Background: Association between rectal or colon cancer risk and serine hydroxymethyltransferase 1 (SHMT1) C1420T or methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms was assessed. The serum total homocysteine (HCY), marker... more
Background: Association between rectal or colon cancer risk and serine hydroxymethyltransferase 1 (SHMT1) C1420T or methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms was assessed. The serum total homocysteine (HCY), marker of folate metabolism was also investigated. Methods: The SHMT1 and MTHFR genotypes were determined by real-time PCR and PCR-RFLP, respectively in 476 patients with rectal, 479 patients with colon cancer and in 461 and 478, respective controls matched for age and sex. Homocysteine levels were determined by HPLC kit. The association between polymorphisms and cancer risk was evaluated by logistic regression analysis adjusted for age, sex and body mass index. The population stratification bias was also estimated. Results: There was no association of genotypes or diplotypes with colon cancer. The rectal cancer risk was significantly lower for SHMT1 TT (OR = 0.57, 95 % confidence interval (CI) 0.36-0.89) and higher for MTHFR CT genotypes (OR = 1.4, 95%CI 1...
In recent years some serologic parameters emerged as potential prognostic factors. The neutrophil-to-lymphocyte ratio (NLR) has the most evidence; however, other serologic factors were also reported. The only established systemic... more
In recent years some serologic parameters emerged as potential prognostic factors. The neutrophil-to-lymphocyte ratio (NLR) has the most evidence; however, other serologic factors were also reported. The only established systemic treatment in triple-negative breast cancer (TNBC) is chemotherapy which is preoperatively applied more widely. For these patients few data are available on which serologic markers would be the best predictor for disease-free (DFS) and overall survival (OS). Data of 137 TNBC patients treated (2005-2016) with neoadjuvant chemotherapy at our center were analyzed. Beyond pathological factors, white blood cell (WBC), neutrophil (NE), lymphocyte (LY) and platelet (PL) counts, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII) were investigated. In univariate analysis, most parameters (NE1, LY1, NLR1, PLR1, SII1) measured at baseline and before the third cycle (NE3, LY3, etc.) of chemotherapy showed s...
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This prospective study compares the characteristics of cystic disease of the breast (CDB) of patients who developed breast cancer (BCa) during the follow-up (1.25-4 years) period with those who did not. K+, Na+, albumin,... more
This prospective study compares the characteristics of cystic disease of the breast (CDB) of patients who developed breast cancer (BCa) during the follow-up (1.25-4 years) period with those who did not. K+, Na+, albumin, dehydroepiandrosterone (DHA), DHA-sulphate, oestrone, oestradiol, testosterone and progesterone levels were determined in breast cyst fluid (BCF). Patients presented data about their menstrual status, reproductive history, lactation period, date of first and the number of BCF aspirations, gynaecological interventions, use of oral contraceptives, family history of cancer, smoking habits and coffee consumption. The BCa incidence of patients was compared with the expected number of BCas in an age-matched group of 5143 women. Out of 147 patients 6 developed BCa. The standardized incidence rate was 6.29. There were significant differences in testosterone, oestrone and progesterone levels and also reproductive history of patients who developed BCa compared with patients w...
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In this study we have tried to find new prognostic markers to extend the therapeutical modalities for patients with head and neck squamous cell carcinoma. During evolution the development of the pharyngolaryngeal region differs in males... more
In this study we have tried to find new prognostic markers to extend the therapeutical modalities for patients with head and neck squamous cell carcinoma. During evolution the development of the pharyngolaryngeal region differs in males and females, therefore this region can be considered as one of the target organs for sex steroids. Some of the tumours, originating from this area, contain hormone receptors that theoretically makes them susceptible for hormone therapy. Therefore the real concentration of steroid receptors is of great clinical importance. We determined the estradiol, progesterone and testosterone receptor content using biochemical method in tumour tissue of 33 male patients with head and neck squamous cell carcinoma. The receptors in the macroscopically intact mucosa in 15 of all tumour cases were also measured. The patients were followed for 18-24 month after operation and postoperative irradiation performed according to the protocol of the Head and Neck Surgery dep...
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Research Interests: Chemistry, Fluorescence, Synchrotron Radiation, Sample Preparation, Cell line, and 15 moreElectron Transfer, Physical sciences, Iron, Mitochondrial Respiratory Chain, Ferritin, CHEMICAL SCIENCES, XANES, Spectrum, Cancer Cell, X Ray, Total Reflection X-ray Fluorescence, X ray Fluorescence, TXRF, Cell Growth, and Elemental composition
: In this study we have tried to find new prognostic markers to extend the therapeutical modalities for patients with head and neck squamous cell carcinoma. During evolution the development of the pharyngolaryngeal region differs in males... more
: In this study we have tried to find new prognostic markers to extend the therapeutical modalities for patients with head and neck squamous cell carcinoma. During evolution the development of the pharyngolaryngeal region differs in males and females, therefore this region can be considered as one of the target organs for sex steroids. Some of the tumours, originating from this area, contain hormone receptors that theoretically makes them susceptible for hormone therapy. Therefore the real concentration of steroid receptors is of great clinical importance. We determined the estradiol, progesterone and testosterone receptor content using biochemical method in tumour tissue of 33 male patients with head and neck squamous cell carcinoma. The receptors in the macroscopically intact mucosa in 15 of all tumour cases were also measured. The patients were followed for 18-24 month after operation and postoperative irradiation performed according to the protocol of the Head and Neck Surgery department. There were 26/33 (79%) estradiol receptor positive, 14/33 (42%) progesterone receptor positive and 18/30 (60%) testosterone receptor positive cases among the tumour samples. The healthy mucosa samples were positive in 6/15 (40%), 2/15 (13%) and 3/15 (20%) of cases, respectively. The differences in proportion of positive status between tumour and healthy mucosa was statistically significant. We established that during the control period the highest rate of the tumour-free survival was in the estradiol receptor positive, progesterone receptor negative group. Consequently the steroid receptor status of head and neck squamous cell carcinomas might help in assessing the prognosis of survival, and in possible choice for endocrine treatment, in order to complete the complex tumour therapy.
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The role of d,l-leucovorin (d,l-LV) dose on efficacy and toxicity of first-line bevacizumab+mFOLFIRI or mFOLFIRI treatment has never been investigated in patients with metastatic colorectal cancer. This study was an investigator initiated... more
The role of d,l-leucovorin (d,l-LV) dose on efficacy and toxicity of first-line bevacizumab+mFOLFIRI or mFOLFIRI treatment has never been investigated in patients with metastatic colorectal cancer. This study was an investigator initiated retrospective observational investigation performed on 450 consecutive patients. The mFOLFIRI regimen consisted of irinotecan (180 mg/m(2)), d,l-LV low (200 mg/m(2)) or high (400 mg/m(2)) dose and bolus 5-fluorouracil (5-FU) (400 mg/m(2)), followed by a 46-h infusion of 5-FU (2400 mg/m(2)). The bevacizumab+mFOLFIRI regimen consisted of bevacizumab (5 mg/kg)+mFOLFIRI. The efficacy (objective response [OR], progression-free [PFS] and overall survival [OS]) and toxicity was evaluated and compared. The use of high versus low dose d,l-LV in bevacizumab+mFOLFIRI regimen improved the OR rate (63 and 38 %, respectively; P = 0.00015), median PFS (13 and 9 months, respectively; P = 0.000005) and median OS (26 and 21 months, respectively; P = 0.0058). The efficacy of mFOLFIRI and the toxicity pattern of both bevacizumab+mFOLFIRI and mFOLFIRI regimens were independent of d,l-LV dose. Beside the d,l-LV dose the bevacizumab-related hypertension was an independent marker of longer survival. The use of high d,l-LV dose in bevacizumab+mFOLFIRI regimen would enhance the antiangiogenic effect of bevacizumab and subsequently the efficacy of treatment without increasing the number of adverse events. These findings need to be further confirmed in a randomized controlled prospective trial.
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3581 Background: TS, the target enzym of 5-FU has a 28 bp polymorphism in the promoter region containing commonly double of triple tandem repeats of a 28 bp sequence (2R or 3R), and a 6bp ins/del polymorphism on the 3'UTR. Our aim was... more
3581 Background: TS, the target enzym of 5-FU has a 28 bp polymorphism in the promoter region containing commonly double of triple tandem repeats of a 28 bp sequence (2R or 3R), and a 6bp ins/del polymorphism on the 3'UTR. Our aim was to study the influence of these TS polymorphisms on tumor response to adjuvant FUFA therapy in CRC patients. Methods: : 89 CRC patients receiving adjuvant FUFA were involved in the study. FUFA was given as bolus (Mayo regimen) or continuous infusion (de Gramont protocoll). TS polymorphisms were determined by PCR PAGE and RFLP method. Results: DFS was significantly longer (p=0,036 logrank test) in patients with +6/+6,+6/-6 genotypes than in –6/-6 genotype.OS was significantly longer (p=0,025) in 3/3 genotype than in 2/3and 2/2 genotype. In rectal cancer +/+ and +/- 3'UTR patients had longer OS than -/- patients (p=0,007).No significant correlation between gene polymorphisms, age, gender, and localization were found. Conclusions: Both TS polymorphisms studied do affect the cli...
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Epidermal growth factor receptor (EGFR) is highly expressed in adenoid cystic carcinoma (ACC). The efficacy and toxicity of cetuximab with concomitant platinum-based chemoradio- or chemotherapy in patients with locally advanced or... more
Epidermal growth factor receptor (EGFR) is highly expressed in adenoid cystic carcinoma (ACC). The efficacy and toxicity of cetuximab with concomitant platinum-based chemoradio- or chemotherapy in patients with locally advanced or metastatic ACC, respectively, was evaluated. Eligible patients (9 with locally advanced tumour and 12 with metastases) had positive tumour EGFR expression. The cetuximab loading dose (400 mg m⁻²) was followed by 250 mg m⁻² per week. Locally advanced tumours were irradiated (mean dose 65 Gy) and treated with concomitant cisplatin (75 mg m⁻², intravenously). Patients with metastases received concomitant cisplatin and 5-fluorouracil (4 × 1000 mg m⁻²). For patients with locally advanced disease (median follow-up: 52 months), the median progression-free survival (PFS) was 64 months and the 2-year overall survival (OS) rate was 100%. For patients with metastases (median follow-up: 72 months), the median PFS and OS were 13 and 24 months, respectively. In both gro...
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Head and neck squamous cell carcinoma (HNSCC) is diagnosed mainly in male patients (more than 80% of the cases) with a history of smoking and heavy alcohol consumption. However, only a few percent of all alcoholics develop head and neck... more
Head and neck squamous cell carcinoma (HNSCC) is diagnosed mainly in male patients (more than 80% of the cases) with a history of smoking and heavy alcohol consumption. However, only a few percent of all alcoholics develop head and neck cancer. to investigate the hormonal status in HNSCC patients as compared to healthy controls and alcoholic persons in order to find changes, if any, characteristic for cancer. The liver function expressed by gamma-GT levels, the hypophysis gonadotrop hormone (FSH, LH, prolactin) and sex steroid hormone serum levels were examined in 130 male HNSCC patients, in 54 men with alcoholic liver disease but without any known cancer and in 56 healthy men as controls. When compared to the healthy controls, both alcoholics and tumor patients had abnormal liver function, testosterone, sex hormone binding globuline and prolactin levels, reflecting the presence of alcoholic liver disease in tumor patients as well. However, abnormally elevated circulating FSH (p<...
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The relationship between the composition of breast cyst fluid (BCF), the menstrual status and in addition some endocrine events in the history of patients (n = 131) with gross cystic breast disease was investigated. The... more
The relationship between the composition of breast cyst fluid (BCF), the menstrual status and in addition some endocrine events in the history of patients (n = 131) with gross cystic breast disease was investigated. The dehydroepiandrosterone (DHA) levels in type II (K+/Na+ < 1) cysts of the follicular group were significantly higher compared to the type II cysts of the luteal or postmenopausal groups. For testosterone a significant difference existed between the type I (K+/Na+ > or = 1) follicular and type I postmenopausal groups. Estrone levels were significantly higher in type I BCF of patients in the luteal phase compared to both the follicular and postmenopausal type I cysts. Progesterone levels were lowest in the postmenopausal subgroups (both in type I and II cyst). Significant correlations were found between the number of pregnancies and the levels of DHA-sulfate and also progesterone in BCF. DHA levels were correlated with the period of lactation. The K+/Na+ ratios we...
Research Interests: Lactation, Medicine, Progesterone, Humans, Female, and 15 moreRegression Analysis, Potassium, Risk factors, Anticancer, Middle Aged, Adult, Sodium, Dehydroepiandrosterone, Risk Factors, Exudates and Transudates, Follicular phase, Premenopause, Breast Neoplasms, postmenopause, and fibrocystic breast disease
Gross cystic disease (GCD) of the breast may be associated with a higher risk for the development of breast cancer. High levels of sex steroids, steroid hormone precursors, prolactin and cations have been found in breast cyst fluid (BCF)... more
Gross cystic disease (GCD) of the breast may be associated with a higher risk for the development of breast cancer. High levels of sex steroids, steroid hormone precursors, prolactin and cations have been found in breast cyst fluid (BCF) by several investigators. Accordingly, endocrine parameters and the cationic composition of BCF may be considered as useful characteristics to follow patients bearing macrocysts. In this study we have investigated the concentrations of estradiol (E2), progesterone, testosterone, dehydroepiandrosterone (DHA) and DHA-3-sulfate (DHA-S), prolactin, potassium (K+) and sodium (Na+) in BCF aspirated from 99 women. The mean age of the patients was 49.8 years (range 32-58). The hormone levels were measured by RIA methods; K+ and Na+ were determined by flame photometry. Estradiol, progesterone, testosterone, DHA, DHA-S, prolactin and K+ showed significant accumulation in the BCF compared with their respective serum values. The K+/Na+ ratio proved to be useful...
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To differentiate the antagonistic and agonistic effect of toremifene at the level of the hypothalamus-hypophysis axis a leutinizing hormone-releasing hormone (LHRH) test was performed during a phase II clinical trial. In 15 postmenopausal... more
To differentiate the antagonistic and agonistic effect of toremifene at the level of the hypothalamus-hypophysis axis a leutinizing hormone-releasing hormone (LHRH) test was performed during a phase II clinical trial. In 15 postmenopausal patients with advanced breast cancer, follicle-stimulating hormone (FSH) and LH release--induced by an LHRH agonist (Suprefact injection, 0.5 mg s.c.)--was monitored during a 16-week period of toremifene treatment (60 mg/day p.o.). Prolactin, estradiol, and sex hormone-binding globulin (SHBG) levels were also measured. The functional test was carried out prior to toremifene therapy and then 4, 8, 12, and 16 weeks afterward. The drug sensitized the pituitary to the action of the gonadotrophins; the LHRH-induced FSH and LH release showed a considerably increasing tendency during the toremifene therapy. Estradiol levels decreased statistically significantly and SHBG levels showed a statistically significant increase. A decreased level of prolactin is the sign of an antiestrogenic effect of toremifene on the hypophysis and, as a result, provides evidence for a direct influence of toremifene upon the pituitary. An increase in LH and prolactin release in response to the LHRH test was characteristic in the responders. According to the LHRH test, the antagonistic effect of toremifene seems to be more dominant than the concomitantly existing agonistic property. Neither clinical nor endocrinological side effects could be observed at the level of the CNS during a prolonged period of toremifene administration.
Research Interests: Breast Cancer, Sex Hormones, Medicine, Humans, Prolactin, and 14 moreFemale, Statistical Significance, Central Nervous System, Psychosocial advanced breast cancer, Gonadotropin Releasing Hormone, Side Effect, Mechanism of action, Sex hormone-binding globulin, Ovary, Follicle stimulating hormone, Functional Testing, Breast Neoplasms, Pharmacology and pharmaceutical sciences, and postmenopause
Background: The literature data regarding colon cancer patients with liver-only metastases (CLM) show that NLR determined before metastasectomy is a prognostic marker of shorter relapse-free survival (RFS), but no results has been... more
Background: The literature data regarding colon cancer patients with liver-only metastases (CLM) show that NLR determined before metastasectomy is a prognostic marker of shorter relapse-free survival (RFS), but no results has been reported to date for rectal cancer patients with liver-only metastases (RLM). This study aimed to investigate the NLR and SII in CLM and RLM.Methods: Relapse-free (RFS) and overall survival (OS) were evaluated in 67 CLM and 103 RLM patients with a median follow-up of 46.5 and 59.8 months, respectively. Pre- and/or postoperative chemotherapy ± targeted treatment was applied in 96% and 87% of CLM and RLM patients, respectively. The cut-off level for hematologic parameters were determined by receiver operating characteristic (ROC) analysis. Univariate analysis was performed by Kaplan-Meier method and log rank test. For multivariate analysis Cox regression was applied.Results: In univariate analysis low NLR (cut-off 2) and SII (535) were predictors of longer R...
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Preventing the ototoxicity caused by cisplatin is a major issue yet to be overcome. Useful preventive treatments will soon be available. Consequently, the next step is to filter out those patients who are more prone to develop... more
Preventing the ototoxicity caused by cisplatin is a major issue yet to be overcome. Useful preventive treatments will soon be available. Consequently, the next step is to filter out those patients who are more prone to develop ototoxicity. The aim of this study was to prospectively evaluate potential predictive markers of acute ototoxicity as determined by measures of distortion product otoacoustic emissions (DPOAEs). A total of 118 patients from our previous DPOAE analysis were put under evaluation. Ototoxic cases were divided according to unilateral (n = 45) or bilateral (n = 23) involvement. The clinicopathological characteristics, hearing test results, germline GSTT1, GSTM1, and GSTP1 polymorphisms, and common laboratory parameters were included in the new analysis. Univariate and multivariate statistical tests were applied. According to multivariate logistic regression, the only independent predictor of unilateral ototoxicity (vs. non-affected) was a GSTM1 null genotype (OR = 4...
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e16522 Background: Cs are commonly used in the treatment of mCRPC, because of their inhibitory effects on the secretion of ACTH and their palliative effects. Inhibition of ACTH results in downregulation of adrenal androgens. Cs may have a... more
e16522 Background: Cs are commonly used in the treatment of mCRPC, because of their inhibitory effects on the secretion of ACTH and their palliative effects. Inhibition of ACTH results in downregulation of adrenal androgens. Cs may have a cytotoxic effect on prostate cancer cells, mediated in part by the downregulation of androgen receptors and the activation of glucocorticoid receptor-mediated signaling and downstream antiangiogenic activity. The rationale for adding Cs to D chemotherapy is for the management of symptoms and adverse events rather than for improving responses. D (without Cs) + ADT (androgen-deprivation therapy) vs ADT alone in castration-sensitive prostate cancer has resulted in significant increase in survival (NEJM, 2015). Cs has been reported to adversely influence OS during enzalutamide (NEJM, 2012). In the COU-AA-301 trial Cs use at baseline was an independent prognostic factor in multivariate analysis, but not in a stepwise selection model (JCO, 2013). Methods...
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In practice it is still not clear whether a drug holiday in sunitinib (Su) treatment can be safety, without impairing the overall outcome of patients with metastatic renal cell carcinoma (mRCC). The aim was to retrospectively evaluate the... more
In practice it is still not clear whether a drug holiday in sunitinib (Su) treatment can be safety, without impairing the overall outcome of patients with metastatic renal cell carcinoma (mRCC). The aim was to retrospectively evaluate the outcome in patients who restarted Su after an interruption of ≥3 months and a combined analysis of case studies from literature. From 556 patients treated between January 2006 and March 2016 a group of 38 patients were selected whose treatment was interrupted for other reasons than disease progression. During interruption Su was restarted in case of RECIST-defined progression. The primary objective was the objective response (OR) and progression free survival (PFS) of baseline and restarted therapy. The secondary objective was the overall survival (OS) calculated from the start of baseline treatment. Multivariate survival analysis was also applied. The major causes of interruption were toxicity (39%) and patient' choice (24%). Median duration o...
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To investigate the overall survival (OS) of chemotherapy refractory patients with metastatic castration-resistant prostate cancer who were treated with abiraterone acetate + prednisolone (AA + P) beyond prostate specific antigen (PSA) and... more
To investigate the overall survival (OS) of chemotherapy refractory patients with metastatic castration-resistant prostate cancer who were treated with abiraterone acetate + prednisolone (AA + P) beyond prostate specific antigen (PSA) and radiographic progression (PRP) until clinical progression in comparison to patients treated until PRP. At our institute the AA + P treatment started in 2011 in an early-access protocol trial. In October 2012 AA became generally available. From April 2011 to November 2014, 116 patients received AA + P. The clinical trial patients (T; n = 56) were treated beyond PRP until clinical progression. In the nonclinical trial group (NT; n = 57) the treatment was covered until PRP. Three patients are still under treatment. The 2 groups were statistically homogeneous, except AA + P treatment duration. The primary objective was the OS and the secondary the PSA progression-free and radiographic progression-free survivals. The median OS was significantly longer (...
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To prospectively examine early hearing damage detectable with distortion product otoacoustic emission (DPOAE) after the first cycle of cisplatin treatment of patients with testicular tumor. Both ears of 137 consecutive patients were... more
To prospectively examine early hearing damage detectable with distortion product otoacoustic emission (DPOAE) after the first cycle of cisplatin treatment of patients with testicular tumor. Both ears of 137 consecutive patients were examined at 0.75 to 8 kHz before (B) and after (A) the first cycle of cisplatin (dose: 100 mg/m(2) / 5 days). The mean amplitudes (B vs. A) were compared with paired t test at each frequency. Ototoxic changes were considered when an individual amplitude difference (B-A) > 14 dB at 0.75 Hz or > 7 db at 1 to 8 kHz occurred. The mean amplitudes were statistically significantly lower after first cycle at 0.75, 6, and 8 kHz. The majority of patients (96%) presented positive differences (B-A) in one or both ears; in 85 (62%) cases, the positive difference reached the level of ototoxicity out of which 34 (40%) and 19 (22%) of patients suffered ototoxicity in one or both ears, respectively. The difference between right and left ears in distribution of otot...
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to investigate the clinical outcome of HNSCC patients, and their hormonal status. The liver function (GGT), hypophysis gonadotrop hormone (FSH, LH, prolactin) and sexsteroid hormone serum levels were examined in 130 male HNSCC patients.... more
to investigate the clinical outcome of HNSCC patients, and their hormonal status. The liver function (GGT), hypophysis gonadotrop hormone (FSH, LH, prolactin) and sexsteroid hormone serum levels were examined in 130 male HNSCC patients. Clinical parameters for age, primary tumor site and clinical tumor stage were also recorded. The survival was disadvantageously influenced by the following parameters: age, the presence of lymph node metastasis, advanced tumor stage, the lower than normal testosterone and the higher than normal FSH serum levels. Elevated FSH and decreased testosterone serum levels showed significant correlation with the survival of head and neck cancer patients. The better understanding of their exact role in the biology of HNSCC requires further investigations.
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Research Interests: Humans, Prolactin, Head and Neck Cancer, Male, Squamous Cell Carcinoma, and 12 moreHead and neck squamous cell carcinoma, non alcoholic fatty liver disease (NAFLD), Liver Function, Alcohol Consumption, Sex Steroids, Middle Aged, Oral Squamous Cell Carcinoma (OSCC), Cancer Patient, Sex hormone-binding globulin, Oncology and Molecular Pathology, Alcoholic liver disease, and Head and neck neoplasms
Randomized trials in advanced biliary tract cancer (BTC) did not show benefit of cetuximab addition over chemotherapy. This is probably due to the lack of predictive biomarkers. The aim of this study was to explore possible predictive... more
Randomized trials in advanced biliary tract cancer (BTC) did not show benefit of cetuximab addition over chemotherapy. This is probably due to the lack of predictive biomarkers. The aim of this study was to explore possible predictive factors. Between 2009 and 2014, 57 patients were treated in 3-week cycles with cetuximab (250 mg/m(2)/week, loading dose: 400 mg/m(2)), gemcitabine (1000 mg/m(2) on day 1 and 8), and capecitabine (1300 mg/m(2)/day on days 1-14). The objective response rate (ORR), progression-free (PFS) and overall survival (OS) and the adverse events (AEs) were evaluated. An exploratory analysis was performed to find possible predictive factors on clinicopathological characteristics, routine laboratory parameters and early AEs, which occurred within 2 months from the beginning of treatment. The ORR was 21%. The median PFS and OS were 34 (95% CI: 24-40) and 54 (43-67) weeks, respectively. The most frequent AEs were skin toxicities. In univariate analysis performance sta...
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The aim was to assess the relationship between treatment efficacy and adverse events (AEs) for patients with advanced renal cell carcinoma treated with first-line sunitinib. 274 patients were treated with sunitinib (50 mg/d, 4-weeks-on... more
The aim was to assess the relationship between treatment efficacy and adverse events (AEs) for patients with advanced renal cell carcinoma treated with first-line sunitinib. 274 patients were treated with sunitinib (50 mg/d, 4-weeks-on and 2-weeks-off schedule). Physical and laboratory evaluations were done every sixth week. AEs were diagnosed at every visit. Clinical response was assessed every 3 months. The objective response rate (ORR), median progression-free (mPFS) and median overall survival (mOS) and AEs were evaluated. Besides χ(2) and log rank tests, multivariate Cox regression analysis and for synergism 1-sided t tests were used. The ORR was 25%. After a median follow-up of 32 months, the mPFS and mOS were 9 and 19 months, respectively. Hypertension, diarrhea, hypothyroidism, mucositis, hand-foot syndrome (HFS), skin toxicity, and leukopenia were the most frequent treatment-associated AEs. Significantly longer (P &amp;amp;amp;amp;amp;amp;lt; .01) mPFS and mOS were observed when hypertension, diarrhea, HFS, hypothyroidism, skin toxicity, or leukopenia occurred. A statistically significant synergistic effect of the listed AEs was observed for progression-free survival (P &amp;amp;amp;amp;amp;amp;lt; .001) and overall survival (P &amp;amp;amp;amp;amp;amp;lt; .001). Multivariate analysis revealed that besides the prognostic category, the higher number of AEs (3-6 vs. 0-2) was an independent marker of longer mPFS (24 vs. 5 months, respectively; P &amp;amp;amp;amp;amp;amp;lt; .001) and mOS (51 vs. 9 months, respectively; P &amp;amp;amp;amp;amp;amp;lt; .001). Results of this study provide evidence for the synergistically enhanced efficacy of sunitinib treatment in patients who present multiple AEs. These AEs are diagnosed routinely and their coexistence can help physicians to predict which group of patients would benefit the most from first-line sunitinib treatment.
The authors investigated the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in 101 metastatic colorectal cancer patients treated with 5-fluoropyrimidine-based therapy and in 196 healthy individuals by PCR-RFLP method.... more
The authors investigated the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in 101 metastatic colorectal cancer patients treated with 5-fluoropyrimidine-based therapy and in 196 healthy individuals by PCR-RFLP method. There was no significant difference in genotype distribution of patients and healthy controls, and between subgroups investigated according to clinical parameters (age, gender, tumor location, grade and treatment type). However, after a 3-30 (median 18.5) months follow-up the survival of patients with T allele proved to be better than that of patients with wild type (CC) genotype (p=0.036). In case of CT and TT genotypes the survival of patients receiving only first line therapy was significantly shorter than that of patients receiving more lines of treatment (p=0.015). Determination of MTHFR C677T polymorphism has prognostic value in case of patients with metastatic colorectal cancer receiving 5-fluoropyrimidine-based therapy, and may help in designing the individual (group) tailored therapy.
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Non-steroidal anti-inflammatory drugs (NSAIDs) may be able to enhance the antitumor effect of cancer drugs. Cyclooxygenase-2 (COX-2) is the best characterized target of NSAIDs. It was demonstrated that elevated dihydropyrimidine... more
Non-steroidal anti-inflammatory drugs (NSAIDs) may be able to enhance the antitumor effect of cancer drugs. Cyclooxygenase-2 (COX-2) is the best characterized target of NSAIDs. It was demonstrated that elevated dihydropyrimidine dehydrogenase (DPD) and COX-2 activities influence the response to 5-fluorouracil (5-FU). We previously showed that NSAIDs increased 5-FU sensitivity only in high COX-2-expressing cancer cells. The effect of indomethacin and NS-398 on DPD activity and mRNA expression in a high COX-2-expressing (determined by Western blotting, immunoflourescence and immunohistochemistry) cell line (24-, 48-hour, 10-day treatment) and xenograft (3-week treatment) was investigated. The coexistence of high COX-2 and DPD activity or low activities of both enzymes were detected. After treatment with NSAIDs, a simultaneous and significant decrease of both activities was also demonstrated. NSAIDs could be promising modulators of fluorouracil-based chemotherapy, especially in high CO...
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The cytotoxic effect of 5-fluorouracil (5-FU) is mediated by the inhibition of thymidylate synthase (TS), however, at the same time 5-FU is catabolized by dihydropyrimidine dehydrogenase (DPD). Efficacy of 5-FU may therefore depend on the... more
The cytotoxic effect of 5-fluorouracil (5-FU) is mediated by the inhibition of thymidylate synthase (TS), however, at the same time 5-FU is catabolized by dihydropyrimidine dehydrogenase (DPD). Efficacy of 5-FU may therefore depend on the TS and DPD activity and on pharmacogenetic factors influencing these enzymes. Our aims were (1) to determine the distribution of DPD activity, the frequency of DPD deficiency and the DPD (IVS14+1G>A) mutation in the peripheral blood mononuclear cells of colorectal cancer (CRC) patients, and study the relationship between DPD deficiency and toxicity of 5-FU; (2) to investigate the influence of TS polymorphisms and DPD activity on the survival of CRC patients receiving 5-FU-based adjuvant therapy. The frequency of DPD deficiency was determined by radiochemical methods in the peripheral blood mononuclear cells (PBMCs) of 764 CRC patients treated with 5-FU. The relationship between the TS polymorphisms, DPD activity and the disease-free and overall ...
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The authors investigated the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in 101 metastatic colorectal cancer patients treated with 5-fluoropyrimidine-based therapy and in 196 healthy individuals by PCR-RFLP method.... more
The authors investigated the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in 101 metastatic colorectal cancer patients treated with 5-fluoropyrimidine-based therapy and in 196 healthy individuals by PCR-RFLP method. There was no significant difference in genotype distribution of patients and healthy controls, and between subgroups investigated according to clinical parameters (age, gender, tumor location, grade and treatment type). However, after a 3-30 (median 18.5) months follow-up the survival of patients with T allele proved to be better than that of patients with wild type (CC) genotype (p=0.036). In case of CT and TT genotypes the survival of patients receiving only first line therapy was significantly shorter than that of patients receiving more lines of treatment (p=0.015). Determination of MTHFR C677T polymorphism has prognostic value in case of patients with metastatic colorectal cancer receiving 5-fluoropyrimidine-based therapy, and may help in designing...
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Pharmacologic modulation of 5-fluorouracil (5-FU) metabolism provides a possibility for the enhancement of its clinical efficacy. The purpose of the present work was to study the effect of 5-ethyl-2'-deoxyuridine (EUdR), a potent 5-FU... more
Pharmacologic modulation of 5-fluorouracil (5-FU) metabolism provides a possibility for the enhancement of its clinical efficacy. The purpose of the present work was to study the effect of 5-ethyl-2'-deoxyuridine (EUdR), a potent 5-FU modulator, on different molecular mechanisms, influenced by 5-FU itself, and to obtain further data about the mode of action of the combination. SW620 cell line was used for the experiments. Cytotoxicity was studied by MTT test, cell kinetic changes by FACStar flow cytometer, apoptosis by fluorescent microscope after staining the cells with acridine orange and ethydium bromide, DNA fragmentation by PAGE electrophoresis after RNase and proteinase-K digestion, thymidine incorporation with 3H-thymidine, p53 and PCNA protein expression by Western blotting. The cytotoxicity of 5-FU was potentiated dose dependently by EUdR. One hundred muM concentration of EUdR resulted in a 40% decrease of the IC50 value of 5-FU. Cell cycle arrest in the G2/M transition...
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to investigate the clinical outcome of HNSCC patients, and their hormonal status. The liver function (GGT), hypophysis gonadotrop hormone (FSH, LH, prolactin) and sexsteroid hormone serum levels were examined in 130 male HNSCC patients.... more
to investigate the clinical outcome of HNSCC patients, and their hormonal status. The liver function (GGT), hypophysis gonadotrop hormone (FSH, LH, prolactin) and sexsteroid hormone serum levels were examined in 130 male HNSCC patients. Clinical parameters for age, primary tumor site and clinical tumor stage were also recorded. The survival was disadvantageously influenced by the following parameters: age, the presence of lymph node metastasis, advanced tumor stage, the lower than normal testosterone and the higher than normal FSH serum levels. Elevated FSH and decreased testosterone serum levels showed significant correlation with the survival of head and neck cancer patients. The better understanding of their exact role in the biology of HNSCC requires further investigations.
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Research Interests:
The purpose of this study was to investigate whether specific combinations of polymorphisms in 5-fluorouracil (5-FU) metabolism-related genes were associated with outcome in 5-FU-based adjuvant treatment of colorectal cancer. We analyzed... more
The purpose of this study was to investigate whether specific combinations of polymorphisms in 5-fluorouracil (5-FU) metabolism-related genes were associated with outcome in 5-FU-based adjuvant treatment of colorectal cancer. We analyzed two cohorts of 302 and 290 patients, respectively, one cohort for exploratory analyses and another cohort for validating the exploratory analyses. A total of ten polymorphisms in genes involved in 5-FU pharmacodynamics and pharmacokinetics were studied. End points were disease-free survival (DFS) and overall survival. Multifactor dimensionality reduction was used to identify genetic interaction profiles associated with outcome. Low-expression alleles in thymidylate synthase (TYMS) were associated with decreased DFS and overall survival (DFS:hazard ratio [HR] exploration 2.65 [1.40-4.65]; p = 0.004, HR validation 1.69 [1.03-2.66]; p = 0.03). A specific multifactor dimensionality reduction derived combination of dihydropyrimidine dehydrogenase and TYMS polymorphisms was associated with increased DFS (HR exploration 0.69 [0.49-0.98]; p = 0.04, HR validation 0.66 [0.45-0.95]; p = 0.03). Specific combinations of functional polymorphisms in DPYD and TYMS were demonstrated to be associated with DFS and overall survival in patients receiving adjuvant 5-FU-based treatment. Specifically high TYMS expression alleles seem to be associated with decreased DFS.
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Research Interests:
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Epidermal growth factor receptor (EGFR) is highly expressed in adenoid cystic carcinoma (ACC). The efficacy and toxicity of cetuximab with concomitant platinum-based chemoradio- or chemotherapy in patients with locally advanced or... more
Epidermal growth factor receptor (EGFR) is highly expressed in adenoid cystic carcinoma (ACC). The efficacy and toxicity of cetuximab with concomitant platinum-based chemoradio- or chemotherapy in patients with locally advanced or metastatic ACC, respectively, was evaluated. Eligible patients (9 with locally advanced tumour and 12 with metastases) had positive tumour EGFR expression. The cetuximab loading dose (400 mg m⁻²) was followed by 250 mg m⁻² per week. Locally advanced tumours were irradiated (mean dose 65 Gy) and treated with concomitant cisplatin (75 mg m⁻², intravenously). Patients with metastases received concomitant cisplatin and 5-fluorouracil (4 × 1000 mg m⁻²). For patients with locally advanced disease (median follow-up: 52 months), the median progression-free survival (PFS) was 64 months and the 2-year overall survival (OS) rate was 100%. For patients with metastases (median follow-up: 72 months), the median PFS and OS were 13 and 24 months, respectively. In both gro...