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P Klener

Publications and source records attributed to P Klener.

At least 19 recordsLinked to original sources
PubMed2006

Cell death signalling pathways in the pathogenesis and therapy of haematologic malignancies: overview of apoptotic pathways.

Apoptosis, a Greek descriptive term for falling leaves or petals, plays an important role in the progression of many diseases. Apoptosis is essential for the development and survival of multi-cellular organisms. Malignant diseases, including haematologic malignancies, are associated with defects in the cell death mechanism. These defects are not only important for the growth advantage of malignant clones, but when understood can be used for specific therapeutic targeting of malignant cells while sparing normal cells. The cellular and molecular mechanisms of apoptosis have been extensively demonstrated and are reviewed in this article. In this part of the review we focus on basic details of the apoptosis pathways, key players of the receptor-mediated apoptosis, and molecules involved in the cross-talk between individual apoptosis pathways and apoptosis regulation.

Animals↗
PubMed2006

Cell death signalling pathways in the pathogenesis and therapy of haematologic malignancies: overview of therapeutic approaches.

Malignant diseases, including haematologic malignancies, are associated with defects in the cell death mechanism. These defects are not only important for the growth advantage of the malignant clone, but when understood can be used for specific therapeutic targeting of malignant cells while sparing normal cells. The promising groups of agents that trigger, directly or indirectly, apoptosis of haematologic cancer cells are reviewed in this article. Some of the agents have recently been approved for therapy, some are under the clinical evaluation in various phases of clinical trials and some are tested under the experimental laboratory conditions.

Animals↗
PubMed2006

[Some new findings in the pathogenesis of myeloproliferative disorders and new insight into more effective treatment].

Advances in molecular biology and genomics enabled more detailed view on the pathogenesis of myeloproliferative disorders, which are considered to be a diseases of hematopoietic stem cell. The autor provides an brief overview of the genetic alterations, leading to the chronic myeloid leukemia, myelodysplastic syndrome and acute myeloid leukemia. In the second part, molecular targeted therapies that have been developed based on these insights are reviewed. These are particularly methods preventing increased proliferation such as inhibition of tyrosinkinases (imatinib, dasatinib), inhibitions of farnesyltransferase (tipifarnib), inhibition of angiogenesis (bevacizumab, vatalanib), induction of diferentiation (hypomethylating agenents) and induction of apoptosis (bortezomib). More detailed information is given on some novel drugs which are currently in clinical trials.

Humans↗
PubMed2006

[High dose therapy with autologous stem cell transplantation in patients with Hodgkin's lymphoma: long-term follow-up in patients treated in one center].

BACKGROUND: Majority of patients with Hodgkin's Lymphoma (HL) can be cured by first line therapy. The high dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the option which can be used in the situation when the conventional therapy failed. METHODS AND RESULTS. Beginning 1994 till 2005 84 pts with HL who did not respond the conventional chemotherapy underwent 105 HDT procedures with ASCT. The median age at the time of HDT was 30.5 years. The reason for salvage therapy followed by HDT with ASCT was the failure to achieve 1st complete remission-- CR (n 16) or the subsequent relapse or progression (n 68). The disease status at the time of HDT after conventional salvage chemotherapy was assessed as chemosensitive in 65 pts (77.4%) and chemoresistant in 19 pts (22.6%). The most frequent HDT regimen used was BEAM (82 HDT), 22 pts entered into the tandem HDT program. Bone marrow only was used as the source of progenitor cells in 4 ASCT, peripheral blood progenitor cells (PBPC) only were used in 85 ASCT and the combination of both in 16 ASCT. The disease status after the HDT with ASCT was assessed (77 pts were qualifiable) as CR in 39 pts (50.6%), PR in 31 (40.3%) and as stable disease or progression in 7 pts (9.1%). Treatment related mortality in HDT with PBPC was 3.9%. The median follow up is 5.3 years. The five year probability of event free survival (EFS) is 43.1% and overall survival 53.2%. The EFS and OS probability respectively for the chemosensitive patients was 48.6% and 62.9% respectively. The status at HDT and the results after it have prognostic significance. There were observed 39 deaths and 26 of them were caused by disease progression. Secondary tumor was observed in 5 pts and in all of them it caused the death. CONCLUSIONS: The HDT with ASCT allows the long-term survival without disease progression in about a half of the patients with reasonable toxicity.

Adult↗
PubMed2006

[Cefepime as an empiric treatment of febrile neutropenia in patients after high dose therapy and autologous stem cell transplantation].

BACKGROUND: Febrile neutropenia is one of the most frequent complications in intensively treated hematooncological patients and almost inevitably occurs after high dose therapy and autologous stem cell transplantation. Empiric broad-spectrum antibiotic treatment is indicated in the initial management. Fourth-generation cephalosporins are the option. This retrospective study was initiated to assess efficacy and safety of cefepime as an empiric therapy of febrile neutropenia following high dose therapy and autologous stem cell transplantation. METHODS AND RESULTS: 319 high dose therapy procedures with autologous stem cell transplantation in 287 patients mostly with hematological malignancies were performed at our department between January 2002 and December 2005. We present analysis of 169 out of 229 febrile episodes in 163 patients (median age 53) being treated with cefepime in the initial empiric treatment of febrile neutropenia. 12 episodes (7.1 %) were clinically documented (pneumonia 9, sinusitis 2, acute cholecystitis 1), 60 (35.5 %) were confirmed microbiologically (presented as bacteremia) and 97 (57.4 %) were fever of unknown origin. 50 isolates (83.4 %) out of 60 microbiologically documented infections were G-positive bacteria, 8 isolates (13.3 %) were G-negative bacteria and 2 (3.3 %) were mixed G-positive and G-negative cultures. According to the MASCC score 14 episodes were assessed as high risk. Effect of cefepime as a single agent was observed in 85 episodes (50.3 %) and in 22 (13.0 %) episodes treated with combination therapy due to susceptibility of isolated pathogen in blood culture. Combination therapy of two antibiotics (cefepime + aminoglycoside or glycopeptide) given for persistent fever was effective in 13 patients (7.7 %). Treatment failure was observed in 48 (28.4 %) episodes, we registered 10 death. CONCLUSIONS: Therapy with cefepime represents an appropriate choice for empiric antibiotic treatment of febrile neutropenia in hematooncological patients. Cefepime demonstrates clinical safety and efficacy and can be used in monotherapy or in combination with other drugs (overall response 72.2 %, as a single agent 50.3 %).

Adult↗
PubMed2005

The use of comparative duplex PCR in monitoring of patients with non-Hodgkin's lymphoma and chronic lymphocytic leukaemia.

Various quantitative PCR approaches have been utilized during the last years to provide information about the treatment efficacy and the risk of recurrent disease in haematological malignancies. Apart from the frequently used real-time PCR, cost-saving modified standard PCR methods may be applied as well. This report evaluates the utility of the end-point comparative duplex PCR. We have used this method for monitoring of 35 patients with either NHL or CLL and observed a good correlation between quantitative molecular results and clinical outcome. There was also an agreement between comparative duplex PCR and real-time PCR in patients who were monitored by both methods. We therefore believe that use of this technique should be strongly considered instead of simple qualitative detection in monitoring of therapeutic outcome in NHL or CLL patients.

Genetic Markers↗
PubMed2005

[Current and perspective treatment of chronic lymphocytic leukemia].

Chronic lymphocytic leukemia represents the most frequent hematological malignancy in the western population. Important role in its pathogenesis has the inhibition of apoptosis, disturbances in differentiation of B-lymphocytes, slightly increased proliferation and induction of angiogenesis. Current treatment options (chemotherapy and immunotherapy) can improve the quality of life and prolong disease-free survival, but the overall survival is not significantly influenced. The only curative treatment alternative is the allogeneic hematopoietic stem cell transplantation. However, this treatment is accompanied by the risk of peritransplantation mortality and its use is limited for younger patients. Number of new compounds is clinically tested. New drugs can influence intracellular events such as induction of apoptosis or inhibition of the transduction cascade. Review summarises treatment alternatives and presents an algorithm for their clinical application.

Humans↗
PubMed2005

[Bortezomib (Velcade) in relapsed/refractory multiple myeloma--the first experience in the Czech Republic].

BACKGROUND: Multiple myeloma is the second most prevalent and mostly fatal hematologic cancer. Further advances have been made in understanding the mechanisms involved in the myeloma pathogenesis and elucidation of critical signalling pathways as therapeutical targets. Proteasome inhibitors are the example of this new approach and bortezomib is the first agent in this class to enter clinical trials. METHODS AND RESULTS: In 6 hematological centers in Czech Republic 29 patients with refractory/relapsed myeloma had been treated with bortezomib (Velcade, Millennium Pharmaceuticals) in 2004. The initial dose 1.3 mg/m2 of Velcade was given, in 1 case the dose was adjusted due to pre-existing renal failure to 1 mg/m2. The response was achieved in 17 patients (59%). Four patients had complete, 11 partial and two minor responses. In 5 cases stabilization of disease was observed and 6 patients progressed during the therapy. CONCLUSIONS: Unfortunately, one patient died immediately after the start of therapy due to sepsis. The most common adverse events were thrombocytopenia, anaemia, neuropathy, gastrointestinal complication, renal failure and fatigue. Grade 4 adverse events occurred in 37.9% of patients (4x thrombocytopenia, 2x gastrointestinal, 2x renal failure, 1x sepsis, leucopenia, hepatopathy and anaemia, respectively). Peripheral neuropathic pain of grade 3 was reported in 4 cases, in one patient therapy had to be interrupted due to this complication. We confirmed promising results of phase II trials.

Adult↗
PubMed2004

[Imatinib--a new perspective in the treatment of tumors].

Among novel promising approaches to anticancer therapy belongs the targeting inhibition of signal transduction. This review outlines present-day experiences with imatinib (Glivec), a potent inhibitor of the tyrosine kinases bcr-abl, c-kit and platelet-derived growth factor receptor kinase. Due to inhibition of bcr-abl tyroxine kinase, imatinib has rapidly become the standard therapy for chronic myelocytic leukemia; inhibition of c-kit receptor explains its effectivity in the treatment of patients with gastrointestinal stromal tumors. Another known target of imatinib is tyrosine kinase of PDGFR, which is activated in numerous malignancies, particularly in dermatofibrosarcoma protuberans. Discovery of the novel fusion gene in hypereosinophilic syndrome (FIPILI-PFGFRA, whose product is an imatinib sensitive protein kinase) permitted to treat successfully this event. Possible combination of imatinib with conventional chemotherapeutic drugs and other key signal transduction inhibitors are mentioned.

Antineoplastic Agents↗
PubMed2004

[Proteasome inhibitors--new option in the treatment of tumor diseases].

Chemotherapy itself probably will not substantially improve the prognosis of cancer patients in the future. Therefore new methods are needed one of the promising option is the direct interference with intracellular metabolism--"the targeted therapy". Proteasome inhibitors are the example of this new approach and bortezomib is the first agent in this class, which enters clinical trials. We summarize theoretical background and the first clinical experiences with this drug.

Animals↗
PubMed2002

[Predictive features of positron emission tomography after two cycles of induction therapy in malignant lymphoma].

BACKGROUND: Positron emission tomography (PET) is a modern functional imaging method, recently introduced to clinical oncology. The aim of our study was the evaluation of prognostic value of PET performed in malignant lymphoma patients after two cycles of chemotherapy. METHODS AND RESULTS: From 9/99 to 11/00 PET was performed in 37 patients with malignant lymphoma (9x m. Hodgkin, 21x HG + IG-NHL, 7x LG-NHL; 26x new diagnosis, 11x relaps of disease). Freedom from progression interval (FFP) and overall survival (OS) were evaluated. Attenuation corrected PET imaging was done by dedicated ECAT EXACT PET scanner from base of the skull to the upper thighs 1 hour after intravenous administration of 18-FDG (7.6 +/- 1.3 MBq/kg). Statistical analysis was done using Kaplan-Meier method. Significance of differences between groups was determined by log-rank test on the level of 5%. After the induction therapy, 30 patients were in complete remission, 3 patients in partial remission and in 4 cases progression of disease were observed. Progression of disease was seen in 4 patients. Median follow up of living patients was 7 months (1-13 months) from the end of therapy. Progression, resp. relapse of disease occurred in 13 patients during this period, two patients died. PET performed after the second course of therapy was positive in 18 patients and negative in 19 patients. Two progressions, resp. relapses of disease were documented in PET-negative group and 11 in PET-positive group. FFP was significantly different in PET positive and PET negative groups (p < 0.05). The negative and positive predictive values of PET for malignant lymphoma relapse or progression were estimated 89%, 63% respectively. CONCLUSION: Regardless the short follow-up period, our preliminary results reflect very good prognostic value of PET performed after the second course of chemotherapy in malignant lymphoma patients.

Adolescent↗
PubMed2002

[Intensive therapy with paclitaxel (Taxol) and cyclophosphamide followed by administration of G-CSF as a mobilization regimen in patients with breast carcinoma and indications for autologous hematopoietic cell transplantation].

Cyclophosphamide (4 g/m2) and paclitaxel (Taxol) (175, 200 or 250 mg/m2) therapy with subsequent administration of G-CSF (10 micrograms/kg) has been used as intensification and as mobilization therapy for patients with breast cancer. This regimen was used in 19 patients, as part of adjuvant therapy in 14 and as part of therapy of metastatic disease in five. Median number of collected CD34+ cells was 17.5 x 10(6)/kg (2.9-48.1). All patients except one (94.7%) reached minimal required number of CD34+ cells (> or = 3 x 10(6)/kg). Median number of leukapheresis was two. The required number of cells (> or = 3 x 10(6)/kg) was collected in one leukapheresis in 17 out of 19 patients (89.5%) and more than five and 10 x 10(6)/kg CD34+ cells respectively were collected in 14 (73.7%) and 11 (57.9%) patients respectively. No factor significantly influencing the amount of collected cells (except the trend in favour of later year of therapy and large-volume leukapheresis) was identified. Leukopenia gr. 4 was observed in 88.9% of treated patients and febrile neutropenia developed in 46.2% patients. Although the antitumour activity of this chemotherapy was not possible to assess it seems that this intensification could be successfully used as a therapy and as very potent mobilization regimen.

Adult↗
PubMed2002

[Long-term culture of plasma cells from patients with myeloma and establishment of a permanent cell line].

UNLABELLED: Multiple myeloma plasma cells are actively dividing cells with the long surviving ability in the ex-vivo culture. In the effort for better understanding of the proliferative potential of malignant myeloma cells and establishment of permanent myeloma cell lines we performed long term cultures of human myeloma cells ex-vivo. During the last two years we cultured 41 bone marrow samples from 39 patients with multiple myeloma. Cells were cultured in the RPMI 1640 culture medium with 15% fetal calf serum at 37 degrees C in 5% CO2 and approximately one third of the culture medium was changed regularly twice a week. Most of the marrows cultures died by apoptosis within 30 days. Four bone marrow samples were cultured for more than 11 months, however, no culture can be qualified as an established cell line. In three cases permanent B-lymphoblastoid cell lines were established (UHKT-55, UHKT-56 a UHKT-57) but secondary immortalization by Epstein-Barr virus was suggested. CONCLUSIONS: Presented results suggest that myeloma plasma cells can survive and are able to proliferate in the ex-vivo culture for several months up to one year independently on the addition of any external growth factor without spontaneous apoptosis or necrosis. The probability of the establishment of a permanent cell line of plasma cell origin is, however, low. Presence of accessory bone marrow cells was the most important factor for the long-term survival of myeloma cells.

Adult↗
PubMed2002

[Kidney involvement in light-chain deposition disease].

An overview concerning different types of kidney involvement associated with monoclonal gammapathy (MG) is given, focused on light-chain deposition disease (LCDD). Pathophysiologic basis of LCDD remains in the light-chain tissue deposition (resp. in tissue deposition of immunoglobulin's stable domain). This mechanism is typical for monoclonal immunoglobulin's overproduction as found in MG. Clinical picture of LCDD reflects multiorgan character of disorder, while renal lesions rank among the most frequent, serious and best documented ones. Clinical data referring to a group of six patients, treated in our nephrologic department are presented. Diagnosis of LCDD was established on basis of the renal biopsy finding. Renal functions were decreased at the time of diagnosis in all patients, whereas haemodialysis treatment was started in one patient. On conclusion therapeutic possibilities of LCDD are discussed, in which number symptomatic therapy of renal failure is combined with corticosteroids therapy and cytostatic therapy; prognosis of most patients remains serious.

Aged↗
PubMed2002

[Renal infiltration in lymphoma--diagnosis in renal biopsy (case report)].

A case story of a patient with renal biopsy (RB) proven infiltration with lymphoma is given. RB in patient with known malignancy and onset of renal failure was indicated with regard to an atypical picture of kidney involvement (non-enlarged kidneys, without any structural changes typical for tumour mass presence). Though spread of the primary tumour to the kidney is not uncommon, involvement severe enough to impair renal function is unusual and occurs primarily with rapidly growing haematologic malignancies; diagnosis is being established by renal biopsy only rarely.

Aged↗
PubMed2001

[Perspectives in antineoplasm chemotherapy].

The unsatisfactory results of current anti-cancer therapies require the search for new drugs and new approaches. The review summarizes different possibilities of future treatments such as antiangiogenesis, inhibition of metastatic cascade, induction of differentiation. The most promising is to the influence signal transduction and to the control cell cycle progression. Increased understanding in the mechanisms driving cellular proliferation emerges novel therapeutics that are more specific and less toxic than classical chemotherapy.

Antineoplastic Agents↗