PubMed Health⌕ Search

Biomedical subjects

R Jakesz

Publications and source records attributed to R Jakesz.

At least 73 records · Page 4Linked to original sources
PubMed1998

[Results of interdisciplinary sacrum resection in sacral recurrence of rectal carcinoma].

The authors present a retrospective analysis of 12 consecutive patients surgically treated with curative intention for recurrent rectal cancer involving the sacrum. After radical partial sacral resection--extended resection in seven cases--the operative mortality rate was zero, postoperative long-term survival was reached in 17%, while effective palliation of pain was achieved in all cases. Nevertheless, 50% did not survive more than 1 year after the operation. The overall mean survival time was 22 months. Sacral recurrence can be resected safely and potentially curatively after careful patient selection.

Combined Modality Therapy↗
PubMed1997

Transcription and activity of 5-fluorouracil converting enzymes in fluoropyrimidine resistance in colon cancer in vitro.

Cellular resistance to 5-fluorouracil (5-FU) is not completely understood. Since 5-FU shares the pyrimidine pathway with the physiological pyrimidines, we investigated the relationship between fluoropyrimidine metabolism, nucleic acid uptake and cytotoxicity of 5-FU in eight colon tumour cell lines including 5-FU-resistant subclones. The cytotoxicity of 5-FU was increased up to 423-fold when the anabolites 5-fluorouridine (FUrd), 5-fluorodeoxyuridine (FdUrd), and 5-fluorodeoxyuridine monophosphate (FdUMP) were compared with the parent drug in vitro. The enzymes uridine phosphorylase and thymidine phosphorylase were predictive for the cytotoxicity of 5-FU in 5/7 cell lines. Inhibition of uridine phosphorylase and thymidine phosphorylase by antisense strategies effectively antagonised 5-FU, abolishing 84% and 79% of its toxicity. The importance of thymidine phosphorylase was supported by a highly restricted enzyme activity in 5-FU-resistant cells. In 5-FU naive cells, a stimulating effect of 5-FU on thymidylate synthase mRNA and ribonucleotide reductase mRNA expression was observed. In these cells, antisense oligonucleotides to ribonucleotide reductase significantly reduced cell growth. Downregulation of ribonucleotide reductase mRNA in 5-FU-resistant subclones suggests different mechanisms in primary and secondary resistance to 5-FU. Most of the intracellular 5-FU was selectively incorporated into RNA (range: 45-91%) and generally spared DNA (range: 0.2-11%). In synthesising our data, we conclude that drug resistance could be overwhelmed through bypassing limiting steps in the activation of 5-FU. In the majority of colonic tumours, the activity of uridine phosphorylase and thymidine phosphorylase may have prognostic relevance for the cytotoxicity of 5-FU in vitro.

Antimetabolites, Antineoplastic↗
PubMed1997

5-fluorouracil kinetics in the interstitial tumor space: clinical response in breast cancer patients.

Several anticancer drugs fail to exhibit sufficient activity against solid tumors in vivo despite effective inhibition of tumor cell growth in vitro. This may be due to impaired drug transfer from plasma into solid tumors. The present study, therefore, aimed at measuring interstitial tumor 5-fluorouracil (5-FU) pharmacokinetics and 5-FU transfer rates from plasma into the tumor interstitium in breast cancer patients. Microdialysis probes were inserted into the primary tumor and the periumbilical s.c. adipose layer of 10 breast cancer patients (8 females and 2 males) scheduled to receive neoadjuvant chemotherapy due to locally advanced breast cancer. Thereafter, patients received 5-FU (600 mg/m2, i.v). 5-FU kinetics were followed in plasma and tumor and s.c. interstitial fluid. Mean interstitial 5-FU load, expressed as area under curve (AUC), in breast tumors was 61 +/- 11% (means +/- SE) of the mean plasma 5-FU load. 5-FU displayed similar kinetics in the interstitial space of s.c. adipose tissue and tumor tissue. A high interstitial tumor AUC was associated with increased tumor response. There was no association with tumor response for s.c. or plasma AUC of 5-FU. Measurement of interstitial drug concentrations in breast tumors by in vivo microdialysis may predict response to chemotherapy. This information may explain drug resistance in some patients and help to optimize dosing and administration schedules. In the future, selection of novel cytotoxic compounds with favorable tumor penetration characteristics may become possible.

Adipose Tissue↗
PubMed1997

The in vitro effects of interleukin-12 upon tumor-infiltrating lymphocytes derived from renal cell carcinoma.

Clinical trials utilising interleukin (IL)-2 with tumor-infiltrating lymphocytes (TIL) have demonstrated efficacy in the treatment of metastatic renal cell carcinoma (RCC). Several cytokines, as well as growth factors have demonstrated modulatory effects upon the biological properties of TIL from RCC, suggesting a potentially important role for cytokines other than IL-2 in the development of active and tumor-specific TIL. IL-12 was recently characterized as a natural-killer-cell-stimulatory factor or cytotoxic-T-cell-maturation factor. These properties of IL-12 prompted us to investigate the impact of this cytokine upon the activation of TIL from human RCC. In an attempt to enhance the in vitro growth and activity of renal TIL, we have grown eight renal TIL cultures in varying concentrations of IL-2 (8, 40, 80, 400 U/ml) and IL-12 (200 U/ml). In addition, IL-12 (200 U/ml) was added to TIL cultures pre-activated with IL-2 (400 U/ml). Growth, cell expansion, and the ability of TIL to release certain cytokines upon tumor stimulation were determined. Proliferation assays, phenotypic analysis, and cytotoxicity assays were performed at an early and a late culture stage. IL-12, alone and when added to suboptimal concentrations of IL-2, failed to induce TIL growth. While the addition of IL-12 to optimal doses of IL-2 suppressed TIL culture expansion, sequential culture exposure first to IL-2 and then to IL-2+IL-12 increased the number of cells expressing CD3+/CD56+ and these cultures demonstrated enhanced in vitro lysis of autologous tumor. IL-12 clearly demonstrated a sequence-dependent impact of the biological behaviour of TIL from RCC. The optimal use of IL-12 in the in vitro expansion of renal TIL may result in cells with an enhanced specific anti-tumor effect.

CD3 Complex↗
PubMed1997

p53 protein expression, cell proliferation and steroid hormone receptors in ductal and lobular in situ carcinomas of the breast.

p53 and c-erbB-2 expression, and their correlation with cell proliferation and steroid hormone receptors, were investigated in 121 carcinomas, 23 lobular in situ carcinomas (LCIS), 74 intraductal carcinomas (DCIS) and 24 minimal invasive carcinomas. DCIS were classified according to the EORTC classification. All markers were measured immunohistochemically on paraffin sections. None of the LCIS, 9 DCIS and 9 minimal invasive cancers showed nuclear positivity for p53. A strong association between histological type and p53 expression was found. Proliferation rates correlated with p53 expression. c-erbB-2 positivity was found in 1 LCIS, 27 DCIS and 12 minimal invasive cancers. There was a significant correlation between p53 expression and c-erbB-2. Both parameters were associated with high proliferation rate and negativity for steroid hormone receptor status. Nuclear pleomorphism could become a comparable prognostic marker in DCIS as it is for infiltrating carcinomas.

Biomarkers, Tumor↗
PubMed1997

The diagnostic value of planar and SPET scintimammography in different age groups.

Planar scintimammography (SMM) with 99Tcm-sestamibi (99Tcm-MIBI) has proved to be a useful method in the evaluation of breast lesions. The aim of our study was to determine the diagnostic value of planar and single photon emission tomograpic (SPET) SMM in different age group. We investigated women with breast lesions for which the surgeon recommended biopsy or careful follow-up. Seventy consecutive patients underwent supine planar SMM, while supine SPET was performed in 68 of the patients. Twenty-seven carcinomas in 23 patients and 35 benign lesions in 31 patients were confirmed histologically. In the remaining 16 patients, the findings were classified as benign at follow-up. The carcinomas and benign lesions had a mean (+/- S.D.) diameter of 25 +/- 17 and 17 +/- 11 mm respectively (P < 0.05). A sensitivity/specificity of 67/96% and 88/91% was obtained with the planar and SPET techniques respectively. The accuracy of both techniques was 90%. In patients aged 40 years or less, SPET increased the sensitivity from 50 to 100% (P < 0.01), whereas it decreased the specificity and accuracy from 94 to 81% and 91 to 81% respectively (N.S.). In patients aged 41-50 years, the sensitivity increased from 63 to 100% (P < 0.01), whereas there was a small decrease in specificity and an increase in accuracy (from 91 to 89% and 86 to 91% respectively, N.S.) We conclude that, in younger patients, a negative SPET SMM study indicates the need for careful follow-up rather than biopsy. However, the addition of SPET in supine scintimammography does-not change the overall accuracy significantly.

Adult↗
PubMed1996

Use of resistance index for the diagnosis of breast tumours.

AIM: To determine whether the resistance index (RI) contributes to the differential diagnosis of breast masses. PATIENTS AND METHODS: In 56 breast tumours colour-coded Doppler sonography was performed and their resistance indices calculated from their spectral Doppler tracings. Histologic evaluation was obtained by excision biopsy. RESULTS: In seven of 28 benign tumours (25%) no lesion was seen on ultrasound. In another seven benign tumours, no intratumoral vessels were demonstrated. The resistance index of the remaining 14 lesions (50%) varied between 0.5 and 0.75 with a mean value of 0.62 (standard deviation 0.08). Ultrasound missed one of 28 carcinomas (3.5%) and in one other tumour (3.5%) no flow was demonstrable. The resistance index of 26 malignant tumours varied between 0.56 and 0.9 with a mean value of 0.7 (standard deviation 0.08). CONCLUSION: Breast malignancies have higher resistance indices with a wider range as assessed by colour-coded Doppler ultrasound (81% exceed 0.6) than do benign lesions. Due to the considerable overlap of the range of the resistance index, the measurements in any single patient may not be diagnostic. The absence of flow does not definitively exclude malignancy.

Adolescent↗
PubMed1996

[Plasminogen activator inhibitor 1 and prognosis in breast carcinoma].

The proteolytic enzyme urokinase-type plasminogen activator (uPA) plays an important role in degrading extracellular matrix. This seems to be an important step in cancer invasion and metastasis. uPA antigen levels correlate significantly with disease recurrence and death in breast cancer. To build up tumour stroma in primary tumours as well as in metastases, inhibition of proteolytic activity is necessary. In this study we investigated the correlation of the Plasminogen Activator Inhibitor 1 (PAI-1), which is the specific inhibitor of uPA and which seems to be important for tumour formation, with prognosis in breast cancer. PAI-1 antigen levels were measured in cytosols of 268 primary breast cancers. In 205 cases we correlated the PAI-1 status (cut-off value: 1 ng/mg) with the clinical outcome. Furthermore we investigated PAI-1 antigen levels in 10 benign breast tumours and 33 metastases. PAI-1 levels were significantly higher in primary carcinomas (median value: 0.62 ng/mg, range: 0 to 30.7) than in benign tumours (median value: 0 ng/mg, range: 0 to 0.1) and metastases showed elevated levels (median value: 1.05 ng/mg, range: 0 to 7.8) in comparison to the primary tumours (Kruskal-Wallis test: p < 0.05). We found that the PAI-1 status correlated significantly with early disease recurrence (Mantel-Test p = 0.0069) and overall survival (Mantel-Test p = 0.0121). After a median follow-up of 32 months (range 2-58), 36% of patients with PAI-1 antigen levels > or = 1 ng/mg (n = 72) showed an early relapse and 24% died, whereas only 19% of patients with PAI-1 antigen levels < 1 ng/mg (n = 133) relapsed and 9% died within the study period. A multivariate analysis revealed that in our study population PAI-1 is not an independent prognostic factor. According to our findings PAI-1 seems to be involved in the formation of extracellular matrix in primary carcinomas and metastases and is related to poor prognosis in breast cancer.

Adult↗
PubMed1995

Cutaneous side effects in breast cancer patients treated with cytostatic polychemotherapy and rh GM-CSF: immune phenomena or drug toxicity?

The application of recombinant colony stimulating factors for chemotherapy induced granulocytopenia is becoming common in clinical oncology. Here we report on localized cutaneous side effects after subcutaneous administration of recombinant human granulocyte-macrophage colony-stimulating factor (rh GM-CSF) in 11 patients with breast cancer receiving cytostatic treatment. Seven patients suffering from inflammatory breast cancer received cytostatic chemotherapy with mitoxantrone/cyclophosphamide, whereas four patients suffering from noninflammatory breast cancer received high-dose epirubicin/cyclophosphamide, respectively. rh GM-CSF was applicated subcutaneously in a dose of 5 micrograms/kg/d for at least ten days. In all patients, sharply demarked, maculous itching and burning erythemas restricted to the injection sites occurred after three to four injections of rh GM-CSF. These eruptions cleared within 2 to 3 weeks, but reappeared after reexposure to rh GM-CSF. In contrast to previous sporadic reports, no generalized erythemas were observed. Because of this unexpected and subjectively intolerable side effect, rh GM-CSF administration had to be interrupted in all patients. Histopathological findings revealed skin infiltration with lymphocytes, monocytes/macrophages, neutrophils, and occasionally eosinophils, respectively. Since GM-CSF is known to alter immune functions, it seems likely that the eruptions were at least in part due to local immune reactions.

Adenocarcinoma↗
PubMed1995

Interphase cytogenetics reveals a high incidence of aneuploidy and intra-tumour heterogeneity in breast cancer.

The occurrence of aberrations involving chromosomes 11 and 17 in malignant tissues of breast cancer patients has not yet been studied systematically. Using fluorescence in situ hybridisation (FISH) with centromere-specific probes, we determined chromosome 11 and 17 status in interphase nuclei from primary and/or metastatic breast cancer cells. In all cancerous specimens obtained from 30 patients, FISH identified cells with clonal chromosomal abnormalities, with aneuploidy rates ranging from 6% to 92% (median 59%). There was a gain of centromeric signals for chromosome 11, most likely corresponding to hyperploidy; aberrations of chromosome 17 in specimens from 26 patients (87%) were hyperploid as well; however, four cases (13%) showed loss of chromosome 17 centromeres. All specimens contained heterogeneous aneuploid cell populations with excessive gain of signals in some cases. The pattern of aneuploidy did not appear to correlate with tumour grade/stage and was comparable in primary tumours and corresponding metastatic axillary lymph nodes, indicative of genetic instability early in tumour development. Screening with a panel of FISH probes may lead to enhanced sensitivity and specificity in detecting malignant cells, as demonstrated in this study with effusions which could not be conclusively interpreted as being malignant by cytological criteria.

Adult↗
PubMed1995

Stereospecific pharmacokinetics of rac-5-methyltetrahydrofolic acid in patients with advanced colorectal cancer.

1. The pharmacokinetics and toxicity of racemic 5-methyltetrahydrofolic (rac-5-MTHF) acid after i.v. infusion were investigated in 18 patients with advanced colorectal cancer. Doses of 100-600 mg rac-5-MTHF/m2 were administered over 2 h together with a bolus of 500 mg/m2 5-fluorouracil (5-FU) as a midpoint injection. 2. The pharmacokinetics of both diastereoisomers were linear in the range from 100-600 mg 5-MTFH/m2. Independent of the administered dose, the maximal plasma concentration of [R]-5-MTHF was nearly twice that of [S]-5-MTHF. The elimination of [S]-5-MTHF from plasma was considerably faster than that of the [R]-isomer (elimination half-life: 3.1 +/- 1.0 h vs 8.3 +/- 3.2 h). No metabolites were detected in plasma and in urine samples. 3. The plasma protein binding was stereoselective ([R]-5-MTHF bound: 88.2 +/- 2.7%; [S]-5-MTHF bound: 59.9 +/- 6.8%; P < 0.001), causing a significantly higher renal clearance for [S]-5-MTHF when compared with the [R]-isomer (37.5 +/- 23.7 ml min-1 vs 12.7 +/- 11.2 ml min-1, P < 0.001). There was no dose dependence, but gender influenced renal clearance (CLren[R]-5-MTHF: male vs female: 20.5 +/- 14.5 ml min-1 vs 7.8 +/- 4.7 min-1, P = 0.03; CLren [S]-5-MTHF: male vs female: 57.2 +/- 21.7 ml min-1 vs 25.7 +/- 16.2 ml min-1, P = 0.006). 4. Toxic side effects of the combination 5-FU/5-MTHF were rare and generally mild, and included stomatitis, nausea/emesis, diarrhoea, anaemia, leukopenia, and thrombocytopenia. 5. In combination with 500 mg 5-FU/m2 a single dose of 600 mg rac-5-MTHF/m2 can safely be administered to patients with colorectal cancer. A similar therapeutic benefit of 5-MTHF to folinic acid in the biochemical modulation of 5-FU is supported by the comparison of in vitro and in vivo data.

Aged↗
PubMed1994

Different stereospecific protein binding of tetrahydrofolates to human serum albumin.

The protein binding of the tetrahydrofolates folinic acid (FA) and its metabolite 5-methyltetrahydrofolic acid (5-MTHF) to human serum albumin (HSA) is stereoselective. At therapeutically relevant concentrations of tetrahydrofolate (range, 5-100 microM), the protein binding was stereoselective to the (R)-isomers of FA and 5-MTHF. The binding of (R)-FA and (R)-5-MTHF was saturated at a concentration of 7% HSA [(R)-tetrahydrofolate bound, ca. 80%]. In contrast to (S)-FA, which was not bound to HSA, (S)-5-MTHF was bound to 45% under physiological conditions. (R)-FA did not influence the protein binding of (S)-FA. Hypoalbuminemia is common in patients with advanced colorectal cancer and affects differentially the protein binding of the diastereoisomers of FA and 5-MTHF. Thus, an influence on the biochemical modulation of 5-fluorouracil by tetrahydrofolates should be taken into consideration.

Chromatography, High Pressure Liquid↗
PubMed1994

Thymidine labeling index and Ki-67 growth fraction in breast cancer: comparison and correlation with prognosis.

In situ determination of proliferative activity was performed on 184 consecutive primary invasive breast cancers. Methods used were monoclonal antibody Ki-67 in immunohistochemistry and thymidine labeling index. Tumor proliferation correlated between both methods (p = 0.0001). For thymidine labeling index and Ki-67, respectively, significant correlations existed with histologic tumour grade and steroid hormone receptors (Tumor grade: TLI p = 0.0001; Ki-67 p = 0.0001. ER-ICA: TLI = 0.0001; Ki-67 p = 0.014. PgR-ICA: TLI p = 0.0001; Ki-67 p = 0.0008). For thymidine labeling index a significant correlation was demonstrated for overall survival (p = 0.001) and recurrence free survival (p = 0.01). No statistical significance was observed for clinical outcome and Ki-67 (overall survival p = 0.18; recurrence free survival p = 0.1). None of the factors, TLI or Ki-67, was an independent prognostic factor as demonstrated by multivariate analysis.

Breast Neoplasms↗
PubMed1994

Double modulation of 5-fluorouracil by high-dose leucovorin and interferon alpha 2b in advanced colorectal cancer: a phase I and a phase II study of weekly administration.

In an attempt to evaluate the feasibility of 5-fluorouracil (FU) treatment modulated by (R,S)-leucovorin (LV) and interferon alpha (IFN alpha) in patients with advanced colorectal cancer, we conducted a phase I trial with increasing doses of subcutaneous IFN alpha (3 x 1 x 10(6) U, 3 x 3 x 10(6) U, 3 x 3 x 10(6) U, 3 x 5 x 10(6) U and 3 x 10 x 10(6) U/week) and 500 mg/m2 LV i.v. as a 2-h infusion with 600 mg/m2 FU i.v. as a midpoint injection. Unacceptable side-effects occurred in all 3 patients at the highest dose level of IFN alpha, while toxicity was tolerable at 3 x 5 x 5 x 10(6) U IFN alpha/week. Thus, this dose was defined as the maximal tolerable dose for IFN alpha in combination with FU and LV. In a subsequent phase II study a total of 83 treatment courses (median: 2.8, range: 2-10) were administered to 30 evaluable patients. Side-effects were acceptable with no WHO grade IV toxicities. Grade III toxicities consisted in thrombopenia (2/30), stomatitis (2/30), diarrhoea (3/30) and nausea/vomiting (4/30). After a median observation time of 17 months (range: 8-22 months), no complete remission was observed and 9 patients experienced a partial response lasting for a median of 6.6 months (range: 3-13+ months), for an overall response rate of 30% (95% confidence interval: 15%-49%). These results show that the described regiment of FU doubly modulated by LV and IFN alpha is active in colorectal cancer and can be safely administered in an out patient setting with acceptable toxicity. Thus, this regimen is suitable to be used for further evaluation in clinical trials.

Adult↗
PubMed1994

Pharmacokinetics of rac-leucovorin vs [S]-leucovorin in patients with advanced gastrointestinal cancer.

1. The pharmacokinetics of [R]-leucovorin ([R]-LV), [S]-leucovorin ([S]-LV) and the circulating metabolite [S]-5-methyltetrahydrofolate ([S]-5-MTHF) were studied after administration of racemic LV and [S]-LV in 21 subjects. 2. After intravenous infusion of 600 mg m-2 rac-LV (group 1, n = 7) or 300 mg m-2 [S]-LV (group 3, n = 7), the decay of [S]-LV in plasma was biexponential with a distribution half-life of 0.8 to 1 h and an elimination half-life of 11 to 23 h. When rac-LV was administered as a 2 h i.v. infusion (400 mg m-2) following a loading dose of 200 mg m-2 (group 2, n = 7), the plasma concentrations of [R]-LV and [S]-5-MTHF decayed monoexponentially with mean (+/- s.d.) half-lives of 10 +/- 3 h and 7 +/- 2 h, respectively. 3. The AUC of [S]-5-MTHF was significantly higher after infusion of 300 mg m-2 [S]-LV than after infusion of 600 mg m-2 rac-LV (83 +/- 22 micrograms ml-1 h vs 53 +/- 22 micrograms ml-1 h; P = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Adjuvant intraperitoneal cisplatin chemotherapy does not improve long-term survival after surgery for advanced gastric cancer.

PURPOSE: The long-term survival probability of patients who undergo surgery for stage 3 and 4 gastric cancer is poor, predominantly due to metastatic spread of the tumor. Depending on the type of tumor histology, the pathway of metastases is mainly peritoneal or hepatic dissemination. Interruption of this mechanism may be possible by intraperitoneal chemotherapy (IPT). PATIENTS AND METHODS: In a prospective randomized trial of 67 patients undergoing surgery for stage 3 and 4 gastric cancer, 33 patients underwent adjuvant postoperative IPT with cisplatin, while 34 control subjects remained untreated. RESULTS: Patients in the treatment group received a median of four IPT perfusions. Apart from frequent nausea, no adverse reactions or complications were noted. The median disease-free survival durations were 12.7 months and 9.7 months in treated patients and controls, respectively (P = .8). After a median follow-up duration of 72 months, 54 patients (80%) had died of primary disease or related complications. The median survival duration for IPT patients was 17.3 months as compared with 16.0 months for controls (P = .6). Autopsies were performed on 12 (18%) of 54 patients who died, and showed tumor spread to the peritoneal cavity and/or to the liver, irrespective of the application of IPT. CONCLUSION: IPT with cisplatin monotherapy does not improve survival probability after surgery for stage 3 and 4 gastric cancer. The reasons for ineffectiveness of IPT may be the choice of an unsuitable chemotherapeutic agent, an inefficient modus of application, or a lack of sufficient drug penetration into the serosa or peritoneal metastasis.

Aged↗