Abstract
Trastuzumab has improved the prognosis of HER2 positive breast cancer, but cardiotoxicity remains a concern. We aimed to identify risk factors for trastuzumab-induced cardiotoxicity, with an ...emphasis on the HER2 Ile655Val single nucleotide polymorphism. This single-center case–control study included 1056 patients with early-stage HER2 positive breast cancer that received adjuvant trastuzumab. Cardiotoxicity was defined as a decline in left ventricular ejection fraction (LVEF) > 15% in patients without previous cardiomyopathy, or > 10% in patients with baseline LVEF of < 50%. Patient characteristics and cardiac parameters were compared in 78 (7.38%) cases and 99 randomly assigned controls, and the polymorphism was genotyped using real-time polymerase chain reaction. Cardiotoxicity was independently associated with advanced age (
P
= 0.024), lower body mass index (
P
= 0.023), left breast involvement (
P
= 0.001), N3 status (
P
= 0.004), diabetes (
P
= 0.016), and a family history of coronary artery disease (
P
= 0.019). Genotype distribution was as follows: A/A (Ile/Ile) was found in 111 (62.7%) patients, A/G (Ile/Val) in 60 (33.9%) patients, and G/G (Val/Val) in 6 (3.4%) patients. The genotype was not associated with cardiotoxicity or the severity of heart failure, reversibility, and recovery time. We found no association between the HER2 Ile655Val polymorphism and trastuzumab-induced cardiotoxicity; therefore, we do not recommend routine cardiotoxicity-risk stratification using this polymorphism.
Knowledge about the patient's experience and perception of side effects and their impact on daily life is crucial for the adequate planning of interventions to provide the highest attainable levels ...of quality of life during oncology treatment. We conducted a study on consecutive samples of 69 early breast cancer patients treated with four cycles of neoadjuvant or adjuvant anthracycline-based chemotherapy. Patients completed the questionnaire about side effects experienced after the previous cycle of chemotherapy. The questionnaire was a modified PRO for the evaluation of treatment toxicity consisting of 18 questions related to the very common and common side effects of doxorubicin and cyclophosphamide, valued from 0 to 3 according to the subjective assessment of the patient. During the same cycles of therapy, data were also collected by the physician who completed a questionnaire consisting of the same questions as the questionnaire for patients, on the same scale. Most of the side effects reported by patients were mild to moderate in intensity, while physicians reported side effects much less frequently. The results also indicated a disproportionate reporting, in which physicians reported statistically significantly fewer side effects than patients. This study reported a level of disagreement between patients and physicians in the experience of therapy toxicity. In conclusion, use of PRO in clinical practice can help us avoid physician subjectiveness in the estimation of side effects and determine the group of patients who can benefit from additional and individualized supportive care measures, which could lead to better adherence to therapy and ultimately best outcomes.
Body composition has been studied relatively recently as part of oncology trials in different types of tumors. There are numerous studies that define the impact of chemotherapy side effects on the ...quality of life (QoL) of breast cancer patients, however, there are few studies that analyze the impact of body composition on the QoL of premenopausal patients in the course of cytotoxic treatment. The study was performed on a sample of premenopausal patients treated with neoadjuvant or adjuvant AC chemotherapy for early-stage breast cancer at Day Hospital of the Department of Medical Oncology, University Hospital for Tumors in Zagreb. The study included 68 patients, median age 46.6 years. Analysis of the QoL questionnaires and their association with body composition indicated several interesting results. At the beginning of treatment, most pronounced was the connection between body composition and physical and sexual functioning and hair loss, while in subsequent treatment cycles the effect on other QoL subdomains, in particular fatigue and diarrhea, was more pronounced. In conclusion, we found body composition to have a significant impact on certain QoL subdomains during treatment.
Body composition changes could indicate health conditions and potential health risks. Although several methods are currently available for quantitative assessment, each has limitations. Indirect ...methods are most frequently used because of their availability and simplicity. One of those methods, which found wide use in clinical trials and everyday clinical practice and was found to be of great value in oncology patients, is bioelectrical impedance (BIA). Assessed muscle volume and mass, measured by BIA, were associated with chemotherapy toxicity and overall prognosis, regardless of the primary tumor site. It has been shown that calculated phase angle could be a strong prognostic factor for a particular endpoint and an independent prognostic factor in patients with advanced malignancies. Body composition was also found to correlate with the quality of life (QoL) of patients with cancer, and several studies have shown a significant impact on various QoL subdomains. Measuring body composition and the information it provides could be used for the development of different clinical interventions that can help cancer patients live longer and better lives.
Highly disordered protein regions are prevalently hydrophilic, extremely sensitive to proteolysis in vitro, and are expected to be under-represented as T-cell epitopes. The aim of this research was ...to find out whether disorder and hydropathy prediction methods could help in understanding epitope processing and presentation. According to the pan-specific T-cell epitope predictors NetMHCpan and NetMHCIIpan and 9 publicly available disorder predictors, frequency of epitopes presented by human leukocyte antigens (HLA) class-I or -II was found to be more than 2.5 times higher in ordered than in disordered protein regions (depending on the disorder predictor). Both HLA class-I and HLA class-II binding epitopes are prevalently hydrophilic in disordered and prevalently hydrophobic in ordered protein regions, whereas epitopes recognized by HLA class-II alleles are more hydrophobic than those recognized by HLA class-I. As regards both classes of HLA molecules, high-affinity binding epitopes display more hydrophobicity than low affinity-binding epitopes (in both ordered and disordered regions). Epitopes belonging to disordered protein regions were not predicted to have poor affinity to HLA class-II molecules, as expected from disorder intrinsic proteolytic instability. The relation of epitope hydrophobicity and order/disorder location was also valid if alleles were grouped according to the HLA class-I and HLA class-II supertypes, except for the class-I supertype A3 in which the main part of recognized epitopes was prevalently hydrophilic. Regarding specific supertypes, the affinity of epitopes belonging to ordered regions varies only slightly (depending on the disorder predictor) compared to the affinity of epitopes in corresponding disordered regions. The distribution of epitopes in ordered and disordered protein regions has revealed that the curves of order–epitope distribution were convex-like while the curves of disorder–epitope distribution were concave-like. The percentage of prevalently hydrophobic epitopes increases with the enhancement of epitope promiscuity level and moving from disordered to ordered regions. These data suggests that reverse vaccinology, oriented towards promiscuous and high-affinity epitopes, is also oriented towards prevalently hydrophobic, ordered regions. The analysis of predicted and experimentally evaluated epitopes of cancer–testis antigen MAGE-A3 has confirmed that the majority of T-cell epitopes, particularly those that are promiscuous or naturally processed, was located in ordered and disorder/order boundary protein regions overlapping hydrophobic regions.
Display omitted
Triple-negative breast cancer (TNBC) occurs in around one-sixth of all breast cancer (BC) patients, with the most aggressive behavior and worst prognosis of all BC subtypes. It is a heterogeneous ...disease, with specific molecular characteristics and natural dynamics of early recurrence and fast progression. Due to the lack of biomarkers or any valid treatment targets, it can only be treated with classic cytotoxic chemotherapy. We analyzed a cohort of 152 patients, median age 58 years, diagnosed with and treated for early stage TNBC at the university Hospital for Tumors, Sestre milosrdnice university Hospital Centre, Zagreb, Croatia, during the 2009-2012 period. Patients were treated with primary surgical approach, adjuvant chemotherapy and adjuvant irradiation. We observed a relatively large proportion of locally advanced TNBC at diagnosis, with large tumor size and nodal involvement, with high grade and high proliferation index Ki67. Patient age, tumor size and lymph node involvement, as expected, were significant and clinically most important prognostic factors for 5-year disease-free survival (67%; 95% CI 60%-75%) and overall absolute survival rate (74%; 95% CI 66%-81%). Key words: Triple negative breast cancer; Early disease; Adjuvant treatment; Tumor size; Lymph node; Disease free survival; Overall survival; Prognostic factor
The antiproliferative activity of previously synthesized (
Z)-cholest-4-en-6-one oxime (
1), (
E)-cholest-4-en-6-one oxime (
2), 7-aza-B-homocholest-4-en-6-one (
3) and 6-aza-B-homocholest-4-en-7-one ...(
4) and newly synthesized 6-thioxo-7-aza-B-homocholest-4-ene (
5) and 6-aza-7-thioxo-B-homocholest-4-ene (
6) was tested for their possible effects against two human tumor cell lines, cervical carcinoma (HeLa) and chronic myelogenous leukemia (K-562). Compounds
1–
6, exerted a dose-dependent antiproliferative effect toward cell lines used in experimental design, showing high selectivity in their action for tumor cells in comparison to normal immunocompetent cells (non-stimulated PBMC and PHA-stimulated PBMC). Compounds
2,
3 and
4 exhibited a very high but selective antitumor activity, by inducing apoptosis in sensitive, for that purpose targeted tumor cell line (HeLa cells). Low toxic effect upon both non-stimulated, and PHA stimulated PBMCs from control, healthy volunteers, has been detected for compounds
1,
2,
3 and
4. The possible reasons for profound differences in the effects of this spectrum of steroidal compounds between tumor cell lines and normal stimulated and non-stimulated PBMCs are discussed. The molecular mechanisms for apoptotic events in HeLa cell line are suggested. The guidelines for further research are underlined.
Circulating tumor cells (CTCs) are a major contributor of cancer metastases and hold a promising prognostic significance in cancer detection. Performing functional and molecular characterization of ...CTCs provides an in-depth knowledge about this lethal disease. Researchers are making efforts to design devices and develop assays for enumeration of CTCs with a high capture and detection efficiency from whole blood of cancer patients. The existing and on-going research on CTC isolation methods has revealed cell characteristics which are helpful in cancer monitoring and designing of targeted cancer treatments. In this review paper, a brief summary of existing CTC isolation methods is presented. We also discuss methods of detaching CTC from functionalized surfaces (functional assays/devices) and their further use for ex-vivo culturing that aid in studies regarding molecular properties that encourage metastatic seeding. In the clinical applications section, we discuss a number of cases that CTCs can play a key role for monitoring metastases, drug treatment response, and heterogeneity profiling regarding biomarkers and gene expression studies that bring treatment design further towards personalized medicine.
Tumor stimulates specific innate and acquired immune mechanisms. Main carriers of body’s immune response to tumor are T lymphocytes and main mechanism is killing of tumor cells by cytotoxic T ...lymphocytes CD8 +. In some cases, immune system can also have a protumor role, which is a paradox, given that it is known that the inflammatory state promotes tumor growth. One of the major characteristics of tumors is the evading of immune response, in particular by mechanisms of inhibition of active antitumor immune response via two major physiological inhibitory signals, CTLA-4 and PD1 / PDL1. Blockade of these checkpoints, that are T cell inhibitory mechanisms, has recently yielded best results in an immunotherapy approach to cancer treatment. Immune infiltrate in the tumor, as evidence of existence of an active intrinsic response of the organism, is heterogeneous, and composition often differs between different tumors and tumor cells, and mainly divides into two main cell lines: lymphoid and myeloid. On type of cell lines in the immune infiltrate and their activation and orientation depends the clinical response in different tumors. It is well known that immune infiltrate, especially tumorinfiltrating lymphocytes (TILs), can be predictive of response to therapy and have a prognostic role. In some solid tumors they are a good sign, while in some they signal worse prognosis. Numerous studies have evaluated role of lymphocytic infiltrate in breast cancer (BC) and, based on this knowledge, first consensus on standardization of TILs evaluation in solid tumors has been established on the BC model. Prognostic role of TILs in triple-negative breast cancer has received the most attention.
In the first part of this paper we generalize results on common fixed points in ordered cone metric spaces obtained by I. Altun and G. Durmaz I. Altun, G. Durmaz, Some fixed point theorems on ordered ...cone metric spaces, Rend. Circ. Mat. Palermo, 58 (2009) 319–325 and I. Altun, B. Damnjanović and D. Djorić I. Altun, B. Damnjanović, D. Djorić, Fixed point and common fixed point theorems on ordered cone metric spaces, Appl. Math. Lett. (2009)
doi:10.1016/j.aml.2009.09.016 by weakening the respective contractive condition. Then, the notions of quasicontraction and
g
-quasicontraction are introduced in the setting of ordered cone metric spaces and respective (common) fixed point theorems are proved. In such a way, known results on quasicontractions and
g
-quasicontractions in metric spaces and cone metric spaces are extended to the setting of ordered cone metric spaces. Examples show that there are cases when new results can be applied, while old ones cannot.
PDF
