NGAL, albumin and cystatin C during cisplatin therapy.

Cisplatin is a commonly used chemotherapeutic drugs. It is known for its nephrotoxic side effects with an increased risk of acute kidney injury. Finding of clinically feasible cisplatin nephrotoxicity markers is of importance. In our study, we compared neutrophil gelatinase-associated lipocalin (NGAL) in serum and urine, the estimated glomerular filtration rate (based on serum cystatin C) and urine albumin as markers of nephrotoxicity. The study involved 11 men and 9 women (mean ± SD age 58.2±9.5 years) with different malignancies treated with cisplatin in four cycles of chemotherapy (I - IV). Samples 0-4 were taken before, immediately after, in 3, 6 and 24 hours after administering chemotherapy. We detected significant increase of ACR in Sample 2 (p=0.03) and decrease of eGFR in Sample 4 (p=0.03) up to 24 hours after cisplatin administration in the first chemotherapy cycle only. When cumulative effect of cisplatin was assessed, significantly increased values of urine albumin (vs cycle I) were found in Sample 0 (p=0.00058), 1 (p=0.00256), 2 (p=0.00456), 3 (p=0.00006) and 4 (p=0.00319) in cycles II to IV. We found a correlation between values of urine NGAL and urine albumin (r=0.68, p<0.0001). In conclusion, urine albumin was the only measured marker that consistently and statistically significantly increased after cisplatin containing chemotherapy cycles.

Side Effects and Efficacy of Immunotherapy.

BACKGROUND: Modern immunotherapy based on immune checkpoint inhibitors is an innovative treatment, which is already used in the treatment of a number of malignancies, and many other checkpoint inhibitors have been investigated in clinical trials. Monoclonal antibodies against CTLA-4 (cytotoxic T-lymphocyte antigen-4) and PD-1 (programmed cell death-1) or PD-L1 (programmed cell death-1 ligand) are the most commonly used agents. The side effects of these treatments are similar in nature to those of autoimmune diseases. Recently, increasing evidence has indicated that some adverse effects of immunotherapy are associated with the beneficial effect of this treatment. PURPOSE: The aim of this review was to summarize current knowledge of the association between the adverse effects of checkpoint inhibitors and the outcomes of patients treated with this therapy. CONCLUSION: The association between the effect of immunotherapy and the occurrence of adverse reactions has been identified in a number of studies. It has been best documented in patients with malignant melanoma, non-small cell lung cancer, and renal cell carcinoma. Many studies published so far are limited by the relatively low number of patients and their retrospective design, leaving many questions still unanswered. This work was supported by the National Sustainability Program I (NPU I) Nr. LO1503 provided by the Ministry of Education Youth and Sports of the Czech Republic and by the Charles University Research Fund (Progres Q39) and by the European Regional Development Fund-Project „Application of Modern Technologies in Medicine and Industry” (No. CZ.02.1.01/0.0/0.0/17_048/0007280). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 3. 11. 2019 Accepted: 8. 12. 2019.

[Pilot Study on MicroRNAs as Biomarkers of Response to Sunitinib Treatment in Patients with Metastatic Renall Cell Carcinoma]. / MikroRNA jako biomarkery odpovedi na lécbu sunitinibem u pacientu s metastatickým karcinomem ledvin - pilotní studie.

BACKGROUND: Renal cell carcinoma (RCC) accounts for 2-3% of all malignant tumours. Metastatic RCC (mRCC) is commonly treated with tyrosine kinase inhibitors (TKI). Effective TKIs administration can be achieved only by accurate prediction of therapeutical response. Therefore, the aim of this study was to analyse papers concerning predictive potential of microRNA (miRNA). MATERIAL AND METHODS: We chose seven candidate miRNAs and analysed their expression on 44 patients divided into cohort with poor and good response to sunitinib treatment. Patients were divided into two groups according to progression-free survival. RNA from tissue samples was isolated and expression of selected miRNAs was measured using quantitative PCR with miRNA-specific TaqMan probes. RESULTS: We successfully validated two miRNAs to be differentially expressed in responding and non-responding patients to sunitinib treatment. Other analysed miRNAs have not shown predictive potential. CONCLUSION: From miRNAs studied so far, two miRNAs had predictive value according to present study.Key words: microRNA - renal cell carcinoma - sunitib The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Supported by Ministry of Health of the Czech Republic, grant No. 15-34678A. All rights reserved.Submitted: 19. 3. 2018Accepted: 20. 3. 2018.

[A Development and Overview of the Use of Chemotherapy and the Role of Radiotherapy and Surgery in Patients with Newly Diagnosed Pancreatic Tumor and Cancer in the Current 5-year Center Practice]. / Vývoj a prehled vyuzití chemoterapie a role radioterapie a chirurgie u pacientu s nove diagnostikovaným tumorem a karcinomem pankreatu v bezné 5leté praxi centra.

BACKGROUND: Chemotherapy (CHT), surgery and radiotherapy (RT) are essential modalities in the treatment of pancreatic malignancies. Their use in practice may be influenced by a number of factors. PATIENTS AND METHODS: Retrospective analysis of CHT, surgery and RT indications and CHT results in patients reported with pancreatic tumor in Pilsen in 2012-2016. RESULTS: A total of 348 patients with median age 68 (19-89) years with newly diagnosed pancreatic tumor, resp., with histology/cytology verified carcinoma in 74.5% cases, with v. s. carcinoma without verification in 21% and with other malignancy not further analyzed here in 4.5% (mostly neuroendocrine tumor). In patients with generalized malignancy (n = 195), exploratory laparotomy was performed in 23% to get tissue samples or verify staging - palliative anastomoses were done in 25% of operated patients, CHT was performed in 29% of the generalized tumors, palliative RT of tumor was performed in 1 patient, and RT of metastases in 3 patients. In patients with local or regional nodal affection (n = 137) laparotomy was done in 59%, R0 resection in 34 (42%) of 81 operated, R1 in 6%, palliative anastomoses were done in 17% and irreversible electroporation in one patients, CHT or radiochemotherapy after R0 and R1 resections was provided in 61% operated patients. The most commonly used CHT was monotherapy with gemcitabine or FOLFIRINOX. The indication of CHT in cytology/histology verified generalized cancers and with excluding patients refusing CHT was proposed in 2012 to 16%, in 2014 to 49% and in 2016 to 84% of patients. In the case of a local or regional nodal involvement the CHT was proposed to 40, 55 and 86% of patients. Median overall survival in generalized tumor patients receiving CHT (n = 137) vs. not-receiving CHT (n = 56) was 2 vs. 8 months (p = 0.0001), and in the local or regional nodal involvement patients receiving CHT (n = 74) vs. not-receiving CHT (n = 62) was 5 vs. 16 months (p = 0.0001). CONCLUSION: CHT and surgery are the dominant treatment modalities. There has been a marked increase in the CHT and histology/cytology verifications indications, with a major factor being a clinician evaluation of a patient to be fit for CHT and its benefit or to complete pancreatic tumor verification. With still very limited results in pancreatic cancer treatment, a careful assessment of each patients indication, respecting patients desire, is always required, knowing that even in the case of advanced disease, CHT can bring benefit, albeit limited.Key words: pancreas - carcinoma - chemotherapy The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. This study was supported by the grant of Ministry of Health of the Czech Republic - Conceptual Development of Research Organization (Faculty Hospital in Pilsen - FNPl, 00669806).Submitted: 13. 3. 2018Accepted: 18. 4. 2018.

Diagnostic exome sequencing in early-onset Parkinson's disease confirms VPS13C as a rare cause of autosomal-recessive Parkinson's disease.

Parkinson's disease (PD) is a genetically heterogeneous disorder and new putative disease genes are discovered constantly. Therefore, whole-exome sequencing could be an efficient approach to genetic testing in PD. To evaluate its performance in early-onset sporadic PD, we performed diagnostic exome sequencing in 80 individuals with manifestation of PD symptoms at age 40 or earlier and a negative family history of PD. Variants in validated and candidate disease genes and risk factors for PD and atypical Parkinson syndromes were annotated, followed by further analysis for selected variants. We detected pathogenic variants in Mendelian genes in 6.25% of cases and high-impact risk factor variants in GBA in 5% of cases, resulting in overall maximum diagnostic yield of 11.25%. One individual was compound heterozygous for variants affecting canonical splice sites in VPS13C, confirming the causal role of protein-truncating variants in this gene linked to autosomal-recessive early-onset PD. Despite the low diagnostic yield of exome sequencing in sporadic early-onset PD, the confirmation of the recently discovered VPS13C gene highlights its advantage over using predefined gene panels.

[Immunotherapy in the Treatment of Lung Cancer]. / Imunoterapie v lécbe karcinomu plic.

BACKGROUND: Lung cancer occupies the leading position of cancer incidence and mortality worldwide, including in the Czech Republic. Despite significant advances in systemic oncology treatments, lung cancer still has the worst prognosis, which is driving the need for innovative therapies and methods to treat this disease. Immunotherapy is a developing area of systemic oncology treatment, which has recently begun to be significantly applied to patients with lung carcinoma. The most useful type of immunotherapy currently employs checkpoint inhibitors, including CTLA-4 inhibitors (ipilimumab and tremelimumab) and PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, durvalumab, and avelumab). Except for monotherapy, different combinations of these inhibitors or combinations between one more of these inhibitors and chemotherapy or targeted treatment are being actively studied. Despite intensive investigations, anti-tumor vaccines and cytokines have not had an important impact on the treatment of lung cancer. Checkpoint inhibitors have yielded favorable results, especially for the treatment of advanced (i.e., stage IIIB and IV) non-small cell lung cancer (NSCLC) and are being extensively investigated for the treatment of SCLC. AIM: The aim of this review was to summarize the most important achievements, possibilities, and perspectives of modern immunotherapy for the treatment of patients with lung cancer. CONCLUSION: Immunotherapy is an important tool in todays arsenal of oncology treatments, and for patients with lung cancer it offers the hope of prolonging life and img iprovints quality.Key words: immunotherapy - lung cancer - NSCLC - SCLC - checkpoint inhibitors This work was supported by National Sustainability Programme I No. LO1503 provided by Ministry of education, youth and sports and program No. 17-30748A devided by The Ministry of Health of the Czech Republic. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 31. 8. 2017Accepted: 7. 9. 2017.

[A new perspective on axillary dissection in situations of metastatic sentinel node]. / Nový pohled na exenteraci axily pri metastáze v sentinelové uzline.

INTRODUCTION: Breast cancer is the most common malignant disease in women and represents a worldwide problem. Up-to-date diagnostics methods, mammography screening and complex treatments have resulted in a substantial reduction of mortality rates. However, the incidence of the disease keeps growing constantly, although in a moderate way. The struggle against this disease has several levels, such as prevention, primary tumour therapy as well as the management of recurrent or generalized disease. Therefore, it is very significant to evaluate the prognosis on the basis of biological characteristics of the tumour and to determine the right individual therapy in each patient. AIM OF THE STUDY: Our aim was to determine a group of patients with malignant breast disease based on biological characteristics of the tumour who can be treated without axillary exenteration even with a metastasis in the sentinel lymph node, thereby reducing the morbidity associated with this surgery, without worsening the prognosis. METHOD: The research project lasted from June 2012 to June 2015. It was a prospective randomized study where the main investigated group consisted of women with primarily surgically treated mammary cancer undergoing sentinel lymph node biopsy (SNB) during their surgery. These patients were divided into three groups: group 1 - positive SNB without axillary exenteration (axillary dissection - AD); group 2 - positive SNB with AD; and group 3 - negative SNB. Group 4 consisted of patients with primarily performed AD. We investigated statistically significant prognostic factors of metastatic lymph nodes and early disease progression. The results were statistically processed and differences between individual groups were evaluated, determining prognostically usable biological characteristics of the tumour in connection with metastases in lymph nodes and progression-free survival. RESULTS: The study included 214 patients with breast cancer. No metastases of axillary lymph nodes were found in 136 patients (64%); on the other hand, 78 patients (36%) had positive axillary lymph nodes and included: 28 (13%) patients with a micrometastasis in the sentinel lymph node; 38 (17%) patients with 13 positive lymph nodes; 8 (4%) patients with 49 positive lymph nodes; and 4 (2%) patients had more than 10 metastatic lymph nodes. A statistically significant difference with respect to metastatic lymph node involvement was found for the tumour size, expression of oestrogen receptors, proliferative activity and grading. CONCLUSION: The following prognostic factors of metastatic lymph nodes and early disease progression were shown to be statistically significant: tumour size over 2 cm, negative expression of oestrogen receptors, tumours with moderate and high proliferative activity, and tumour grades G2 and G3. In the course of the three years of this study, no regional recurrence was found in axillary lymph nodes in any patient, and therefore, it clearly follows that the completion of axillary exenteration can be omitted in the case of tumour sizes below 2 cm, present expression of oestrogen receptors, low proliferative activity and grade 1 even if one or two positive sentinel lymph nodes are present, provided that adjuvant radiation therapy can be used. Also, axillary exenteration is not needed if a micrometastasis or isolated tumour cells are found in the sentinel lymph node.Key words: breast cancer - sentinel lymph node biopsy - axillary exenteration - prognostic factors.

Prognostic role of serum C-reactive protein in patients with advanced-stage NSCLC treated with pemetrexed.

Pemetrexed is an intravenously administered antifolate cytostatic agent targeting several folate-dependent enzymatic pathways, widely used in the treatment of patients with advanced non-small cell lung cancer (NSCLC). It has been previously demonstrated that the superiority of pemetrexed is limited to patients with non-squamous histology. Aside from the non-squamous histology, there is still no available molecular biomarker predicting treatment efficacy of pemetrexed-based chemotherapy. The aim of our retrospective study was to evaluate the association of baseline serum levels of C-reactive protein (CRP) with outcomes in a large cohort of patients with non-squamous NSCLC treated with pemetrexed. Clinical data of 325 patients were analysed. Serum samples were collected within one week before the initiation of treatment. The median progression-free (PFS) and overall survival (OS) for patients with high CRP was 2.1 and 9.5 compared to 4.2 and 20.5 months for those with normal CRP (p=0.002 and p<0.001, respectively). The multivariable Cox proportional hazards model revealed that serum CRP (HR=1.46, p=0.002) was significantly associated with PFS and also with OS (HR=1.95, p<0.001). In conclusion, the study results suggest that pretreatment serum CRP is associated with poor outcome of non-squamous NSCLC patients treated with pemetrexed.

[Everolimus in Daily Clinical Practice Focusing to Oral Mucosa Damage Issues - Single Oncology Centre Experience within the Course of the Year 2016]. / Everolimus v denní klinické praxi se zamerením na problematiku postizení sliznice dutiny ústní - zkusenost onkologického centra v prubehu roku 2016.

BACKGROUND: Oral mucositis, mTOR associated stomatitis, is a major complication in everolimus (EVE) treatment with an incidence of 44-64%. The management of it in the daily practice has not been described enough, so far. PATIENTS AND METHODS: Retrospective analysis of patients treated with EVE in 2016 at our center, n = 42 patients (69% female), median age 66 (37-81) years, breast cancer in 20 (48%) and renal cell carcinoma in 22 (52%), starting EVE dose of 10mg/day in 34 (81%) and 5mg/day in 8 (19%) patients. RESULTS: Discomfort and/or dysgeusia without mucosa defects (grade 1 NCI-CTC) was in 4/34 (12%) patients, mucosal defects without oral intake limitation (grade 2) in 6/34 (17.5%), mucosal defects limiting oral intake (grade 3) in 7/34 (20.5%) patients. ACTIONS TAKEN: in grade 1 EVE dose reduced to 5mg/day in 1/4 affected patients, in grade 2 locally administered dexamethasone solution recommended in 2/6, reduction of EVE to 5mg/day in 4/6 (in two cases the reduced dose left because of complications recurrences), in grade 3 locally administered dexamehasone solution recommended in 5/7, transient reduction of EVE to 5mg/day in 1/7, permanent reduction of EVE in 5/7 (recurrent aphthous lesions), EVE terminated in 1/7. In patients with EVE starting dose of 5mg/day there was one case (1/8, 12.5%) of grade 2 complication requiring no intervention. The complications developed within 2-20 weeks after EVE initiation (median of 8 weeks). CONCLUSION: The incidence of stomatitis and its severity in this cohort is comparable with published trials data, it confirms the significant incidence of damage affecting the quality of life, oral intake and anti-cancer treatment in daily practice. The interventions used in groups of similarly affected patients appears slightly heterogeneous, influenced by individual physician approach. There is tendency not to interrupt the EVE treatment and keep it either in a dosage of 10 or 5mg/day if the oral damage is tolerable. Local treatment with dexamethasone is not yet fully exploited.Key words: everolimus - stomatitis - mucositis - oral cavity Supported by the grant of Ministry of Health of the Czech Republic - Conceptual Development of Research Organization (Faculty Hospital in Pilsen - FNPl, 00669806) and National Sustainability Program I (NPU I) No. LO1503 provided by the Ministry of Education Youth and Sports of the Czech Republic. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 27. 2. 2017Accepted: 26. 3. 2017.

[Carcinoid of the Appendix Goblet Cells Metastasize to the Orbit - a Clinical Case Report and Review of the Literature]. / Karcinoid z pohárkových bunek apendixu metastazovaný do orbity -  klinická kazuistika a prehled literatury.

Goblet cell carcinoid (GCC) of the appendix is extremely rare, representing approximately 5% of all primary appendiceal neoplasms. Histologically there are three groups of GCC: group A (typical GCC), adenocarcinoma ex GCC signet ring cell type (group B), and adenocarcinoma ex GCC poorly differentiated carcinoma type (group C), which is the most aggressive. GCC metastasizes in 15-60% of cases, mainly to the ovaries, pelvis, abdominal cavity, ribs, vertebrae, and lymph nodes. Hematogenous metastasis to the liver or other parenchymal organs can occur, but this is very rare. The different organs metastases havent been described yet. The primary mode of treatment is radical surgical resection or debulking, followed by chemotherapy; however, patients with unresectable or recurrent GCC are candidates for systemic therapy. Here, we report a case of very aggressive GCC of the appendix, which had metastazed to the liver at the time of diagnosis and subsequently metastasized to the orbit.

Serum albumin is a strong predictor of survival in patients with advanced-stage non-small cell lung cancer treated with erlotinib.

Molecular targeted therapy based on tyrosine kinase inhibitors (TKI), directed at epidermal growth factor receptor (EGFR) is one of the novel effective agents in management of advanced-stage of Non Small Cell Lung cancer (NSCLC). However several candidate predictors have been extensively studied, apart from activating EGFR gene mutations, no reliable biochemical or molecular predictors of response to erlotinib have been validated. The aim of our retrospective study was to evaluate the association of baseline serum albumin with outcomes in a large cohort of patients with advanced-stage NSCLC treated with erlotinib. Clinical data of 457 patients with locally-advanced (III B) or metastatic stage (IV) NSCLC treated with erlotinib were analysed. Serum samples were collected and the measurement was performed one day before the initiation of erlotinib treatment. Before the treatment initiation, low albumin was (<35 g/l) measured in 37 (8.1%) patients and normal albumin (≥ 35 g/l) was measured in 420 (91.9%). The median PFS and OS for patients with low serum albumin was 0.9 and 1.9 months compared to 1.9 and 11.4 months for patients with normal serum albumin (p=0.001 and p<0.001). The multivariate Cox proportional hazards model revealed that EGFR mutation status (HR=2.50; CI: 1.59-3.92; p<0.001) and pretreatment serum albumin (HR=1.73; CI: 1.21-2.47; p=0.003) were significant independent predictive factors for PFS, whereas EGFR mutation status (HR=3.14; CI: 1.70-5.81; p<0.001), stage (HR=1.48; CI: 1.09-2.02; p=0.013), ECOG PS (HR=1.77; CI: 1.37-2.29; p<0.001) and pretreatment serum albumin (HR=4.60; CI: 2.98-7.10; p<0.001) were significant independent predictive factors for OS. In conclusion, the results of present retrospective study indicate that pretreatment hypoalbuminemia is associated with poor outcome of NSCLC patients treated with erlotinib. Based on these results, measuement of serum albumin is an objective laboratory method feasible for estimation of prognosis of patients with advanced-stage NSCLC.

[Polyneuropathic pain therapy with a patient suffering from generalized castrate- resistant prostate cancer -  clinical case report]. / Lécba polyneuropatické bolesti u nemocného s generalizovaným, kastracne rezistentním karcinomem prostaty -  klinická kazuistika.

BACKGROUND: Tapentadol is a µâ€Š-opioid receptors agonist as well as an inhibitor of noradrenaline reuptake. This pharmacologic profile of tapentadol makes it a suitable drug of choice in nociceptive and neuropathic pain control. CASE REPORT: This clinical report pressents a 65year old man with poorly differentiated prostate cancer -  Gleason score 8 (4 + 4) with metastatic bone disease. Besides the initial application of bisphosphonates, the patient had been treated with androgen deprivation therapy (cyproterone acetate + leuprolide acetate) for the period of 18 months. This therapy was terminated due to an increase of PSA levels. Subsequently, the patient underwent palliative docetaxelbased chemotherapy. There were eight cycles applied with positive clinical and laboratory effect. However, the further application was limited by the averse effects, namely the peripheral neuropathy manifested by pain in arms and legs. The peripheral neuropathy had progressive tendency even after the end of chemotherapy, and supportive treatment with gabapentin and amitryptiline failed to succeed. Four months after zoledronic acid monotherapy, the patient was started on tapentadol in 50-mg dose b.i.d., consequently escalated to 100 mg b.i.d. (to this point, 25 µg of transdermal fentanyl were used for pain management). Significant relief from neuropathic discomfort was observed three weeks from the onset of tapentadol therapy. Patients state of health normalized within three months after the initiation of therapy. Consequently, the patient was able to receive docetaxel chemotherapy again, without any neuropathic pain exacerbation on the maintenance dose of tapentadol 50 mg b.i.d. CONCLUSION: Tapentadol administration resulted in stable and longtime relief from neuropathic pain which is a frequent side effect in the course of castrate-resistant prostate cancer therapy with taxanes.

[Chylous ascites as a serious complication of the neuroendocrine tumor of ileum -  case report]. / Chylózní ascites jako závazná komplikace neuroendokrinního tumoru ilea -  kazuistika.

BACKGROUND: Chylous ascites is a rare complication of the gastrointestinal neuroendocrine tumor. There are two mechanisms of its origin: mechanical obstruction by the tumor mass and fibrosis of the surrounding tissue due to overproduction of serotonin. Its presence restricts treatment options. CASE: We report a case of 66year old man suffering from recurrent diarrhoea and ascites. We found elevated tumor marker Chromogranin A and elevation of hydroxyindoleacetic acid (5- HIAA) in the urine. A subsequent whole body scintigraphy scan by octreoscan confirmed multinodal process with increased somatostatin receptors activity in the wall of the ileum, rectosigmoideum, lymph nodes of the retroperitoneum and mesenterium and left supraclavicular area. We performed bio-psy from the lymph node of supraclavicular area, and there was metastasis of the neuroendocrine tumor. Start of cytostatic therapy was repeatedly complicated by recurrent massive chylous ascites. The patient underwent only one series of palliative chemotherapy. Another procedure was again complicated by chylous ascites that caused hospitalization at the internal department, and the patient died four months after dia-gnosis. CONCLUSION: Chylous ascites is a very rare complication of gastrointestinal neuroendocrine tumor. It is not only a marker of poor prognosis, but also a complication that makes systemic treatment very difficult.

Erlotinib in the treatment of advanced squamous cell NSCLC.

Erlotinib is an epidermal growth factor receptor tyrosine-kinase inhibitor. Clinical trials have shown its efficacy in advanced non-small cell lung cancer (NSCLC). We conducted a large retrospective study based on clinical experience aiming to prove erlotinib's efficacy and safety in patients with advanced-stage squamous cell NSCLC. Totally 375 patients with advanced-stage (IIIB, IV) squamous cell NSCLC were treated with erlotinib. Erlotinib was continued until disease progression or intolerable toxicity. 1 (0.3%) complete response (CR), 28 (7.5%) partial responses (PR) and 198 (52.8%) stable diseases (SD) were achieved. Overall response rate (ORR) and disease control rate (DCR) were 7.8% and 60.5%, respectively. Median progression-free survival (PFS) was 3.0 months and median overall survival (OS) was 7.6 months. PFS of patients with CR/PR, SD and PD were 7.6, 3.9 and 1.0 months, respectively (P<0.001). OS of patients with CR/PR, SD and PD were 13.3, 10.9 and 3.8 months, respectively (P<0.001).The most common adverse effects were rash and diarrhoea. In conclusion ertlotinib is effective and well-tolerated in patients with advanced-stage squamous cell NSCLC.

Comparison of EGFR-TKI and chemotherapy in the first-line treatment of advanced EGFR mutation-positive NSCLC.

Molecular targeted therapy based on EGFR tyrosine kinase inhibitors (EGFR-TKI) is currently astate of the art option for management of advanced stage NSCLC. Activating EGFR mutations are preferable for a good treatment response to EGFR-TKI. The presented retrospective study evaluated a clinical observation of EGFR-TKI aiming at its efficacy and safety in comparison to a standard chemotherapy in the first-line treatment of advanced stage NSCLC. Total number of patients with advanced stage (IIIB, IV) EGFR mutation-positive NSCLC was 54 of which 23 were treated with EGFR-TKI and 31 patients with various chemotherapy regimens in the first line. The treatment efficacy was characterized in terms of disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). The comparison of DCR was performed using Fisher's exact test and the differences in survival were tested using log-rank test. DCR for EGFR-TKI treatment was 95.6% vs. 70.9% for chemotherapy (p=0.032). Median of PFS in patients treated with EGFR-TKI was 7.2 months vs. 2.5 months in patients treated with chemotherapy (p<0.001). Median of OS was 14.5 months vs. 21.4 months (p=0.729). EGFR-TKI was associated with higher incidence of skin rash and diarrhoea; chemotherapy was associated with higher incidence of haematologic adverse events and nausea or vomiting. The analysis results showed a favourable DCR and PFS in patients treated with EGFR-TKI in the first line. The non-significant difference in OS could be attributed to a cross-over during the patient follow-up as well as the differences in performance status and age between both groups. EGFR-TKI is the optimal choice for the first-line treatment of EGFR mutation-positive NSCLC.

Skin rash as useful marker of erlotinib efficacy in NSCLC and its impact on clinical practice.

Erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor used in treatment of advanced NSCLC. Patients harboring EGFR or KRAS mutations represent minority of all patients in caucasian population and there is no available predictor for a predominant group of patients harboring the wild-type EGFR and wild-type KRAS genes. Skin rash is the most frequent manifestation of cutaneous toxicity of erlotinib. Rash is associated with a good therapeutic response. We aimed at the evaluation of rash as a predictor of therapeutic effect of erlotinib in patients harboring the wild-type EGFR and KRAS wild-type genes and to assess its possible usage in a clinical practice.Totally 184 patients with advanced stage NSCLC (IIIB, IV) harboring the wild-type EGFR and wild-type KRAS genes were analysed. Comparison of ORR, PFS and OS according to the occurrence of rash was performed. In order to assess the impact of rash in clinical practice it was conducted landmark analysis of the group of patients whose rash was observed during first month of treatment (n=124). Patients in whom progression was observed during the first month of treatment were excluded from the landmark analysis. The comparison of ORR was performed using Fisher's exact test, visualization of survival was performed using Kaplan-Meier survival curves and the differences in survival were tested using the log-rank test. Median PFS in patients who were observed with rash during the treatment was 3.0 vs. 1.2 months in patients with no rash (p<0.001), median of OS in patients who were observed with rash during the treatment was 13.9 vs. 5.8 months in patients with no rash (p<0.001). ORR in patients who were observed with rash during the treatment was 17.4% vs. 3.3% in patients with no rash (p=0.001). Median of PFS after 1 month of treatment in patients who were observed with rash during the first month was 2.9 vs. 1.1 months in patients with no rash (p=0.027). Median of OS after 1 month of treatment in patients who were observed with rash during the first month was 13.8 vs. 9.9 months in patients with no rash (p=0.082). Rash is strongly associated with better survival and ORR in patients harboring wild-type EGFR and wild-type KRAS genes. Occurrence of rash during the first month of treatment is a useful predictor of better effect of erlotinib after one month of treatment. Patients who were not observed with rash during the first month of treatment are in high risk of progression. Optimization of the treatment of these patients can contribute restaging after two months of treatment, assessment of plasma levels of erlotinib and eventually attempt to dose escalation.

Second line treatment in advanced non-small cell lung cancer (NSCLC): comparison of efficacy of erlotinib and chemotherapy.

Molecular targeted therapy based on tyrosine kinase inhibitors, directed at the epidermal growth factor receptor (EGFR) is one of novel options for management of NSCLC. Erlotinib is EGFR tyrosine kinase inhibitor used for treatment of the advanced NSCLC. This presented study is focused on comparison of erlotinib and chemotherapy efficacy in the second line treatment of the advanced NSCLC. DCR and PFS became the primary endpoints.Total number of patients was 290. A group treated with chemotherapy in the second line consisted of 150 patients and a group treated with erlotinib in the second line consisted of 140 patients. Comparison of DCR was performed using Fisher's exact test, visualization of PFS was performed using Kaplan-Meier survival curves and differences were tested using the log-rank test. Genetic testing was performed using PCR direct sequencing. In the group treated with chemotherapy 2 CR, 23 PR and 51 SD were achieved vs. 5 CR, 10 PR and 55 SD in the group treated with erlotinib in the second line. DCR in patients treated with chemotherapy was 54.0% vs. 51.3% in patients without EGFR mutation treated with erlotinib (p=0.707); in patients harboring EGFR mutation, treated with erlotinib (n=9) outstanding results were achieved: 4 CR, 2 PR and 3 SD (not tested). Median of PFS in patients treated with chemotherapy was 2.1 months vs. 1.9 months in patients without EGFR mutation (p=0.879) vs. 8.4 months in patients harboring EGFR mutation treated with erlotinib (p=0.017). Results of analysis show that even patients without EGFR mutation are able to benefit from erlotinib treatment in the second line. The efficacy (DCR, PFS) of erlotinib in patients without EGFR mutation was comparable with chemotherapy. The treatment efficacy in a subgroup of patients harbouring EGFR mutation treated with erlotinib was significantly better than in patients without EGFR mutation.

[EGFR mutations in patients with advanced NSCLC]. / Mutace genu EGFR u pacientu s pokrocilým NSCLC.

BACKGROUND: Molecular targeted therapy based on tyrosine kinase inhibitors, directed at the epidermal growth factor receptor (EGFR) is one of novel options for management of NSCLC. EGFR gene mutations, exon 19 deletions and exon 21 point mutations (L858R) are good predictors of response to EGFR-TKI treatment. The aim of this study was to assess the incidence of EGFR mutations in a large cohort of Europeans with advanced NSCLC and subsequently to evaluate their impact on the effect of EGFR-TKI treatment. PATIENTS AND METHODS: In total, 613 patients with advanced stage NSCLC (IIIB, IV) were genetically tested. The effect of treatment was evaluated in 410 patients treated with EGFR-TKI. Survival was evaluated using Kaplan-Meier method, and statistical comparison was performed using log-rank test. RESULTS: EGFR mutations were detected in 73 (11.9%) patients. Exon 19 deletions were detected in 49 patients, exon 21 point mutations (L858R) were detected in 22 patients, and both mutation types were detected in 2 patients. An increased incidence of EGFR mutations among patients with adenocarcinoma (14.9% vs 7.8%, p = 0.008), women (20.2% vs 7.1%, p < 0.001) and nonsmokers (29.9% vs 7.0%, p < 0.001) was demonstrated. Sixty patients with EGFR mutation and 350 patients with wild-type EGFR were treated with EGFR-TKI. Median PFS in patients harboring EGFR mutation was 7.2 vs 2.0 months in patients harboring wild-type EGFR (p < 0.001), median OS in patients harboring EGFR mutation was 14.5 vs 7.5 months in patients harboring wild-type EGFR (p = 0.019). CONCLUSION: The incidence of EGFR mutations in the studied population, their increased incidence among patients with adenocarcinoma, women and non-smokers correlated with data previously published. Results of survival analysis in patients treated with EGFR-TKI confirmed high potential of EGFR mutations to predict good effect of the EGFR-TKI treatment. Genetic testing in patients with NSCLC should be a standard part of diagnostic procedures

Cytokines and liver regeneration after partial portal vein ligation in porcine experimental model.

THE AIM OF STUDY: The limits of liver surgery are restricted today by the functional reserves of remnant parenchyma. The aim of this article was to acquaint the general surgical and medical public with the results of experimental liver regeneration stimulated by cytokines and thus to enhance their effort to carry on with implementing the research results in clinical practice. METHODS: Authors present their experimental model of liver regeneration after ligation of portal branches for caudate and right lateral, and right medial liver lobes. The regeneration was induced by application of TNF-alpha and IL-6 into the non-occluded portal branches, and compared with the results of other experimental teams. RESULTS AND CONCLUSION: The absolute volume of hypertrophic lobes increases after application of TNF-alpha more rapidly, whereas in the control group, practically no changes were recorded in hypertrophic liver lobes volumes in first three days. The achieved acceleration of growth of hypertrophic liver lobes after application of TNF-alpha and IL-6 confirmed the key role of studied pleiotropic cytokines in the priming of liver parenchyma regeneration after portal vein ligation (Fig. 3, Ref. 26).

Our experience with management of epiphyseolysis in children and adolescents.

A total of 58 children is referred to with fractured growth plates of the distal forearm, proximal humerus, radial condyle of humerus, ulnar epicondyle of humerus, distal tibia, proximal tibia and the distal femur. The related injuries are divided in accord with Salter-Harris classification. The treatment of epiphyseolyses is concerned together with summarizing its results and the appropriate experience. In addition, the indications for both conservative and surgical approaches are delimitated in treating these injuries.