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T Cerny

Publications and source records attributed to T Cerny.

At least 37 records · Page 2Linked to original sources
PubMed2002

The proteasome, a new target for cancer therapy.

The proteasome is a multicatalytic protease and the principal non-lysosomal proteolytic system in all eukaryotic cells. It plays a central role in virtually all regulatory pathways as for instance cell-cycle regulation, differentiation, and apoptosis. The proteasome degrades regulatory proteins and their inhibitors and, thus is an interesting target for therapeutic drugs. Inhibitors of the proteasome are small molecules that function by stabilizing various proteins, including cell-cycle regulators, tumor suppressors and growth factors. Because proteasome inhibition blocks cellular proliferation and induces apoptosis, these agents have been tested as anticancer drugs in tumor models and have shown impressive potential. In addition, treatment with proteasome inhibitors can sensitize cells to other cancer treatments like radio- or chemotherapy. This review introduces the ubiquitin-proteasome pathway and outlines the recent progress in the development of proteasome inhibition as a treatment option for clinical cancer therapy.

Animals↗
PubMed2002

Postradiation high-grade myofibroblastic sarcoma of the prostate -- a rare entity of prostatic tumors -- responding to liposomal Doxorubicin.

BACKGROUND: Prostatic postradiation sarcoma (PRS) is a very rare malignant disease with a dismal prognosis. Aggressive surgical resection is the most widely used therapy for PRS. Chemotherapy so far has been unsatisfactory, with doxorubicin being the only drug with established activity. Liposomal doxorubicin has been shown to have comparable activity and a more favorable toxicity profile compared with unpegylated doxorubicin. CASE REPORT: A 78-year-old man presented with high-grade myofibroblastic sarcoma 13 years after curatively intended pion irradiation of the prostate with 30 Gy. He was treated with liposomal doxorubicin 40 mg/m(2) every 4-6 weeks up to now with a total dose of 800 mg. Partial remission has been achieved after 17 months of treatment with liposomal doxorubicin. Toxicity is minimal with palmoplantar erythrodysesthesia WHO grade 1, resolving completely after extending treatment intervals to 6 weeks. RESULT: Liposomal doxorubicin led to a sustained tumor stabilization over 17 months in a patient with prostatic postradiation high-grade sarcoma. Postradiation sarcoma (PRS) usually has a dismal prognosis and only very limited therapeutic possibilities. As in sarcomas of different origin, anthracyclines including liposomal doxorubicin seem to have potential antitumor activity in postradiation sarcoma of the prostate.

Adenocarcinoma↗
PubMed2001

Taxanes in lung cancer: a review with focus on the European experience.

The introduction of new agents in the treatment of lung cancer raised in the past few years new interest in clinical research on this topic. The use of taxanes as paclitaxel and docetaxel may represent a significant progress in the treatment of lung cancer. Taxanes used as single agents show a substantial activity in lung cancer and, because of their unique mechanism of action, it is possible to combine these drugs with other non-cross-resistant agents. Taxanes share a radiosensitizing effect and their use with concurrent radiotherapy appears to become a new standard. This review will focus on the European clinical experience in the treatment of lung cancer with the two compounds.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Elevated carbohydrate antigen 19-9 (CA 19-9) in patients with Echinococcus infection.

The carbohydrate antigen 19-9 (CA 19-9), a determinant (sialylated lacto-N-fucopentaose 119) of a circulating oligosaccharide antigen, is a frequently used tumor marker. Echinococcus spp. infects humans throughout the world and may be able to synthesize closely related molecules which could interfere with the measurement and interpretation of CA 19-9 concentration. The main objective of the present study was to determine the range of CA 19-9 levels in the sera of patients infected by E. granulosus (cystic hydatide disease; CYSHD) or E. multilocularis (alveolar hydatide disease; ALVHD). Serum samples were collected from patients (aged 10-85 years) over a period of 5 years: from 19 patients with CYSHD and from 20 patients with ALVHD. Infection was confirmed by positive Echinococcus serology and clinical evidence provided by imaging and/or histopathological findings. CA 19-9 was detectable in 13 patients with CYSHD (13.5 +/- 8.5 kU/l) and 13 patients with ALVHD (30.0 +/- 21 kU/l; p < 0.05). Thus ALVHD patients exhibited a significantly higher plasma level of CA 19-9 than CYSHD patients. The serum level of CA 19-9 assessed with an increased cut-off value (> 22 kU/l) was elevated in nine (45%) of 20 ALVHD patients compared to two (11%) of 19 CYSHD patients (p < 0.05). Sera from patients with Echinococcus multilocularis infection contain substances which cross-react with CA 19-9. These substances originate either from the parasite or are synthesized by the host in response to the infection, and possibly bear the Lewis-a antigen or closely related structures which are recognized by anti-CA 19-9 antibodies. Our findings are relevant to the investigation of patients presenting with cystic lesions for which the differential diagnosis includes an infectious or neoplastic origin.

Adolescent↗
PubMed2001

Weekly x 4 induction therapy with the anti-CD20 antibody rituximab: effect on circulating t(14;18)(+) follicular lymphoma cells.

Rituximab 375 mg/m(2) weekly x 4 has been reported to induce a 60% response rate in patients with relapsed follicular lymphomas (FL). Our aim was to examine the effect of this rituximab schedule on circulating FL cells in an ongoing multicenter study. One hundred fifty-four patients with FL were examined by nested polymerase chain reaction (PCR) at baseline for the presence of t(14;18) translocation-carrying lymphoma cells in bone marrow and/or blood. Sixty-four patients (42%) had PCR-detectable t(14;18)(+) FL cells. Pretreatment characteristics of these 64 patients were as follows: one had stage I, nine had stage II, 14 had stage III, and 40 had stage IV disease. Thirty-five patients had bulky disease (> or = 5 cm) and 25 patients had an elevated serum lactate dehydrogenase (LDH) level. Bone marrow was morphologically assessed in 64 patients, and 39 of these patients had an infiltration with FL cells. Blood samples from 51 patients were available for PCR analysis between weeks 8-12 after induction therapy, and 28 of these patients (55%) were PCR negative. Paired blood and bone marrow samples were available for PCR analysis from 39 patients between weeks 8-12 after induction therapy with rituximab. Thirteen of these patients (33%) did not have PCR-detectable cells in blood and bone marrow, while 26 patients (67%) still had circulating t(14;18)(+) cells in either bone marrow (eight patients), blood (one patient), or both (17 patients). PCR negativity in blood and bone marrow in 13 patients was statistically significantly associated with partial or complete response after induction therapy with rituximab (P = 0.006). However, clearance of PCR-detectable t(14;18)(+) cells in bone marrow and/or blood could not be associated with any low tumor burden pretreatment characteristics such as stages I/II, absence of morphological bone marrow infiltration or tumor bulk of > or = 5 cm, and normal serum LDH.

Adult↗
PubMed2000

Prostate stem cell antigen is a promising candidate for immunotherapy of advanced prostate cancer.

Immunotherapy of prostate cancer (CaP) may be a promising novel treatment option for the management of advanced CaP. However, the lack of suitable tumor antigens remains a major obstacle for the rational design of vaccines. To characterize potential CaP antigens, we determined the mRNA expression of the prostate-specific genes C1, C2, C5, PAGE-1, and prostate stem cell antigen (PSCA) in hormone-refractory CaP, benign prostatic hyperplasia, CaP cell lines, and CaP specimens. Among these gene products, only expression of PSCA appears to be retained in the majority of advanced CaP samples, as shown by reverse transcription-PCR analyses. Peptide fragments of PSCA presented in the context of major histocompatibility molecules could serve as recognition targets for CD8 T cells, provided these lymphocytes were not clonally deleted or peripherally tolerized. Our goal was to determine whether the human T-cell repertoire could recognize PSCA-derived peptide epitopes in the context of a common class I allele, HLA-A0201. Of nine peptides that, according to HLA-A0201 binding motifs, were candidate ligands of A0201 class I molecules, three peptides were able to stabilize HLA-A0201 molecules on the cell surface. One of the latter peptides, encompassing amino acid residues 14-22, was capable of generating a PSCA-specific T-cell response in a human lymphocyte culture from a patient with metastatic CaP. PSCA-specific CTLs recognized peptide-pulsed targets as well as three prostate carcinoma lines in cytotoxicity assays, indicating that this peptide could be endogenously processed. In conclusion, our findings establish PSCA as a potential target for antigen-specific, T cell-based immunotherapy of prostate carcinoma.

Antigens, Neoplasm↗
PubMed2000

Experiences in the realisation of a research project on anthroposophical medicine in patients with advanced cancer.

QUESTIONS UNDER STUDY: To date most of the published studies on the effectiveness of complementary therapies in cancer patients have yielded controversial results because of questionable methodology. Research strategies and methodologies acceptable to both conventional and unconventional medicine are difficult to find due to different belief systems. In this publication we describe the development and implementation of a project conducted as part of National Research Programme 34 (NFP 34). Detailed analysis of our experiences might provide some information on how to deal with practical difficulties in the planning and conduct of further research projects in this field. The project involved the anthroposophical Lukas Clinic in Arlesheim and the Institute of Medical Oncology of the University Hospital, Berne. This interdisciplinary research project was devised to study the relative merits of these two schools of medicine in the care of advanced cancer patients. The project was made up of three components: (1) a registration study aimed at comparing the case mix at the two institutions; (2) a three armed randomised study on the effectiveness of supportive therapy, comparing anthroposophy to psychosocial group therapy, and (3) a longitudinal study to monitor the evaluation of quality of life of patients at the anthroposophical clinic. METHODS: After a brief review of the study protocol, which presents the theoretical framework of the project, problems of its implementation are described. Aspects of accrual, acceptance of randomisation and data availability are presented using simple descriptive statistics and logistic regression. RESULTS: The registration study was duly completed with a total of 567 patients. For several reasons (not meeting inclusion requirements, high refusal rate) the accrual into the randomised study was slower than expected and required modification of the original design specifications with regard to inclusion criteria and data collection schedule. Additionally, a high dropout rate contributed to premature closure of this part of the project. The longitudinal study also suffered from low data availability at follow up. CONCLUSIONS: The study protocol constituted a major effort at compromise without loss of scientific rigour, and this effort demonstrates that it is possible to allow for different views on patients, on clinical interventions and on research strategies when establishing collaboration between different schools of medicine. Despite a theoretically sound framework, the randomised part of the project proved difficult in its practical execution. Some unexpected logistical constraints and some unmet expectations influenced the feasibility of this part of the project. Therefore, careful planning of research projects in this field of medicine should always include an extended analysis of various practical aspects of study implementation.

Anthroposophy↗
PubMed2000

Pharmacokinetics of 2-chloro-2'-deoxyadenosine administered subcutaneously or by continuous intravenous infusion.

PURPOSE: Cladribine (2-chlorodeoxyadenosine, 2-CDA) is effective in the treatment of various lymphoproliferative disorders. In the standard protocol the compound is administered by continuous intravenous (i.v.) infusion. In order to allow outpatient therapy alternative modes of administration such as subcutaneous (s.c.) injection would be desirable. The aim of the present study was to compare the pharmacokinetics of 2-CDA after i.v. and s.c. administration. PATIENTS AND METHODS: Nine patients received 0.1 mg/kg 2-CDA per 24 h on one occasion by continuous i.v. infusion and on another occasion as a bolus subcutaneously. The concentrations of 2-CDA in the plasma and urine were determined by HPLC. RESULTS: During i.v. infusion the concentration of 2-CDA in the plasma reached a plateau after 4-8 h, whereas with s.c. administration almost ten times higher peak concentrations were reached within 20 to 60 min. A two-compartment model was fitted to the data points whereby the goodness-of-fit statistics showed R2 values of > 0.98. The calculated rate of elimination, k(elim), averaged 0.336 h(-1) with s.c. and 0.397 h(-1) with i.v. administration. The estimated volumes of distribution were 1.67 and 1.58 l/kg. The areas under the concentration time curves (608 +/- 65 pmol x h/ml after s.c. administration vs 571 +/- 50 pmol x h/ml during i.v. infusion) and the urinary excretion of 2-CDA in 24 h (4.75 +/- 0.95 vs 3.55 +/- 0.53 micromol/24 h) were similar in both groups, indicating identical bioavailability. CONCLUSIONS: Although the pharmacokinetic profile of 2-CDA administered s.c. differs substantially from the profile of a continuous i.v. infusion the areas under the plasma concentration time curves, the urinary excretion of unchanged drug and the estimated pharmacokinetic variables were similar with both modes of administration, indicating that the different time-courses of the plasma concentration did not influence the fraction metabolized or eliminated.

Aged↗
PubMed2000

[Importance of lymph node involvement in breast carcinoma for the oncologist].

Axillary node status is the most important prognostic information regarding treatment and prognosis for breast cancer patients. Localisation and number of involved lymph nodes add further information and are of prognostic relevance as well. The problem of the involvement of different axilla levels as well as skip metastases are discussed. Sentinel lymph node dissection is still considered investigational as well as axilla downstaging by preoperative chemotherapy. New prognostic markers are helpful in individual situations but are not yet considered as standard procedures. Conclusions of practical relevance are summarised.

Axilla↗
PubMed2000

Analgesic action of i.v. morphine-6-glucuronide in healthy volunteers.

The pharmacodynamics of morphine-6-glucuronide (M-6-G) i.v. were assessed in 12 healthy male volunteers in an open study. After a single bolus dose of M-6-G 5 mg i.v., we measured antinociceptive effects, using electrical and cold pain tests, and plasma concentrations of M-6-G, morphine-3-glucuronide (M-3-G) and morphine. Pain intensities during electrical stimulation (at 30, 60 and 90 min after injection) and ice water immersion (at 60 min) decreased significantly (P < 0.005) compared with baseline. Mean plasma peak concentrations of M-6-G were 139.3 (SD 38.9) ng ml-1, measured at 15 min. Our data demonstrate that M-6-G has significant analgesic activity.

Adult↗
PubMed2000

Pneumococcal vaccine in patients with absent or dysfunctional spleen.

Four patients (3 long-term Hodgkin disease survivors and 1 recipient of an allogeneic bone marrow transplant) developed severe infections with Streptococcus pneumoniae after staging splenectomy or due to functional hyposplenism after total body irradiation and bone marrow transplantation. Current guidelines for prevention of infection recommend pneumococcal immunization for patients with Hodgkin disease treated with splenectomy and others with functional hyposplenism. Booster vaccination after 5 years is also advised. Hospital- and community-based vaccination initiatives may help identify at-risk patients.

Acute Disease↗
PubMed2000

The effect of Rituximab on patients with follicular and mantle-cell lymphoma. Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: Clinical activity of the anti CD-20 monoclonal antibody Rituximab has been reported in patients with follicular lymphoma (FL) and mantle-cell lymphoma (MCL). PATIENTS AND METHODS: 120 patients with bi-dimensionally measurable FL or MCL (R.E.A.L. Classification) were treated with Rituximab 375 mg/m2/week for 4 weeks. A central pathology review confirmed the diagnosis of FL in 76 of 78 and of MCL in 39 of 42 cases. The response was evaluated after 8 weeks and confirmed after 12 weeks from the start of treatment. RESULTS: The toxicity of the treatment was, as expected, grade 1-2 fever and rigors during the first infusion and mild asthenia during the treatment period. Serious adverse events, probably or possibly related to the study treatment, included four deaths (3 of cardiac origin, 1 caused by P. carinii pneumonia) and 10 further nonfatal cases, including a permanent agranulocytosis and one case of heart failure. Response rate at week 12 was 52% for FL and 22% for MCL. After treatment, the BCL-2 rearrangement disappeared in 15 of 29 blood but only in 5 of 23 bone marrow samples; BCL-1 disappeared in 5 of 12 blood and 0 of 7 bone marrow specimens, as determined by PCR. CONCLUSIONS: Rituximab is an active agent for the treatment of FL, while its efficacy is modest in MCL. The effect in reducing minimal residual disease is more pronounced on the blood than it is on the bone marrow.

Adult↗
PubMed1999

[Is there progress in the chemotherapy of small cell lung cancer?].

Small cell lung cancer (SCLC) is a frequent neoplastic disease which has shown an increasing incidence during recent years, particularly in women. Because of the high sensitivity of chemotherapy, remission is usually achieved with standard regimens. However, relapses are common and 5-year survival is < 10%. Over the last few years intensive chemotherapy with or without stem cell support has been developed and has brought about an improvement of overall survival in SCLC patients. This therapeutic approach is reviewed.

Antineoplastic Agents↗
PubMed1999

Saturable metabolism of continuous high-dose ifosfamide with mesna and GM-CSF: a pharmacokinetic study in advanced sarcoma patients. Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: The aim of this study was to assess the pharmacology, toxicity and activity of high-dose ifosfamide mesna +/- GM-CSF administered by a five-day continuous infusion at a total ifosfamide dose of 12-18 g/m2 in adult patients with advanced sarcomas. PATIENTS AND METHODS: Between January 1991 and October 1992 32 patients with advanced or metastatic sarcoma were entered the study. Twenty-seven patients were pretreated including twenty-three with prior ifosfamide at less than 8 g/m2 total dose/cycle. In 25 patients (27 cycles) extensive pharmacokinetic analyses were performed. RESULTS: The area under the plasma concentration-time curve (AUC) for ifosfamide increased linearly with dose while the AUC's of the metabolites measured in plasma by thin-layer chromatography did not increase with dose, particularly that of the active metabolite isophosphoramide mustard. Furthermore the AUC of the inactive carboxymetabolite did not increase with dose. Interpatient variability of pharmacokinetic parameters was high. Dose-limiting toxicity was myelosuppression at 18 g/m2 total dose with grade 4 neutropenia in five of six patients and grade 4 thrombocytopenia in four of six patients. Therefore the maximum tolerated dose was considered to be 18 g/m2 total dose. There was one CR and eleven PR in twenty-nine evaluable patients (overall response rate 41%). CONCLUSION: Both the activation and inactivation pathways of ifosfamide are non-linear and saturable at high-doses although the pharmacokinetics of the parent drug itself are dose linear. Ifosfamide doses greater than 14-16 g/m2 per cycle appear to result in a relative decrease of the active metabolite isophosphoramide mustard. These data suggest a dose-dependent saturation or even inhibition of ifosfamide metabolism by increasing high dose ifosfamide and suggest the need for further metabolic studies.

Adult↗