczny i terapeutyczny s-APL u chorej w remisji po leczeniu APL

The RNA-binding landscape of HAX1 protein indicates its involvement in translation and ribosome assembly

HAX1 is a human protein with no known homologues or structural domains. Mutations in the HAX1 gene cause severe congenital neutropenia through mechanisms that are poorly understood. Previous studies reported the RNA-binding capacity of HAX1, but the role of this binding in physiology and pathology remains unexplained. Here, we report the transcriptome-wide characterization of HAX1 RNA targets using RIP-seq and CRAC, indicating that HAX1 binds transcripts involved in translation, ribosome biogenesis, and rRNA processing. Using CRISPR knockouts, we find that HAX1 RNA targets partially overlap with transcripts downregulated in HAX1 KO, implying a role in mRNA stabilization. Gene ontology analysis demonstrated that genes differentially expressed in HAX1 KO (including genes involved in ribosome biogenesis and translation) are also enriched in a subset of genes whose expression correlates with HAX1 expression in four analyzed neoplasms. The functional connection to ribosome biogenesis was also demonstrated by gradient sedimentation ribosome profiles, which revealed differences in the small subunit:monosome ratio in HAX1 WT/KO. We speculate that changes in HAX1 expression may be important for the etiology of HAX1-linked diseases through dysregulation of translation

Home enteral nutrition in children—2010 nationwide survey of the polish society for clinical nutrition of children

Published epidemiologic data on the administration rates of enteral/parenteral home nutrition is very limited. The aim of this first nationwide study was to assess the availability of pediatric home enteral nutrition (HEN) services in Poland. The questionnaire was sent to all regional centers providing pediatric HEN services in Poland (n = 14). The analysis included the number of pediatric patients who received HEN in 2010, their demographic characteristics and geographical distribution. Furthermore, the distributions of indications and methods of enteral nutrition administration were analyzed, along with the reasons of withdrawal from the HEN program. The number and fraction of children receiving HEN increased in 2010, from 433 (11.34 per 1 million inhabitants) on January 1st to 525 (13.75) on December 31st. Marked differences were observed in geographical distribution of this parameter, from zero to up to 30 pediatric patients per 1 million inhabitants. Median age of patients was 6 years (range: 9 months–18 years). In most cases, HEN was prescribed due to neurological disorders (n = 337, 64.2%), and administered by means of gastrostomy (n = 450, 85.71%). This study revealed the dynamic development of pediatric HEN services in Poland but also documented their potential regional shortages

Road to clinical implementation of CAR-T technology in Poznań

The objective of this paper is to present the process of the national and international accreditation leading to the establishment of the first certified chimeric antigen receptor T (CAR-T) Cell Unit in Poland on the basis of the Department of Hematology and Bone Marrow Transplantation in Poznan University of Medical Sciences and first successful CAR-T therapy in Poland. During 12 months from the initial decision to establish the CAR-T Cell Unit to the application of CAR-T cell treatment in the first patient, the center had to undergo the multidisciplinary external and internal training, as well as the adaptation of multiple procedures within the Transplant Unit and Stem Cell Bank. In order to get accreditation for the implementation of CAR-T cell therapy, an initial training of the team involved in handling cellular products and patient care was organized and updated as a continuous process. The Department fulfilled the site-selection international criteria. The first patient diagnosed for refractory/relapsed DLBCL was qualified, and finally CAR-T cells were administered with successful clinical outcome

Polish statement on food allergy in children and adolescents

An adverse food reaction is defined as clinical symptoms occurring in children, adolescents or adults after ingestion of a food or chemical food additives. This reaction does not occur in healthy subjects. In certain individuals is a manifestation of the body hypersensitivity, i.e. qualitatively altered response to the consumed food. The disease symptoms observed after ingestion of the food can be triggered by two pathogenetic mechanisms; this allows adverse food reactions to be divided into allergic and non-allergic food hypersensitivity (food intolerance). Food allergy is defined as an abnormal immune response to ingested food (humoral, cellular or mixed). Non-immunological mechanisms (metabolic, pharmacological, microbiological or other) are responsible for clinical symptoms after food ingestion which occur in non-allergic hypersensitivity (food intolerance). Food allergy is considered a serious health problem in modern society. The prevalence of this disorder is varied and depends, among other factors, on the study population, its age, dietary habits, ethnic differences, and the degree of economic development of a given country. It is estimated that food allergy occurs most often among the youngest children (about 6-8% in infancy); the prevalence is lower among adolescents (approximately 3-4%) and adults (about 1-3%). The most common, age-dependent cause of hypersensitivity, expressed as sensitization or allergic disease (food allergy), are food allergens (trophoallergens). These are glycoproteins of animal or plant origine contained in: cow's milk, chicken egg, soybean, cereals, meat and fish, nuts, fruits, vegetables, molluscs, shellfish and other food products. Some of these allergens can cause cross-reactions, occurring as a result of concurrent hypersensitivity to food, inhaled or contact allergens. The development of an allergic process is a consequence of adverse health effects on the human body of different factors: genetic, environmental and supportive. In people predisposed (genetically) to atopy or allergy, the development of food allergy is determined by four allergic-immunological mechanisms, which were classified and described by Gell-Coombs. It is estimated that in approximately 48-50% of patients, allergic symptoms are caused only by type I reaction, the IgEmediated (immediate) mechanism. In the remaining patients, symptoms of food hypersensitivity are the result of other pathogenetic mechanisms, non-IgE mediated (delayed, late) or mixed (IgE mediated, non-IgE mediated). Clinical symptomatology of food allergy varies individually and depends on the type of food induced pathogenetic mechanism responsible for their occurrence. They relate to the organ or system in which the allergic reaction has occurred (the effector organ). Most commonly the symptoms involve many systems (gastrointestinal tract, skin, respiratory system, other organs), and approximately 10% of patients have isolated symptoms. The time of symptoms onset after eating the causative food is varied and determined by the pathogenetic mechanism of the allergic immune reaction (immediate, delayed or late symptoms). In the youngest patients, the main cause of food reactions is allergy to cow’s milk. In developmental age, the clinical picture of food allergy can change, as reflected in the so-called allergic march, which is the result of anatomical and functional maturation of the effector organs, affected by various harmful allergens (ingested, inhaled, contact allergens and allergic cross-reactions). The diagnosis of food allergy is a complex, long-term and time-consuming process, involving analysis of the allergic history (personal and in the family), a thorough evaluation of clinical signs, as well as correctly planned allergic and immune tests. The underlying cause of diagnostic difficulties in food allergy is the lack of a single universal laboratory test to identify both IgE-mediated and non-IgE mediated as well as mixed pathogenetic mechanisms of allergic reactions triggered by harmful food allergens. In food allergy diagnostics is only possible to identify an IgE-mediated allergic process (skin prick tests with food allergens, levels of specific IgE antibodies to food allergens). This allows one to confirm the diagnosis in patients whose symptoms are triggered in this pathogenetic mechanism (about 50% of patients). The method allowing one to conclude on the presence or absence of food hypersensitivity and its cause is a food challenge test (open, blinded, placebo-controlled). The occurrence of clinical symptoms after the administration of food allergen confirms the cause of food allergy (positive test) whereas the time elapsing between the triggering dose ingestion and the occurrence of clinical symptoms indicate the pathogenetic mechanisms of food allergy (immediate, delayed, late). The mainstay of causal treatment is temporary removal of harmful food from the patient’s diet, with the introduction of substitute ingredients with the nutritional value equivalent to the eliminated food. The duration of dietary treatment should be determined individually, and the measures of the effectiveness of the therapeutic elimination diet should include the absence or relief of allergic symptoms as well as normal physical and psychomotor development of the treated child. A variant alternative for dietary treatment of food allergy is specific induction of food tolerance by intended contact of the patient with the native or thermally processed harmful allergen (oral immunotherapy). This method has been used in the treatment of IgE-mediated allergy (to cow's milk protein, egg protein, peanut allergens). The obtained effect of tolerance is usually temporary. In order to avoid unnecessary prolongation of treatment in a child treated with an elimination diet, it is recommended to perform a food challenge test at least once a year. This test allows one to assess the body's current ability to acquire immune or clinical tolerance. A negative result of the test makes it possible to return to a normal diet, whereas a positive test is an indication for continued dietary treatment (persistent food allergy). Approximately 80% of children diagnosed with food allergy in infancy "grow out" of the disease before the age of 4-5 years. In children with non-IgE mediated food allergy the acquisition of food tolerance is faster and occurs in a higher percentage of treated patients compared to children with IgE-mediated food allergy. Pharmacological treatment is a necessary adjunct to dietary treatment in food allergy. It is used to control the rapidly increasing allergic symptoms (temporarily) or to achieve remission and to prevent relapses (long-term treatment). Preventive measures (primary prevention of allergies) are recommended for children born in a "high risk" group for the disease. These are comprehensive measures aimed at preventing sensitization of the body (an appropriate way of feeding the child, avoiding exposure to some allergens and adverse environmental factors). First of all, the infants should be breast-fed during the first 4-6 months of life, and solid foods (non milk products, including those containing gluten) should be introduced no earlier than 4 months of age, but no later than 6 months of age. An elimination diet is not recommended for pregnant women (prevention of intrauterine sensitization of the fetus and unborn child). The merits of introducing an elimination diet in mothers of exclusively breast-fed infants, when the child responds with allergic symptoms to the specific diet of the mother, are disputable. Secondary prevention focuses on preventing the recurrence of already diagnosed allergic disease; tertiary prevention is the fight against organ disability resulting from the chronicity and recurrences of an allergic disease process. Food allergy can adversely affect the physical development and the psycho-emotional condition of a sick child, and significantly interfere with his social contacts with peers. A long-term disease process, recurrence of clinical symptoms, and difficult course of elimination diet therapy are factors that impair the quality of life of a sick child and his family. The economic costs generated by food allergies affect both the patient's family budget (in the household), and the overall financial resources allocated to health care (at the state level). The adverse socio-economic effects of food allergy can be reduced by educational activities in the patient’s environment and dissemination of knowledge about the disease in the society