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Biomedical subjects

I F Ciernik

Publications and source records attributed to I F Ciernik.

At least 19 recordsLinked to original sources
PubMed2004

[Radiotherapy of rectal cancer].

The hallmark of successful management of rectal cancer is complete resection. In early stage disease, removal of all of the perirectal soft tissue structures, the mesorectum can be achieved with a total mesorectal excision (TME), resulting in high rates of local control. In cases of cancer extending through the muscularis propria or in case of lymphonodal involvement, additional radiation therapy can further substantially reduce the risk of pelvic recurrences. The combined treatment with radiotherapy followed by surgery is more effective than postoperative radiotherapy. Preoperative radiotherapy increases the survival rate of rectal cancer patients using limited doses of ionizing radiation and customized treatment volumes. The introduction of functional imaging with positron-emission tomography integrated in a conventional computer-associated tomography system (PET/CT) can be used for radiation treatment planning enhancing treatment precision and standards. The PET/imaging can be reliably used therapy for the purpose of combined staging and treatment volume assessment.

Combined Modality Therapy↗
PubMed2001

[Endoluminal, cardiovascular radiotherapy: a new standard].

The treatment for cardiovascular disease, especially the treatment of coronary stenosis, has been continuously improving during the last decades. Routine use of angioplasty was improved by the use of coronary stenting further reducing cardiac morbidity. However, the incidence of restenosis after cardiovascular angioplasty remains high. The restenosis process is mainly explained by neointimal proliferation. Therefore, the utility of ionizing radiation has been systematically investigated in order to reduce proliferation of the neointimal tissue. Radiation therapy turns out to be a very efficient approach in reducing the rate of both de novo lesions as well as of instant restenosis. Recent clinical data from randomized trials confirm the utility of intracoronary radiation therapy and change the treatment standards in interventional cardiology.

Angioplasty, Balloon, Coronary↗
PubMed2000

A survey on staging and treatment in uterine cervical carcinoma in the Radiotherapy Cooperative Group of the European Organization for Research and Treatment of Cancer.

BACKGROUND: The treatment outcome of advanced stage uterine cervical carcinoma remains unsatisfactory. In order to elaborate a novel trial within The Radiotherapy Cooperative Group (RCG) of the European Organization for Research and Treatment of Cancer (EORTC), we conducted a survey in 1997-1998 to determine the variability of pre-treatment assessment and treatment options. The variability of choosing surgery, defined radiation therapy techniques and chemotherapy are investigated, as well as the center's choices of future treatment strategies. METHODS: Fifty two of 81 RCG centers from the RCG have participated in the survey. As one would expect, there is a large variation in the techniques used for pretreatment evaluation and treatment options. There is no 'standard' for reporting acute and late side effects. Chemotherapy is used neither systematically nor uniformly, and some centers continue to use neadjuvant chemotherapy modalities. RESULTS: Furthermore, the survey reveals that there is a strong demand for the reduction of overall treatment-time, for clinical investigation of novel combined modality treatment strategies, especially chemo-radiation therapy, and also for the use of new radiation sensitizers. CONCLUSION: We conclude that a more homogeneous approach to the pretreatment evaluation as well as treatment techniques is required in order to allow adequate quality control in any future trial of the RCG in the EORTC.

Brachytherapy↗
PubMed1999

Ionizing radiation enhances immunogenicity of cells expressing a tumor-specific T-cell epitope.

BACKGROUND: p53 point mutations represent potential tumor-specific cytolytic T lymphocyte (CTL) epitopes. Whether ionizing radiation (IR) alters the immunological properties of cells expressing mutant p53 in respect of the CTL epitope generated by a defined point mutation has not been evaluated. METHODS: Mutant p53-expressing syngeneic, nontumor forming BALB/c 3T3 fibroblasts, tumor forming ras-transfected BALB/c 3T3 sarcomas, and DBA/2-derived P815 mastocytoma cells, which differ at the level of minor histocompatibility antigens, were used as cellular vaccines. Cells were either injected with or without prior IR into naive BALB/c mice. Cellular cytotoxicity was assessed after secondary restimulation of effector spleen cells in vitro. RESULTS: Injection of P815 mastocytoma cells expressing the mutant p53 induced mutation-specific CTL in BALB/c mice irrespective of prior irradiation. However, syngeneic fibroblasts or fibrosarcomas endogenously expressing mutant p53 were able to induce significant mutation-specific CTL only when irradiated prior to injection into BALB/c mice. IR of fibroblasts did not detectably alter the expression of cell surface molecules involved in immune response induction, nor did it alter the short-term in vitro viability of the fibroblasts. Interestingly, radioactively-labeled fibroblasts injected into mice after irradiation showed altered organ distribution, suggesting that the in vivo fate of these cells may play a crucial role in their immunogenicity. CONCLUSIONS: These findings indicate that IR can alter the immunogenicity of syngeneic normal as well as tumor forming fibroblasts in vivo, and support the view that ionizing radiation enhances immunogenicity of cellular tumor vaccines.

3T3 Cells↗
PubMed1999

Impaired liver function and retroviral activity are risk factors contributing to HIV-associated thrombocytopenia. Swiss HIV Cohort Study.

OBJECTIVE: To investigate the relationship between thrombopoetin (TPO) serum levels and HIV-associated thrombocytopenia. DESIGN AND METHODS: The relationship between TPO levels and severity of HIV-associated thrombocytopenia was investigated. Thirty-eight patients (19 patients with 30-96x10(9) platelets/l and 19 patients with <10x10(9) platelets/l) were matched with 38 HIV-positive non-thrombocytopenic patients (>150x10(9) platelets/l). RESULTS: HIV-positive patients with normal platelet counts had a median TPO serum level of 137 pg/ml. Patients with 30-96x10(9) platelets/l had decreased TPO levels with a median of 90 pg/ml (P = 0.016), and were more likely to have elevated serum aspartate-transferase levels (P<0.001) and hepatomegaly by palpation or ultrasound imaging (P = 0.005). The median TPO serum level of HIV-infected patients with severe thrombocytopenia was 110 pg/ml (non-significant). All patients with severe thrombocytopenia were positive for antibodies against hepatitis B virus core antigen, compared with 80% of HIV-infected persons without thrombocytopenia. Patients with severe thrombocytopenia were more likely to have high HIV replication compared to patients with normal platelet counts (P = 0.02), and reduction of plasma HIV-1 RNA levels was associated with increasing platelet counts. Severe thrombocytopenia was not associated with liver disease. CONCLUSIONS: Liver disease predisposes for low TPO serum levels and mild thrombocytopenia. High retroviral activity predisposes for severe, immune thrombocytopenic purpura-like thrombocytopenia. At least two distinct categories of severe HIV-associated thrombocytopenia exist, one responsive to antiretroviral treatment and one non-responsive to antiretroviral treatment.

Adult↗
PubMed1999

Delaying treatment with granulocyte colony-stimulating factor after allogeneic bone marrow transplantation for hematological malignancies: a prospective randomized trial.

The use of granulocyte colony-stimulating factor (G-CSF) has been established to improve hematological recovery after allogeneic bone marrow transplantation (BMT). The optimal timing to start with G-CSF has not been determined. This study investigates whether delayed use of G-CSF starting on day 6 is as safe and efficient as starting treatment with G-CSF immediately after BMT. Thirty-eight patients undergoing allogeneic BMT were randomized to either receive post-transplant G-CSF treatment starting at day 1 or at day 6. The time to hematological recovery was monitored and the groups were compared with respect to peritransplant morbidity and mortality. Recovery of the neutrophil granulocyte counts (PMN) to >100/microl, >500/microl and >1000/microl was comparable in both groups. The nadir of the PMN counts after stopping G-CSF was also similar. There was no difference in the recovery of red blood cells and platelet counts and no difference between the two groups with respect to the number of febrile episodes, number of days with antibiotics or number of documented bacterial, fungal or viral infections. Delayed treatment with G-CSF resulted in a reduction of G-CSF treatment from 19 days to 14 days (P = 0.0017). Reducing the length of treatment by 5 days lowered G-CSF treatment costs by 26.3%. Therefore, postponing treatment with G-CSF has no influence on the hematological recovery after allogeneic BMT. There is an economical benefit of postponing G-CSF use without any clinical disadvantages.

Adolescent↗
PubMed1997

Genetic immunotherapy of established tumors with adenovirus-murine granulocyte-macrophage colony-stimulating factor.

Increased local production of granulocyte-macrophage colony-stimulating factor (GM-CSF) by genetically modified tumor cells can induce specific antitumor cellular immunity. We constructed a recombinant adenovirus expressing murine GM-CSF and tested it for therapeutic efficacy in a syngeneic murine lung cancer model system. In vitro transduction of Lewis lung carcinoma cells with adenovirus-mGM-CSF suppressed tumor formation in syngenic mice (C57BL/6), and transduced and irradiated Lewis lung carcinoma cells induced regression of pre-established wild-type tumors without in vitro selection for transductants. Low, but significant, levels of specific antitumor cytotoxic T lymphocytes (CTL) were observed in mice inoculated with GM-CSF but not with reporter virus-transduced tumor cells. GM-CSF-transduced cells induced the accumulation of dendritic cells at the site of tumor, consistent with a mechanism involving improved tumor antigen presentation. These data suggest that transduction of tumor cells with recombinant GM-CSF adenovirus may be an effective and practical cancer gene therapeutic strategy.

Adenoviridae↗
PubMed1997

Destructive pneumococcal septic arthritis in end-stage renal disease.

Pneumococcal arthritis generally presents as non-destructive monoarthritis, although some underlying metabolic disorders such as liver failure and diabetes have been suggested to represent a risk factor for severe joint disease. Here we report a case of destructive pneumococcal arthritis of the left hip joint in a patient suffering from chronic renal failure treated with hemodialysis for ten years. Inspite of effective anti-pneumococcal antibiotic treatment, the patient with preexisting renal osteopathy and a mild osteoarthritis continued to suffer from severe and disabling pain of the left hip. This case demonstrates that pneumococcal joint infection in patients with underlying uremic bone disease can lead to quick deterioration of the affected joint.

Aged↗
PubMed1997

Decreased antigen presentation by dendritic cells in patients with breast cancer.

We evaluated T-cell responses to mitogens and to defined antigens in breast cancer patients. Significant defects in responses to tetanus toxoid and influenza virus were observed in patients with advanced-stage breast cancer. To define whether these defects were associated with a defect in antigen presentation [dendritic cells (DCs)] or effector function (T cells), these cells were studied separately. Purified DCs from 32 patients with breast cancer demonstrated a significantly decreased ability to stimulate control allogeneic T cells, but stimulation of patient T cells with either control allogeneic DCs or immobilized anti-CD3 antibody resulted in normal T-cell responses, even in patients with stage IV tumors. These data suggest that reduced DC function could be one of the major causes of the observed defect in cellular immunity in patients with advanced breast cancer. We then tested whether stem cells from these patients could give rise to functional DCs after in vitro growth with granulocyte/macrophage colony-stimulating factor and interleukin 4. Normal levels of control allogeneic and tetanus toxoid-dependent T-cell proliferation were observed when DCs obtained from precursors were used as stimulators. Those cells also induced substantially higher levels of influenza virus-specific CTL responses than mature DCs from the peripheral blood of these patients, although responses did not quite reach control values. Thus, defective T-cell function in patients with advanced breast cancer can be overcome by stimulation with DCs generated from precursors, suggesting that these cells may better serve as autologous antigen carriers for cancer immunotherapy than mature peripheral blood DCs.

Breast Neoplasms↗
PubMed1996

Antitumor effects of an adenovirus expressing antisense insulin-like growth factor I receptor on human lung cancer cell lines.

Insulin-like growth factors (IGFs) are often essential for the maintenance of the malignant phenotype, and in lung cancer the IGF-I receptor (IGF-Ir) is often expressed at high levels. Stable transfection of antisense plasmids expressing the first 300 bp of the IGF-Ir reduces the tumorigenicity of a variety of tumor cell lines and has been reported to induce systemic antitumor effects on established, non-gene-modified tumors in animal model systems. We have constructed an adenovirus expressing an antisense IGF-Ir (Ad-IGF-Ir/as) in an attempt to develop these observations into a clinical therapeutic approach. A single transduction by Ad-IGF-Ir/as (at a multiplicity of infection of 10:1) decreased the IGF-Ir number by about 50% in human lung cancer cell lines NCI H460 and SCC5, as measured by an 125I-labeled IGF-I competitive binding assay. After the transduction of these human lung cancer cell lines by Ad-IGF-Ir/as, the soft agar clonogenicity was reduced by 84%. The i.p. treatment of nude mice bearing established i.p. NCI H460 cells resulted in prolonged survival compared to that of nude mice treated with a reporter virus. These results suggest that Ad-IGF-Ir/as has a therapeutic effect on established human lung cancer xenografts and may represent an effective and practical cancer gene therapy strategy.

Adenoviridae↗
PubMed1996

Dendritic cells in antitumor immune responses. I. Defective antigen presentation in tumor-bearing hosts.

Induction of specific antitumor cytotoxic T cell responses was studied in BALB/c mice bearing tumors transfected with a mutant human p53 minigene. We observed that mice were resistant to the induction of peptide-specific CTL as early as 5 days after challenge with a minimal lethal dose of tumor cells, and the cell types responsible for this effect were further characterized. The contribution of CD4+ and CD8+ T cells in this response was studied after peptide-pulsed dendritic cell (DC) immunization. In vitro depletion of CD4+ cells during peptide restimulation reduced the level of specific lysis in control mice, and depletion of CD8+ T cells completely abrogated it. Substitution of CD8+ cells from immunized control mice during restimulation of cells from immunized tumor-bearing mice did not change the level of specific lysis. Substitution of the CD4+ from tumor-bearing mice by CD4+ cells from control mice improved CTL response, although this response did not reach control values. Peptide-pulsed dendritic cells isolated from tumor-bearing mice showed a significantly reduced ability to induce specific CTL in control animals and reduced ability to restimulate immune T cells from control mice in vitro. DC from tumor-bearing mice also had a reduced ability to stimulate control allogeneic T cells. Restimulation of T cells from immunized tumor-bearing mice with DC from control animals, but not from tumor-bearing mice, dramatically increased specific CTL responses to control levels. Macrophages at the same concentration were not able to improve CTL function. Thus, defective antigen presentation by DC appears to be a major determinant for CTL nonresponsiveness to peptide antigens in tumor-bearing mice, and addition of control DC can restore specific lysis. These data provide a basis for new approaches to peptide-based cancer immunotherapy.

Amino Acid Sequence↗
PubMed1996

Puncture-mediated gene transfer to the skin.

Simple and efficient gene transfer to the skin would facilitate many local and systemic gene therapy applications. Here we report a novel approach that allows installation and expression of plasmid DNA without a particulate carrier into the skin for the purposes of gene therapy. A device with a constantly high-frequency oscillating bundle of fine metal needles allows puncturing of the skin and leads to DNA transfer to skin-associated cells and expression of reporter genes in mice. Furthermore, puncture-mediated instillation of an expression vector coding for a single T cell epitope induces specific cellular immune responses. If this approach could be optimized, puncture-mediated gene transfer might be useful for the treatment of large body areas with plasmid DNA for the purpose of somatic gene therapy.

Amino Acid Sequence↗
PubMed1996

Induction of cytotoxic T lymphocytes and antitumor immunity with DNA vaccines expressing single T cell epitopes.

Delivery of genetic expression constructs into living animals can effectively induce both humoral and cellular immunity to the expressed proteins. Here we test the effectiveness of genetic immunization with a minigene coding for single epitopes derived from mutant p53 or from HIV gp120. We show that when these constructs are delivered by particle bombardment-mediated DNA transfer into the skin of mice, it results in efficient induction of tumor protective CTL. The immunogenicity of the epitope derived from mutant p53 is significantly enhanced if the epitope sequence is fused in frame with the adenovirus E3 leader sequence to target the epitope to the endoplasmic reticulum, thus acting like a "genetic adjuvant." We conclude that genetic T cell epitope immunization is an alternative to peptide-based techniques for eliciting an effective immune response targeted against a single defined epitope. in some cases, the fusion of the gene product of the DNA vaccine vector with an endoplasmic reticulum targeting sequence may enhance immune induction.

Adenoviridae↗
PubMed1996

Human lung cancer cells endogenously expressing mutant p53 process and present the mutant epitope and are lysed by mutant-specific cytotoxic T lymphocytes.

The p53 oncoprotein frequently contains somatically acquired missense mutations and is often overexpressed in cancer cells. Missense mutations can give rise to new tumor-specific peptide sequences, which can act as targets for T-cell-mediated immunotherapy. To investigate the ability of human lung cancer cells to adequately process and present a mutant p53-derived CTL epitope, we transfected the human cell line HMy-2.C1R and the p53-null human lung cancer cell lines H358 and H1299 with an expression vector containing a human mutant p53 (135 Cys to Tyr). After transfection with the Kd restriction element, these cells were tested as targets for murine mutation-specific CTLs. We show that these human lung cancer cells effectively process and present this endogenous mutant human p53 epitope, resulting in efficient, mutant epitope-specific lysis by CTLs. In the presence of the appropriate restriction element, human lung cancer cells can be effectively targeted by CTLs specific for somatically acquired, endogenous mutant epitopes, supporting targeted immunotherapy efforts in lung cancer.

Animals↗
PubMed1995

Mutant oncopeptide immunization induces CTL specifically lysing tumor cells endogenously expressing the corresponding intact mutant p53.

The p53 nuclear oncoprotein frequently contains somatically acquired missense mutations and is often overexpressed in cancer cells. It is now known that nuclear and cytosolic proteins are processed into peptides and these can be transported into the endoplasmic reticulum and presented on the cell surface with class I MHC. We have previously shown that after treatment with interferon gamma (IFN-gamma), BALB/c 3T3 fibroblasts transfected with mutant p53 (135 C to Y) can be specifically lysed by mutant peptide-induced CTL. Here we show that P815 mastocytomas are effectively lysed by peptide stimulated CTL without treatment of IFN-gamma in vitro.

3T3 Cells↗
PubMed1995

Expression of transforming growth factor beta and transforming growth factor beta receptors on AIDS-associated Kaposi's sarcoma.

Several humoral growth factors may contribute to the development and growth of AIDS-associated Kaposi's sarcoma (KS). They are either provided by chronically activated cells of the immune system or in an autocrine/paracrine manner by the neoplastic cells themselves. Transforming growth factor beta(TGF-beta) may directly enhance the growth of KS cells and tumor matrix formation. To mediate a signal both TGF-beta receptors type I and type II (TbetaR-I and TbetaR-II) have to be expressed. We investigated the expression of TGF-beta, TGF-beta receptors types I and II, and endoglin, a nonsignaling-type TbetaR-III, by means of immunohistochemistry on skin biopsies from patients with AIDS-related KS. We found that the TGF-beta ligand was expressed by KS cells in 9 of 11 samples. TbetaR-II was strongly expressed in 10 of 12 samples, but none of the investigated tumor samples stained for TbetaR-I. Endoglin was weakly expressed on all KS lesions and stained the endothelium of tumor-associated vessels in 92% of the samples. These findings show that most KS lesions have the ability to produce TGF-beta and that KS cells maintain a high expression of TbetaR-II in the absence of TbetaR-I, which may allow KS to escape growth inhibitory effects of endocrine or paracrine TGF-beta.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Prognostic factors and outcome of incompletely resected invasive thymoma following radiation therapy.

BACKGROUND: Stage III and stage IV thymomas with significant macroscopic infiltration to the neighboring structures are rarely completely resectable. It therefore remains unclear to what extent tumors must be surgically debulked to improve prognosis. PATIENTS AND METHODS: We reviewed the cases of 31 patients with incompletely resected invasive thymoma and residual macroscopic disease who were referred to postoperative irradiation. Survival and local tumor control were analyzed. All patients were treated between 1958 and 1990 with megavoltage irradiation at doses ranging from 42 to 66 Gy. The shortest follow-up time for living patients was more than 5 years. RESULTS: The overall median 5-year survival rate was 45%. Eighteen stage III patients had a 5-year survival rate of 61% and a 10-year survival rate of 57%. Thirteen patients had stage IV disease and 5- and 10-year survival rates of 23% and 8%, respectively. Univariate and multivariate analyses confirmed a worse prognosis for stage IV disease. Epithelial or spindle-cell thymoma was associated with stage IV disease. Twenty-two percent of patients with stage III disease had epithelial or spindle-cell thymoma, versus 69% of patients with stage IV disease (P = .02 for univariate and P = .05 for multivariate analysis). Initial tumor diameter greater than 10 cm correlated with poor prognosis in the univariate analysis (P = .05). However, more importantly, debulking of tumor did not significantly improve outcome when compared with patients who received biopsy only. The median survival rate of patients with stage IVa disease did not differ from that of those with stage IVb disease. Mediastinal control was achieved in 23 patients (74%). Stage IV disease did not correlate with an increase in local treatment failure after irradiation, although epithelial or spindle-cell thymoma predisposed for local treatment failure (46% v 11%; P = .04 in univariate and P = .055 in multivariate analysis). CONCLUSION: Tumor debulking leaving macroscopic residual thymoma, as opposed to biopsy alone, does not improve prognosis when followed by radiation. Radiation therapy for local tumor control is most effective in nonepithelial-predominant thymomas.

Adult↗