Prognostic Value of EGFR Exon-20 Insertions in Czech Patients With Advanced Non-small Cell Lung Cancer.

BACKGROUND/AIM: Per literature, patients with epidermal growth factor receptor (EGFR) exon-20 insertions respond poorly to tyrosine kinase inhibitors (TKIs). This study analyzed real-world data to examine the prognostic and predictive value of these mutations. PATIENTS AND METHODS: We conducted a retrospective cohort study using Czech TULUNG Registry data, with data on multiple mutation types, collected in 2011-2020. RESULTS: We analyzed 554 (95.85%) patients with EGFR exon-19 deletions or exon-21 L858R substitutions and 24 (4.15%) patients with exon-20 insertions who received first-line high-value therapies. We summarized clinical characteristics and outcomes in all patients and by cohort. The risk of progression was statistically significantly higher (86%) in the exon-20 insertion cohort compared to the cohort with other mutations. Although not statistically significant, the risk of death was 44% higher in patients with exon-20 insertions. CONCLUSION: Advanced NSCLC patients with rare EGFR exon-20 insertions have a high risk of progression.

Identification of tumors with NRG1 rearrangement, including a novel putative pathogenic UNC5D-NRG1 gene fusion in prostate cancer by data-drilling a de-identified tumor database.

The fusion genes containing neuregulin-1 (NRG1) are newly described potentially actionable oncogenic drivers. Initial clinical trials have shown a positive response to targeted treatment in some cases of NRG1 rearranged lung adenocarcinoma, cholangiocarcinoma, and pancreatic carcinoma. The cost-effective large scale identification of NRG1 rearranged tumors is an open question. We have tested a data-drilling approach by performing a retrospective assessment of a de-identified molecular profiling database of 3263 tumors submitted for fusion testing. Gene fusion detection was performed by RNA-based targeted next-generation sequencing using the Archer Fusion Plex kits for Illumina (ArcherDX Inc., Boulder, CO). Novel fusion transcripts were confirmed by a custom-designed RT-PCR. Also, the aberrant expression of CK20 was studied immunohistochemically. The frequency of NRG1 rearranged tumors was 0.2% (7/3263). The most common histologic type was lung adenocarcinoma (n = 5). Also, renal carcinoma (n = 1) and prostatic adenocarcinoma (n = 1) were found. Identified fusion partners were of a wide range (CD74, SDC4, TNC, VAMP2, UNC5D), with CD74, SDC4 being found twice. The UNC5D is a novel fusion partner identified in prostate adenocarcinoma. There was no co-occurrence with the other tested fusions nor KRAS, BRAF, and the other gene mutations specified in the applied gene panels. Immunohistochemically, the focal expression of CK20 was present in 2 lung adenocarcinomas. We believe it should be considered as an incidental finding. In conclusion, the overall frequency of tumors with NRG1 fusion was 0.2%. All tumors were carcinomas. We confirm (invasive mucinous) lung adenocarcinoma as being the most frequent tumor presenting NRG1 fusion. Herein novel putative pathogenic gene fusion UNC5D-NRG1 is described. The potential role of immunohistochemistry in tumor identification should be further addressed.

IDH1 mutation is associated with lower expression of VEGF but not microvessel formation in glioblastoma multiforme.

INTRODUCTION: Glioblastoma multiforme (GBM) represents the most malignant primary brain tumor characterized by pathological vascularization. Mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) were observed in GBM. We aimed to assess the intra-tumor hypoxia, angiogenesis and microvessel formation in GBM and to find their associations with IDH1 mutation status and patients prognosis. METHODS: 52 patients with a diagnosis of GBM were included into the study. IDH1 R132H mutation was assessed by RT-PCR from FFPE tumor samples obtained during surgery. The expression of markers of hypoxia (HIF2α), angiogenesis (VEGF), tumor microvascularity (CD31, CD34, vWF, CD105), and proliferation (Ki-67) were assessed immunohistochemically (IHC). IDH1 mutation and IHC markers were correlated with the patient survival. RESULTS: 20 from 52 GBM tumor samples comprised IDH1 R132H mutation (38.5%). The majority of mutated tumors were classified as secondary glioblastomas (89.9%). Patients with IDH1 mutated tumors experienced better progression-free survival (P = 0.037) as well as overall survival (P = 0.035) compared with wild type tumors. The significantly lower expression of VEGF was observed in GBM with IDH1 mutation than in wild type tumors (P = 0.01). No such association was found for microvascular markers. The increased expression of newly-formed microvessels (ratio CD105/CD31) in tumor samples was associated with worse patient's progression-free survival (P = 0.026). SUMMARY: No increase in HIF/VEGF-mediated angiogenesis was observed in IDH1-mutated GBM compared with IDH1 wild type tumors. The histological assessment of the portion of newly-formed microvessels in tumor tissue can be used for the prediction of GBM patient's prognosis.

The Effectiveness of Febrile Neutropenia Prophylaxis with Lipegfilgrastim in Routine Clinical Practice.

Febrile neutropenia (FN) is a common and potentially fatal complication of anticancer treatment, particularly in patients receiving myelosuppressive chemotherapy. It has been shown that prophylaxis with granulocyte colony-stimulating factor (G-CSF), especially its pegylated forms, significantly reduces the incidence of FN, the likelihood of chemotherapy dose intensity reduction and, also, the number of hospitalizations due to FN. This review discusses currently published results from clinical trials dealing with FN prophylaxis in routine clinical practice in patients with solid tumors and myeloproliferative malignancies with a focus on lipegfilgrastim, which is the newest modification of the original molecule filgrastim. The discussed results proved that prophylactic administration of lipegfilgrastim can almost eliminate the risk of FN and significantly reduce the risk of chemotherapy (CHT) dose reduction in routine clinical practice in cases of a clear high-risk chemotherapy regimen or in the presence of risk factors (such as age, comorbidities, performance status, etc.) in patients who received chemotherapy with medium risk of FN.

Evaluation of Tumor Markers and Their Impact on Prognosis in Gallbladder, Bile Duct and Cholangiocellular Carcinomas - A Pilot Study.

BACKGROUND/AIM: The behavior of tumor markers in biliary tract malignancies is not well-known and has been scarcely studied. Such markers could play important roles in diagnostic and prognostic schemes as well as in decision-making about the best treatment strategies. This study analyzed the preoperative serum levels of conventional tumor markers (AFP, CEA, CA 19-9, CA 72-4), proliferative marker thymidine kinase (TK) and cytokeratins (TPA, TPS and CYFRA 21.1) in patients with gallbladder carcinoma, bile duct carcinoma (Klatskin) and cholangiocellular carcinoma, in relation to the patient prognosis. The study aimed in finding the role of tumor markers in not properly investigated diseases, where their importance is often marginalized. MATERIALS AND METHODS: The study included 43 patients, who underwent either radical surgical procedure (n=21) or explorative laparotomy without any surgical treatment (n=22) for gallbladder carcinoma, bile duct carcinoma (Klatskin tumor) and cholangiocellular carcinoma (24, 8 and 11 patients, respectively) between 2003 and 2010 at our Department. The association of serum tumor markers and patients' prognosis were assessed for the entire cohort and for each cancer type and also with regard to treatment (radical surgery versus explorative laparotomy). Overall survival (OS) and disease-free interval (DFI) were estimated by the Kaplan-Meier method and statistically evaluated using the LogRank test. DFI was computed only in the subgroup of patients treated by radical surgery. RESULTS: The statistical analysis of tumor markers revealed TK as a poor prognostic factor for shorter DFI (HR=3.5, 95%CI=0.6-21.3, p<0.05) and also OS (HR=4.6, 95%CI=1.0-4.7, p<0.05) in patients with gallbladder carcinoma treated with radical surgery. TPS was demonstrated as a poor prognostic factor for OS in patients with gallbladder carcinoma (HR=12.7, 95%CI=1.4-117.7, p<0.05). CEA was proven to be a factor of poor prognosis with shorter OS in patients after explorative laparotomy for all cumulated studied diagnoses (HR=9.8, 95%CI=1.05-92.7, p<0.05). CONCLUSION: The results of this study suggested the importance of tumor markers for assessment of prognosis (OS or DFI) in patients with gallbladder carcinoma, bile duct carcinoma, and cholangiocellular carcinoma.

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) represents the most malignant primary brain tumor in adults with generally dismal prognosis, early clinical deterioration and high mortality. GBM is extremely invasive, characterized by intense and aberrant vascularization and high resistance to multimodal treatment. Standard therapy (surgery, radiotherapy and chemotherapy with temozolomide) has very limited effectiveness, with median overall survival of patients no longer than 15 months. Progress in genetics and epigenetics of GBM over the past decade has revealed various aberrations in cellular signaling pathways, the tumor microenvironment, and pathological angiogenesis. A number of targeted anticancer drugs, such as small-molecule kinase inhibitors and monoclonal antibodies, have been evaluated in clinical trials with newly-diagnosed, as well as recurrent GBM. Unfortunately, to date, only a single anti-angiogenic agent, bevacizumab, has been approved for the treatment of recurrent GBM in the USA and Canada. The novel possibilities of cancer immunotherapy, especially immune checkpoint inhibitors, are being evaluated in clinical trials of patients with GBM. The most recent clinical experiences with targeted therapy as well as immunotherapy of GBM are given in this review. The relative lack of success of some of these approaches recently revealed in well-designed randomized clinical trials is also discussed.

Pre-transplant Quantitative Determination of NPM1 Mutation Significantly Predicts Outcome of AIlogeneic Hematopoietic Stem Cell Transplantation in Patients with Normal Karyotype AML in Complete Remission.

BACKGROUND/AIM: Minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) before allogeneic hematopoietic stem cell transplantation (alloHSCT) can influence the results of therapy. With the aim of evaluating the potential role of pre-transplant MRD, we studied the impact of pre-transplant MRD level on the outcome of alloHSCT in patients with AML in complete remission (CR). PATIENTS AND METHODS: From 2/2005 to 9/2014, 60 patients with a median age of 54 years (range=30-66 years) with normal karyotype-AML harboring nucleophosmin 1 (NPM1) mutation [53% Fms-related tyrosine kinase receptor 3 internal tandem duplication (FLT3/ITD)-positive] in first (n=45) or second (n=15) CR underwent myeloablative (n=16) or reduced-intensity (n=44) alloHSCT (27% related, 73% unrelated). The MRD level was determined from bone marrow samples using real-time polymerase chain reaction for detection of NPM1 mutations before starting the conditioning regimen. RESULTS: The estimated probabilities of 3-year relapse, event-free survival (EFS) and overall survival (OS) for the whole cohort were 28%, 54%, and 59%, respectively. Statistical analysis showed that only age over 63 years and high MRD level affected alloHSCT outcome. Pre-transplant MRD level of 10 mutant copies of NPM1 per 10,000 Abelson murine leukemia viral oncogene homolog 1 (ABL) copies had the strongest statistical significance, and detection of higher MRD level (>10 NPM1-mutant copies) before alloHSCT was associated with increased overall mortality (hazard ratio=3.71; 95% confidence interval=1.55-9.06; p=0.004). The estimated probabilities of 3-year relapse, EFS, and OS were 6%, 72%, and 75% for patients with a low level of MRD and 48%, 35%, and 40% for patients with a higher level. CONCLUSION: Our data showed that the pre-transplant level of MRD in patients with normal karyotype AML harboring NPM1 mutation in CR provides important prognostic information, which as an independent prognostic factor predicts transplant results.

The Role of Cetuximab in the Induction of Anticancer Immune Response in Colorectal Cancer Treatment.

Monoclonal antibodies binding the epidermal growth factor receptor (EGFR), such as cetuximab or panitumumab, are widely used targeted therapeutics for the treatment of patients with colorectal cancer. The clinical significance of these drugs has so far been associated with combined chemotherapy or radiation. It has been shown that these treatment strategies have their clinical limitations and do not fully exploit the immunomodulatory effect of these drugs. In this review, we discuss the mechanisms of immunomodulation together with the anticancer immune response to the monoclonal antibodies targeted to the EGFR. The combination of anti-EGFR monoclonal antibodies with other immunotherapeutic treatment modalities certainly brings new opportunities for targeted therapy in patients with colorectal cancer.

Patient-reported outcomes with lanreotide Autogel/Depot for carcinoid syndrome: An international observational study.

BACKGROUND: Lanreotide Autogel/Depot effectively controls symptoms in patients with carcinoid syndrome associated with neuroendocrine tumours. Data on patient-reported outcomes are sparse. AIM: To evaluate the effect of lanreotide on patient-reported outcomes (PROs) with carcinoid syndrome. METHODS: This was an international, open-label, observational study of adults with neuroendocrine tumours and history of diarrhoea, receiving lanreotide for >3 months for relief of carcinoid syndrome symptoms. The primary PRO measure was satisfaction with diarrhoea control. Secondary PRO measures included severity, change in symptoms and impact on daily life of diarrhoea; and patient satisfaction with flushing control. RESULTS: Of 273 patients enrolled, 76% were 'completely' or 'rather' satisfied with diarrhoea control; 79% reported improvement in diarrhoea with lanreotide. The proportion of patients with 'mild', 'minimal', or 'no diarrhoea' increased from 33% before treatment to 75% during treatment; 75% were unconcerned about the impact of diarrhoea on daily life. Satisfaction with flushing control amongst patients with significant flushing at treatment initiation was 73%. CONCLUSIONS: Lanreotide treatment was associated with improvements in symptoms as well as a range of PROs in patients with neuroendocrine tumours and carcinoid syndrome (ClinicalTrials.gov: NCT01234168).

G12V and G12A KRAS mutations are associated with poor outcome in patients with metastatic colorectal cancer treated with bevacizumab.

The v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are found in 35-45 % of colorectal cancer (CRC) cases. Although the association between the RAS signaling and angiogenesis is well known, the negative predictive value of KRAS mutation has not been established in patients treated with bevacizumab. The aim of this study was to evaluate the association between specific KRAS mutation types and outcome of patients with metastatic CRC treated with bevacizumab. The study included 404 patients with metastatic CRC (mCRC) treated with bevacizumab. Clinical data obtained from the clinical registry CORECT were retrospectively analyzed. The shortest survival was observed in patients with tumors harboring G12V or G12A KRAS mutation (G12V/A). The median progression-free survival (PFS) and overall survival (OS) for patients with tumors harboring G12V/A KRAS mutation was 6.6 and 16.8 compared to 11.6 and 26.3 months for patients with tumors harboring other KRAS mutation type (p < 0.001 and p < 0.001), while the survival of patients harboring other KRAS mutation types was comparable to those with tumors harboring wild-type KRAS gene. In the Cox multivariable analysis, KRAS G12V/A mutation type remains a significant factor predicting both PFS (HR = 2.18, p < 0.001) and OS (HR = 2.58, p < 0.001). In conclusion, the results of the present study indicate that there is a significant difference in biological behavior between tumors harboring G12V/A and other KRAS mutations. Moreover, comparison of the survival of patients with tumors harboring G12V/A KRAS mutations with those harboring wild-type KRAS gene revealed that G12V/A KRAS mutations are prognostic biomarker for inferior PFS and OS in patients with mCRC treated with bevacizumab in univariate as well as multivariable analyses.

Tissue Biomarkers in Predicting Response to Sunitinib Treatment of Metastatic Renal Cell Carcinoma.

AIM: To identify tissue biomarkers that are predictive of the therapeutic effect of sunitinib in treatment of metastatic clear cell renal cell carcinoma (mCRCC). MATERIALS AND METHODS: Our study included 39 patients with mCRCC treated with sunitinib. Patients were stratified into two groups based on their response to sunitinib treatment: non-responders (progression), and responders (stable disease, regression). The effect of treatment was measured by comparing imaging studies before the initiation treatment with those performed at between 3rd and 7th months of treatment, depending on the patient. Histological samples of tumor tissue and healthy renal parenchyma, acquired during surgery of the primary tumor, were examined with immunohistochemistry to detect tissue targets involved in the signaling pathways of tumor growth and neoangiogenesis. We selected mammalian target of rapamycine, p53, vascular endothelial growth factor, hypoxia-inducible factor 1 and 2 and carbonic anhydrase IX. We compared the average levels of biomarker expression in both, tumor tissue, as well as in healthy renal parenchyma. Results were evaluated using the Student's t-test. RESULTS: For responders, statistically significant differences in marker expression in tumor tissue versus healthy parenchyma were found for mTOR (4%/16.7%; p=0.01031), p53 (4%/12.7%; p=0.042019), VEGF (62.7%/45%; p=0.019836) and CAIX (45%/15.33%; p=0.001624). A further significant difference was found in the frequency of high expression (more than 60%) between tumor tissue and healthy parenchyma in VEGF (65%/35%; p=0.026487) and CAIX (42%/8%; p=0.003328). CAIX was expressed at high levels in the tumor tissue in both evaluated groups. CONCLUSION: A significantly higher expression of VEGF in CRCC in comparison to healthy parenchyma can predict a better response to sunitinib.

The Association of Serum Carcinoembryonic Antigen, Carbohydrate Antigen 19-9, Thymidine Kinase, and Tissue Polypeptide Specific Antigen with Outcomes of Patients with Metastatic Colorectal Cancer Treated with Bevacizumab: a Retrospective Study.

The aim of our retrospective study was to analyze the association of selected tumor markers (TMs) including serum carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), thymidine kinase, and tissue polypeptide specific antigen with outcomes in patients with metastatic colorectal cancer (mCRC) treated with bevacizumab. There is an increasing body of evidence from retrospective/observational studies that some serum TMs may be predictive of effect of targeted therapies in mCRC. In our study, the cohort included 152 patients treated with bevacizumab-based therapy between years 2005 and 2014 at Department of Oncology and Radiotherapy, Medical School and Teaching Hospital Pilsen. Serum samples for measurement of TMs were collected within 1 month before the initiation of bevacizumab-based treatment. In multivariate Cox analysis that included serum tumor markers and clinical baseline parameters, the number of metastatic sites (hazard ratio [HR] = 2.00, p = 0.001) and CEA levels (HR = 2.80, p < 0.001) were significantly associated with progression-free survival, whereas CA 19-9 levels (HR = 2.25, p = 0.008) were the only studied parameter associated with overall survival. Quantification of serum CEA and CA 19-9 is simple and readily available, and their candidate prognostic importance in the setting of antiangiogenesis therapy deserves to be studied in prospective trials.

[Deferred breast reconstruction - soul surgery?]. / Odlozené rekonstrukce prsu - chirurgie duse?

BACKGROUND: The loss or mutilation of a breast as a result of surgical treatment of neoplastic disease always represents a negative impact on a woman's psyche and negatively influences the quality of the woman's remaining life. The goal of our work was to implement deferred breast reconstruction into routine practice and the objectification of the influence of reconstruction on bodily integrity, quality of life, and the feeling of satisfaction in women. METHODS AND RESULTS: Women in remission from neoplastic disease after a radical mastectomy were indicated for breast reconstruction. Between January 2002 and December 2011 deferred breast reconstruction was carried out 174 × on 163 women, with an average age of 49.2 and an age range of 29-67 years. The most frequently used reconstruction method was a simple gel augmentation of the breast or a Becker expander/implant - 51 (29.3%) and 37 (21.3%), or in combination with a lateral thoracodorsal flap (31; 17.8% and 47; 27%); reconstruction using a free DIEP flap was carried out 7 × (4%). Complications occurred in 19 operations (10.9%) with a dominance of inflammation and pericapsular fibrosis, in a subjective analysis, satisfaction with the results prevailed, along with an increased quality of life after reconstruction. CONCLUSION: A growing number of deferred breast reconstructions, women's satisfaction with the results, the positive influence of renewed bodily integrity on the feeling of life satisfaction and the quality of life have elevated breast reconstructions to a qualitatively higher level.

The role of cetuximab in the treatment of metastatic colorectal cancer.

Targeted biological therapy is becoming a standard in personalized medicine for patients with advanced stages of cancer. Treatment with cetuximab, an anti-epidermal growth factor receptor (EGFR) antibody, represents an example of personalized anticancer therapy for patients with metastatic colorectal cancer and wild (non-mutated) type of the Kirsten rat sarcoma viral oncogene (KRAS). Here the role of cetuximab in treating metastatic colorectal cancer is discussed with a focus on the treatment of hepatic metastases.

Functional, genetic, and epigenetic aspects of base and nucleotide excision repair in colorectal carcinomas.

PURPOSE: DNA repair capacity (DRC) is a determinant not only of cancer development but also of individual response to therapy. Previously, altered base and nucleotide excision repair (BER and NER) have been described in lymphocytes of patients with sporadic colorectal cancer. We, for the first time, evaluate both excision repair capacities in human colon biopsies to study their participation in colorectal tumorigenesis. EXPERIMENTAL DESIGN: Seventy pairs of tumor and adjacent healthy tissues were analyzed for BER- and NER-specific DRC by a comet repair assay. Tissue pairs were further compared for expression levels of a panel of 25 BER and NER genes complemented by their promoter methylation status. RESULTS: We observed a moderate increase of NER-DRC (P = 0.019), but not of BER-DRC in tumors. There was a strong correlation between both tissues for all investigated parameters (P < 0.001). However, 4 NER (CSB, CCNH, XPA, XPD) and 4 BER (NEIL1, APEX1, OGG1, PARP1) genes showed a 1.08- to 1.28-fold change difference in expression in tumors (P < 0.05). Individual gene expression levels did not correlate with overall DRC, and we did not detect any aberrant methylation of the investigated genes. CONCLUSIONS: Our complex analysis showed that tumor cells are not deficient in BER and NER, but rather follow patterns characteristic for each individual and are comparable with adjacent tissue. Alteration of excision repair pathways is not a pronounced event in colorectal carcinogenesis. This study shows the feasibility of DRC evaluation in human solid tissues, representing a complex marker of multigene DNA repair processes.

Infiltration of colorectal carcinoma by S100+ dendritic cells and CD57+ lymphocytes as independent prognostic factors after radical surgical treatment.

BACKGROUND: S100(+) dendritic cells and CD57(+) lymphocytes are factors reflecting the immune system's ability to suppress the progress of tumor growth. CD57(+) cells include natural killer cells and late stages of T-effector lymphocytes. We evaluated the relationship between the known clinical and histological factors and tumor markers as well as the presence of S100(+) and CD57(+) cells in the tissue of colorectal carcinoma with the aim of detecting patients at high risk of short overall survival (OS) or short disease-free interval (DFI) after radical surgical treatment and we further analyzed whether S100(+) and CD57(+) positivity could bring on new information regarding the treatment regimen. MATERIALS AND METHODS: Data of 150 patients (97 males and 53 females) that underwent an elective radical surgical procedure for colorectal cancer were studied. The influence on DFI and on OS of the following parameters was evaluated: grading, staging and positivity for S100 and CD57 by immunohistochemical staining. We also analyzed the relation of preoperative serum levels of the tumor markers Carcinoembryonic Antigen (CEA), Cancer Antigen 19-9 (CA19-9), Cancer Antigen 72-4 (CA72-4), Thymidine kinase (TK), Tissue-Specific Polypeptide Antigen (TPS) and Tissue Polypeptide Antigen (TPA) in relation to S100 and CD57 positivity/negativity for the same patients. RESULTS: OS at 1, 3 and 5 years was 92.2%, 76.5% and 70.2%; the DFI at 1, 3 and 5 years was 85.3%, 64.3% and 49.4%. CD57 positivity in the tumor mass was proven as a positive prognostic factor for OS. Risk of short OS was 2.5-fold higher in patients with low tumor infiltration by CD57(+) lymphocytes. The combination of N2 stage for lymph nodes and the absence of CD57(+) cells was proven to be the strongest negative prognostic factor for OS. No significant influence of CD57 positivity on DFI appeared. There was no significant influence of S100 positivity on OS or DFI; nor was there any statistical dependence of CD57 and S100 positivity or negativity on preoperative serum levels of CEA, CA19-9, CA72-4, TK, TPS or TPA. Both studied factors were shown to be statistically independent factors. CONCLUSION: The present study showed infiltration of colorectal cancer tissue by CD57(+) cells as being an important independent positive prognostic factor for OS.

Tumour necrosis factor-alpha stimulates liver regeneration in porcine model of partial portal vein ligation.

BACKGROUND/AIMS: Portal vein ligation (PVL) could multiply the future liver remnant volume (FLRV). Tumor necrosis factor- alpha (TNF-α) is a pleiotropic cytokine that is connected with initial phase of liver regeneration. The aim of this basic pilot study was to accelerate regeneration of liver parenchyma after PVL. The experimental porcine model was developed to be as much compatible as possible with portal vein embolization (PVE) in human medicine. METHODOLOGY: After ligation of portal branches of caudate and right lateral and right medial liver lobes recombinant porcine TNF-α (TNF-α group) or physiological solution (control group) were applied into non-occluded portal vein branches. The biochemical and immunoanalytical parameters were assessed. The compensatory hypertrophy was evaluated by periodic ultrasonography. The histological examination of liver was performed. RESULTS: The acceleration of growth of hypertrophic liver lobes was maximal at the 7th postoperative day in comparison with the control group (p<0.05); nevertheless this stimulating effect was lost at the end of experiment. The important differences in biochemical or histological studied parametres between study groups were not proved. CONCLUSIONS: The achieved acceleration of growth of hypertrophic liver lobes after application of TNF-α confirms the role of studied cytokine in priming of liver regeneration.

Inhibition of transforming growth factor beta-1 augments liver regeneration after partial portal vein ligation in a porcine experimental model.

BACKGROUND/AIMS: TGF-ß1 is a pleiotropic cytokine that is over expressed in terminal phase of liver regeneration. METHODOLOGY: Twenty-four hours after partial portal vein ligation monoclonal antibody against TGF-ß1 (TGF-ß1 group, 7 piglets) or physiological solution (control group, 9 piglets) were applied into the central venous catheter. The biochemical parameters (bilirubin, urea, creatinine, alkaline phosphatase, gamma- glutamyl transferase, cholinesterase, aspartate aminotransferase, alanine aminotransferase and albumin) were assessed. The compensatory hypertrophy of the non-occluded liver lobes was evaluated by periodic ultrasonography during the next fourteen days and by histological examination. RESULTS: The acceleration of growth of the hypertrophic liver lobes was maximal between 3rd and 7th postoperative days in comparison with the control group (p<0.05). No important differences in the biochemical or studied histological parameters were proved. CONCLUSIONS: The present study describes a new usage of monoclonal antibody against TGF-ß1 in large animal experimental model of partial portal vein ligation.

Prognostic significance of TIMP-1 in non-small cell lung cancer.

UNLABELLED: Tissue inhibitor of metalloproteinases 1 (TIMP1) regulates not only extracellular matrix catabolism but the major effect in tumor tissue is promotion of cell growth and anti-apoptotic activity. The aim of our study was to evaluate plasma TIMP1 levels and tissue TIMP1 mRNA expression as prognostic markers in NSCLC patients. PATIENTS AND METHODS: We studied a group of 108 patients with NSCLC who had undergone lung surgery. Estimation of TIMP1 mRNA was performed by quantitative polymerase chain reaction (qPCR) and estimation of plasma TIMP1 protein using enzyme-linked immunosorbent assay (ELISA). RESULTS: There was shorter disease-free interval (DFI) for NSCLC patients at stage II, with a higher expression of TIMP1 mRNA in tumor tissue (p=0.0246). We recorded a relationship between tumor tissue TIMP1 mRNA expression and DFI in squamous cell carcinoma (SCC) (p=0.0117). Shorter overall survival was found in patients at stages IIIa+IIIb+IV, with a higher expression of TIMP1 mRNA (p=0.0389). We found differences in plasma TIMP1 levels between patients with SCC and those with adenocarcinoma (p=0.0491). CONCLUSION: A higher tissue level of TIMP1 mRNA is related to an adverse prognosis of patients. However, our results did not show any relation of TIMP1 protein in blood plasma to prognosis.

Vitamin D in colorectal, breast, prostate and lung cancer: a pilot study.

BACKGROUND: Many studies have demonstrated the relationship between vitamin D and cancer of many different sites, including of the breast, colorectum, prostate and lung. Most epidemiological studies have assessed the effects of dietary intake only, although endogenous production after sun exposure is the main source of vitamin D. The aim of our pilot study was to study serum levels of vitamin D in general population and in patients with different type of cancer. PATIENTS AND METHODS: The control group consisted of 214 healthy individuals. Pathological groups of patients included 170 patients with different cancer types (28 patients with prostate cancer, 43 patients with breast cancer, 49 patients with colorectal cancer and 50 patients with lung cancer). All of the patients were enrolled in the early clinical stage of cancer up to clinical stage III. Advanced stages were not included into the study. Vitamin D serum levels were measured using ECLIA Roche method. RESULTS: All the results for serum vitamin D from pathological groups were significantly lower compared to the levels of the control group. All the cancer types had a high incidence rate of very low serum levels of vitamin D. Lung cancer had the highest incidence rate of very low vitamin D serum levels. CONCLUSION: We found a high incidence of hypovitaminosis D in cancer patients compared to a healthy control group among a Czech population. This incidence rate is higher in comparison to data found in literature from the other parts of the world. Based on the data from this study, a large epidemiological study monitoring vitamin D serum levels in the healthy population and in cancer patients in the Czech Republic has been already proposed.