Prevalence and prognosis of PIK3CA mutations in Bulgarian patients with metastatic breast cancer receiving endocrine therapy in first-line setting.

BACKGROUND AND AIMS: In approximately 40% of patients with HER2-negative/HR-positive breast cancer tumors, the PIK3CA gene is mutated. Despite this, clinical outcomes vary between studies in this cohort. We aimed to ascertain the prevalence of PIK3CA mutations in patients with metastatic HR+/HER2- breast in Bulgaria, as well the evaluation and comparison of progression free survival (PFS) between wild-type (WT) and mutation-positive groups in the real-world setting. METHODS: Three oncology centers in Bulgaria collected 250 tissue samples between 2016 and 2022 for this multicentric retrospective study. PIK3CA mutations were identified using Real-Time qPCR. The median follow-up period was 35 months. RESULTS: The mean age of the mutant cohort was 57.6 ± 11.6 years, compared to 56.5 ± 12.2 years for the WT cohort (p = .52). The percentage of patients with visceral metastasis was 58.8% (n = 147). Approximately 84.3% (n = 210) of the patients had reached postmenopause. 29.2% (n = 73) of the patients had PIK3CA mutations. The predominant mutation was present in exon 20, H1047R (46.5%). We found a significant correlation only between the presence of a mutation and the metastatic diseases at diagnosis (p = .002). As first-line therapy, 67.1% of patients received endocrine therapy (ET) plus cyclin dependent kinase (CDK4/6) inhibitor, while the remainder received ET alone. The median PFS of patients in the group with the mutation was 32 months (95%, CI: 22-40) compared to 24 months in the WT cohort ((95%, CI: 21-36) (p = .45)); HR = 0.86 (95%, CI: 0.5-1.3) (p = .46). We corroborated our conclusion using propensity matching score analysis, (36 months [95% CI: 20-40] vs. 26 months [95% CI: 21-38], [p = .69]). CONCLUSIONS: We found that the prevalence of PIK3CA mutations in our patients was comparable to what has been reported in other nations. Our results suggest that PIK3CA mutational status has no bearing to ET efficacy in first-line setting.

A computational framework for finding parameter sets associated with chaotic dynamics.

Many biological ecosystems exhibit chaotic behavior, demonstrated either analytically using parameter choices in an associated dynamical systems model or empirically through analysis of experimental data. In this paper, we use existing software tools (COPASI, R) to explore dynamical systems and uncover regions with positive Lyapunov exponents where thus chaos exists. We evaluate the ability of the software's optimization algorithms to find these positive values with several dynamical systems used to model biological populations. The algorithms have been able to identify parameter sets which lead to positive Lyapunov exponents, even when those exponents lie in regions with small support. For one of the examined systems, we observed that positive Lyapunov exponents were not uncovered when executing a search over the parameter space with small spacings between values of the independent variables.

Sarcopenia and high NLR are associated with the development of hyperprogressive disease after second-line pembrolizumab in patients with non-small-cell lung cancer.

The aim of this multi-center retrospective study was to evaluate the incidence of hyperprogressive disease (HPD) after second-line treatment with pembrolizumab in patients (n = 167) with metastatic non-small-cell lung cancer (NSCLC) whose tumors expressed programmed cell death ligand 1 (PD-L1) in ≥ 1% and to search for hematological and imaging biomarkers associated with its development. Prior to chemotherapy, neutrophil : lymphocyte ratio (NLR1) and platelet : lymphocyte ratio (PLR1), and prior to immunotherapy, NLR2 and PLR2 were retrospectively analyzed. The psoas major muscle area (PMMA) was calculated at the L3 position on computed tomography before chemotherapy (PMMA1) and before immunotherapy (PMMA2) (n = 112). Patients with ∆PMMA (1-PMMA2/PMMA1) × 100 ≥ 10% were considered to have sarcopenia (low muscle mass). After treatment with pembrolizumab on the first computerized tomography (CT) scan evaluation, patients were subdivided as follows as: hyperprogressors (HPs), progressors (Ps), non-progressors (NPs) and pseudoprogressors (PPs). HPs had significantly higher ∆PMMA levels, NLR2 and PLR2 than the other patients. Moreover, in multinomial logistic regression analysis, higher levels of ∆PMMA were associated with a decreased likelihood of being a P [odds ratio (OR) = 0·81; 95% confidence interval (CI) = 0·65-0·99; P = 0·047] or an NP (OR = 0·76; 95% CI = 0·62-0·94; P = 0·012) versus an HP. Higher NLRs tended to decrease the likelihood of being a P versus an HP (OR = 0·66; 95% CI = 0·42-1·06; P = 0·09) and significantly decreased the likelihood of being an NP versus an HP (OR = 0·44; 95% CI = 0·28-0·69; P < 0·0001). Our data suggest that a high pre-immunotherapy NLR2 and the presence of sarcopenia are potential risk factors for the development of HPD.

PlantSimLab - a modeling and simulation web tool for plant biologists.

BACKGROUND: At the molecular level, nonlinear networks of heterogeneous molecules control many biological processes, so that systems biology provides a valuable approach in this field, building on the integration of experimental biology with mathematical modeling. One of the biggest challenges to making this integration a reality is that many life scientists do not possess the mathematical expertise needed to build and manipulate mathematical models well enough to use them as tools for hypothesis generation. Available modeling software packages often assume some modeling expertise. There is a need for software tools that are easy to use and intuitive for experimentalists. RESULTS: This paper introduces PlantSimLab, a web-based application developed to allow plant biologists to construct dynamic mathematical models of molecular networks, interrogate them in a manner similar to what is done in the laboratory, and use them as a tool for biological hypothesis generation. It is designed to be used by experimentalists, without direct assistance from mathematical modelers. CONCLUSIONS: Mathematical modeling techniques are a useful tool for analyzing complex biological systems, and there is a need for accessible, efficient analysis tools within the biological community. PlantSimLab enables users to build, validate, and use intuitive qualitative dynamic computer models, with a graphical user interface that does not require mathematical modeling expertise. It makes analysis of complex models accessible to a larger community, as it is platform-independent and does not require extensive mathematical expertise.

Infrarenal abdominal aortic dissection with aberrant renal arteries and lead-ing symptom right leg ischemia: case report.

INTRODUCTION: Isolated infrarenal abdominal aortic dissection is a rare clinical entity. Most cases are treated by endovascular techniques, and open surgery is seldom necessary. CASE DESCRIPTION: We present a rare case of spontaneous symptomatic infrarenal aortic dissection with leading symptom right leg ischemia. We opted for abdominal surgery as the attempt for open surgical fenestration of the dissecting flap exit through right femoral access was unsuccessful. Dacron vascular prosthesis was implanted with aortoiliofemoral bypass on the right side. One of the two accessory right renal arteries was ligated, which led to a confined zone of renal ischemia. Upon follow-up, complete restoration of the renal parenchyma was observed; kidney function remained unaffected. CONCLUSION: By infrarenal abdominal aortic dissection with accessory renal arteries, abdominal surgery with selective clamping is a reliable therapeutic approach allowing maximal preservation of renal blood flow. HIPPOKRATIA 2019, 23(4): 186-189.

Effects of radial extracorporeal shock wave therapy on hand spasticity in poststroke patient.

BACKGROUND: Hand spasticity after a stroke greatly increases the difficulties of the daily living activities and limits the effectiveness of rehabilitation. Radial extracorporeal shock wave therapy (RESWT) has been suggested as an alternative treatment for spasticity reduction. We demonstrate the effectiveness of RESWT regarding hand spasticity in a stroke patient. CASE DESCRIPTION: We describe the case of a 42-year-old woman with right hemiparesis after ischaemic stroke. Her right arm was plegic with increased spasticity. The patient received a total of six RESWT treatments. Clinical evaluation was performed using the Modified Ashworth Scale, passive dorsal flexion of the wrist and the Disability Assessment Scale (DAS). The measurements were made before initiation, immediately after the sixth treatment, one and three months after the RESWT. Immediately after the RESWT there was a reduction of the spasticity of the hand and fingers and increased passive range of motion of the affected wrist, as well as decreased DAS score. These effects lasted for four weeks. With time, the therapeutic effect regarding spasticity decreased, but three months following termination of treatment there was a better clinical result than before initiation of treatment. CONCLUSION: RESWT is a safe alternative treatment for hand and fingers spasticity reduction after stroke.  Hippokratia 2016, 20(4): 309-312.

Rehabilitation procedures in the management of gait disorders in the elderly.

Gait disorders are common and very disabling in elderly people, leading to an increase of risk of falling and reductions in quality of life. So far, many clinical classifications of gait disorders in the elderly population have been proposed. Here we suggest a novel categorization of gait disorders in elderly people, which takes into account the several resources required during gait. The biomechanical constraints, movement and sensory strategies, orientation in space, control of dynamics and cognitive processing are essential to perform safely gait. Moreover, the strictly connection between gait and balance has been discussed. According to this perspective, a literature search was performed including studies investigating the rehabilitation procedures in the management of balance and gait disorders in elderly people. Training aimed at improving muscle strength and flexibility, movement strategies, sensorimotor integration and sensory reweighting processes, balance in static and dynamic conditions and cognitive strategies have been proposed as possible therapeutic approaches in elderly people affected by gait disorders. Moreover, the role of new technological devices in improving balance and gait control has been also described. A multidisciplinary and interdisciplinary approach is fundamental for the management of gait disorders in elderly people. Rehabilitation procedures should take into consideration all the potential constraints involved in gait disorders in order to select the most appropriate intervention.

[A clinical case of twin pregnancy with intrauterine death of one of the twin (foetus papiraceus)].

Multiple pregnancy is associated with some specific syndromes: twin to twin transfusion syndrome, syndrome of the disappeared twin, intrauterine loss of one of the twin, development of foetus papiraceus and syndrome of asymmetric growth of the twin. We present a case of term pregnancy with death of one of the twin and normal delivery of healthy baby and Foetus papiraceus.

[Using phlebodia in pregnant women during preterm delivery].

Phlebodia possess complex mechanism of action; except the venotonic one, it blocks the production of mediators of inflammation-prostaglandins and leukotriens; thus stops the uterine contractions and the preterm delivery. We use the tablet at pregnant women for preterm delivery. It was given one tablet a day /600 mg/ along with the tocolytic therapy.

[A case of Guillain-Barre syndrome in puerperium].

Guillain-Barre Syndrome is an acquired neurologic disease associated with demyelinisation of the peripheral nerves. It affected 6-24/100,000 population during pregnancy; the frequency is increased after delivery in puerperium. We present a case of Syndrome of Guillain-Barre in puerperium. We discuss the clinical presentation of the disease during pregnancy and in puerperium, diagnosis and treatment.

Building waste management in Bulgaria: challenges and opportunities.

Building waste recycling as aggregates is a modern approach for preventing environmental pollution through both reducing the stocks of waste and decreasing the use of natural aggregates. The reuse of building waste is a relatively new issue for Bulgaria despite the existing considerable quantity of building waste and the significant changes in the environmental rules applied. The paper discusses generated and potential waste streams in Bulgaria in the context of the social and economic restructuring and recent urban development undergone by the country. The main preliminary conditions for developing the recycling activity such as: streams of building waste, experience in recycling, technical and environmental standardization, appropriate technologies, etc. are examined. The authors analyze current practice and research activities with regard to the implementation of advanced EU building-waste recycling methods. Conclusions are drawn about existing opportunities and the priorities of the needed building waste management strategy in the country.

[Peritoneal cyst--a case report]. / Peritonealna kista--s prionos na edin sluchai.

Peritoneal cysts are rare benign tumors of the abdominal and pelvic peritoneum. We present a case of 26 year old patient with a peritoneal cyst treated operatively.

[Drug treatment of tubal pregnancy with methotrexate, with an analysis of 5 cases]. / Medikamentozno lechenie s methotrexate na tubarna bremennost s analiz na 5 sluchaia.

The authors present 5 cases of ectopic pregnancy, treated successfully with Methotrexate. Followed are the levels of beta-fraction of human chorionic gonadotropin. Later on, in two of the patients developed intrauterine pregnancy, which terminated successfully with the delivery of healthy term infants.

Development of model aqueous ophthalmic solution of indomethacin.

A new model aqueous solution of indomethacin was developed on the basis of Pluronic F68 (15%) and F127 (10%). They showed some practical advantages over the models prepared with polyols and polysorbate 80, which were used for comparison. It was found that both Pluronics acted very similarly and were more effective as solubilizers, created an appropriate viscosity, and formed reversible gels at higher temperatures, ensured the indomethacin chemical stability and prolonged in vitro drug diffusion, and showed high physiological tolerance on rabbit eyes. Moreover, indomethacin stability and solution viscosity in the presence of Pluronics did not change after heat sterilization (i.e., the samples can bear heat sterilization).

Levels of expression of CAF7 (CD98) have prognostic significance in adult acute leukemia.

The levels of CD98 antigen expression were studied in 62 consecutive cases of adult acute leukemia including 24 acute lymphoblastic leukemia (ALL) and 38 acute myeloid leukemia (AML) using the monoclonal antibody CAF7 and flow cytometry. The mean follow-up was 13.5 months. The mean relative fluorescence intensity (MIF) of CAF7 varied between 6 and 83 channels (256 channels resolution). No correlation was established between CAF7 cell surface density and most of the predictive parameters such as age, sex, blood counts, immunophenotype, proliferative index (PI) or DNA index. Nevertheless expression of CAF7 correlated positively with survival duration (mean 210 vs 391 days, P = 0.048) and complete remission (CR) duration (mean 132 vs 361, days P = 0.032). The levels of CAF7 differed significantly between ALL and AML (P < 0.001), the ALL cases being all CAF7intermediate or CAF7high. In the AML group the low levels of CAF7 expression correlated with shorter CR duration (mean 132 vs 414 days, P = 0.017). The lack of correlation with other clinical and biological parameters suggested that CAF7 might have an independent prognostic significance in adult AML. Although PI was also positively related to survival duration (P = 0.02), it did not correlate with CR duration or the expression of CAF7. We suppose that the prognostic impact of CD98 is related to the control of cell growth and survival in which the molecule normally participates.

Humoral and cellular immune response to elastin in patients with systemic sclerosis.

The humoral immune response against elastin and collagen was studied in parallel with the delayed type hypersensitivity (DTH) reaction to elastin and the percentage of lymphocyte subpopulations in peripheral blood in 20 patients with systemic sclerosis (SSc). An increase of anti-elastin antibodies of all subclasses was found with a significant prevalence of IgE and IgA antibodies. The profile of anti-collagen type I and type IV antibodies showed an increase of IgE isotypes. In 25% of the patients (5 out of 20) positive DTH reactions to elastin were observed as compared to the negative skin reactions in all control individuals. At the same time a significant hyporeactivity to common bacterial and mould antigens was found in 40% of the patients (versus 16% in the control group) which could be an explanation for the low incidence of positive anti-elastin DTH reaction. The DTH hyporeactivity in SSc cases was in contrast with the increased percentage of CD4 T cells (58.4 vs. 42.0) and increased CD4/CD8 ratio (2.5 vs. 1.5) in the peripheral blood of the patients. This finding together with the increased IgE antibodies to elastin and collagen type I and type IV might suggest a possible shift of the immune balance towards the Th2 type of immune response. This is in line with the increased CD8+CD57+ cells which correlated with the highest number of other parameters studied - disease duration, total skin score, IgE anti-elastin antibodies, IgG anti-collagen type I antibodies, CD4/CD8 ratio and CD19 B cells. The results of this study demonstrated the existence of both humoral and cell-mediated immune response against elastin in SSc patients. However, we could not define whether this was an essential part of pathogenetic mechanisms or a secondary phenomenon reflecting the extent of the damage of connective tissue.

A novel approach to the generation of antibodies against phylogenetically preserved sperm antigens.

Conventional methods for immunization of laboratory animals against human spermatozoa proved not to be efficient enough to identify phylogenetically conserved sperm-specific antigens. A combination of vasectomy and subcutaneous administration of autologous testis homogenates was tested in 5 New-Zealand rabbits, and in 7 Long-Evans and 8 Spraque-Dawley rats in an attempt to induce an autoimmune response against such antigens. This experimental procedure resulted in a generation of sperm autoantibodies cross-reactive with human, rabbit and rat spermatozoa, as demonstrated by sperm-agglutination, ELISA and flow cytometry (FCM). No specific binding to human seminal plasma was detected by ELISA, indicating that intrinsic sperm membrane antigens rather than sperm-coating antigens were involved in establishing cross-reactivity with human spermatozoa. This suggestion was confirmed by the finding that rabbit autoantisera reacted more strongly against epididymal than against ejaculated human spermatozoa as shown by FCM. Humoral antispermatozoal response correlated well with impaired spermatogenesis in rabbits. The autoimmunized rats revealed severe alterations in reproductive tissues, including testicular and epididymal sperm granulomas; however, they showed a lower incidence of circulating antibodies. The results indicate that the established experimental model in rabbits can be further used to identify and characterize evolutionary preserved intrinsic sperm membrane autoantigens, which are desirable candidates for contraceptive vaccine development.

Immunological subtypes of childhood acute lymphoblastic leukemia in Bulgaria.

With regards to the geographical variation in acute lymphoblastic leukemia (ALL) distribution, we present data from the immunophenotyping of 171 newly diagnosed cases of childhood ALL in Bulgaria during a 4 year period (1990-1994). On the basis of 17 phenotypic markers the distribution of immunological subtypes was as follows: AUL 4%; Pro-B ALL 13%; common ALL 42%; Pre-B ALL 11%; B-ALL 1%; T-ALL 28% and unclassified 2%. Most of the cases were between 2 and 5 years of age. Common ALL was predominant (53%) in this age group. The male:female ratio was 1.7:1. The frequency of T-ALL (28%) was significantly higher (P < 0.01; t = 3.49) in comparison to that reported for the U.S.A. and West European countries (mean 13%). It was close to the frequency reported by some authors for France (20%), Greece (26%) and south Italy (28.1%). These countries and Bulgaria might form an environmental area with a moderate frequency of T-ALL.