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Biomedical subjects

R Jakesz

Publications and source records attributed to R Jakesz.

At least 109 records · Page 6Linked to original sources
PubMed1989

Application of a new radiometric system for identification of potentially useful drug combinations for treatment of human gastrointestinal adenocarcinoma.

As an alternative to empirical clinical evaluation of combined drug effects in human tumors, and in an attempt to establish whether the combination of mitoxantrone (DHAD) with other standard drugs would be of any benefit to the patient with advanced gastrointestinal cancer, we have examined the results of simultaneous single-agent testing in vitro in a panel of 8 human colorectal (HCC) and 5 gastric cancer (HGC) cell lines. Cytotoxic drug effects were measured by the use of a new semiautomated radiometric technique (Bactec system), and were quantitated with attention to potentially clinically relevant plasma concentrations. Among several different drug combinations tested, maximal synergistic cell kill was found for DHAD + 5-fluorouracil; continuous incubation of the cells at 1/100 of the peak plasma concentration achievable in humans yielded in vitro responses in 8/8 HCC and 5/5 HGC cell lines. With regard to our results of single-agent testing, our finding of a significant level of in vitro arabinoside-C activity, using prolonged exposure at an in vitro dose corresponding to a clinical high-dose regimen, may provide a rational basis for (re)evaluation of the compound in gastrointestinal cancer patients.

Adenocarcinoma↗
PubMed1989

HER-2 amplification, steroid receptors and epidermal growth factor receptor in primary breast cancer.

Amplification of HER-2 oncogene was analysed in DNAs obtained from 291 primary human mammary carcinomas. 52/291 (18%) were found to contain amplified HER-2 oncogene. Moderate amplification (2- to 5-fold) was noted in 36/291 (12%). Thirteen tumors (4.5%) had a copy number of 5 to 10. A 10- to 20-fold and greater than 20-fold amplification was observed in 2 and 1 patient, respectively. Sample sizes allowed the determination of estrogen receptor (ER) and progesterone receptor (PgR) levels in 253/291 primary breast cancers. HER-2 gene amplification was noted in 14% of ER+ patients and in 28% of ER- patients, respectively (P = 0.02). Similarly a significantly greater number of PgR- primary mammary carcinoma exhibited an amplification of the HER-2 gene compared to PgR+ cases (22% vs. 16%, P = 0.01). Although statistically not significant, tumors with HER-2 gene amplification were found to have lower levels of ER and PgR. No association of HER-2 amplification with the androgen receptor and EGF receptor was observed. Present data combine to suggest that tumor progression is more stringently controlled by the oncogene upon loss of hormone dependency. Differences found in HER-2 amplification between steroid receptor positive and negative tumors could be helpful to define a specific subset of women to whom adjuvant therapy should be directed.

Breast Neoplasms↗
PubMed1988

[Androgen receptors in primary breast carcinoma. Relation to prognostic factors in comparison with estrogen and progesterone receptors].

Androgen receptor content was correlated with various prognostic factors in 274 patients with breast cancer. Receptor content was determined by the dextran-coated charcoal method (DCC). No direct relationship was found between androgen receptor content and age of patient, menstruation status, TN status and number of affected lymph nodes. But in 232 patients in whom tumour differentiation could be determined, there was a highly significant relationship between it and androgen receptor content (P less than 0.01). Similar correlations were found also between these prognostic factors and oestrogen or progesterone receptors. The percentage distribution of tumours of different degrees of differentiation was independent of the kind of demonstrable steroid-hormone receptor. However, the frequency of highly differentiated tumours rose with the number of different receptors that were determined. Thus steroid-hormone receptors can be considered as markers for differentiation. It seems possible that the additional determination of androgen receptors allows for a more exact selection of patients who should receive hormonal treatment.

Adult↗
PubMed1988

Natural killer cell activities of patients with breast cancer against different target cells.

Natural killer (NK) cell activity against K 562 erythroleukemic- and MCF-7 breast carcinoma-derived cells was monitored in short-term (3 h/K 562) and long-term (18 h/MCF-7) chromium release tests for 60 patients with untreated primary breast disease. Target cell lysis was the same for patient groups with benign (n = 13) and malignant (n = 47) breast disease (27% versus 36% mean chromium release; target:effector ratio 40:1 for K 562 and 28% versus 40% for MCF-7 cells). NK activity as defined by short-term lysis of K 562 cells did not correlate with MCF-7 cell lysis in long-term assays for the carcinoma patients. This functional heterogeneity of natural cytotoxic activities of breast cancer patients was confirmed by a different age distribution for K 562 and MCF-7 cell lysis and high levels of MCF-7-directed NK activity in the grade I tumor group (56.2%). Our results indicate that measurement of peripheral blood NK activity against a breast carcinoma-derived cell line (MCF-7) defines a disease-related natural cytotoxic activity which correlates better with prognostic tumor parameters (tumor grading) than NK activity as defined by the lysis of K 562 erythroleukemic cells. NK activity testing against breast carcinoma cell lines should be used to monitor natural cytotoxic activities in breast cancer patients and its modulation by different routes of treatment.

Adult↗
PubMed1988

Influence of two glutamine-containing dipeptides on growth of mammalian cells.

The instability of the amino acid glutamine prompted us to investigate substitute compounds appropriate for culture conditions. The effect of two glutamine-containing dipeptides, alanylglutamine (Ala-Gln) and glycylglutamine (Gly-Gln), on the growth behavior of a hematopoietic cell line in culture (K562) was investigated. Growth rates and [3H]thymidine incorporation rates of cells cultivated in sterile-filtrated media, containing glutamine (Gln) or Ala-Gln or Gly-Gln, were not statistically different. Although heart-sterilization of media containing Gln caused approximately 95% decomposition of the Gln, both dipeptides remained unaltered. Consequently, cell growth was drastically decreased when autoclaved free Gln-containing media were used, but growth was unaffected in the presence of autoclaved dipeptides. Both Ala-Gln and Gly-Gln have an advantage over free Gln as growth factors for cell culture due to the stability of the dipeptides during both autoclaving and storage; the biological activity, however, is comparable.

Cell Division↗
PubMed1988

Escalating dose regimen of intraperitoneal mitoxantrone: phase I study--clinical and pharmacokinetic evaluation.

Mitoxantrone, a recent anthracenedione derivative, is a potentially useful drug for direct intraperitoneal (i.p.) application because of its high tissue binding and therapeutic index. We have carried out studies to establish maximum tolerated doses as well as pharmacokinetic studies with i.p. mitoxantrone in 21 patients (5 male, 16 female) with gastrointestinal (9), ovarian (6), unknown (2) and other (4) primary cancers and peritoneal carcinomatosis. Increasing doses (10-40 mg/m2) were given i.p. every 4 weeks. Five partial remissions (2-8+ months) and 7 stable disease courses (2-6+ months) were achieved. A reduction or disappearance of ascites was seen in an additional 3 patients. Severe toxicity (leucopenia) was observed in 4 patients only after 35 and 40 mg/m2 i.p. Pharmacokinetic analysis using high performance liquid chromatography yielded the following data: The mean ratio of area under curve peritoneal fluid to plasma was 1109. The peritoneal clearance rate was 680 ml/min and the mean disappearance half life was 13.1 h. Mean urinary excretion within 24 h was 0.42% of the i.p. dose. These data indicate that mitoxantrone is sequestered in the intraperitoneal tissue compartment and only slowly released. Based on the outcome of this phase I study we recommend phase II studies at a dose of 30 mg/m2 i.p., repeated every 3-4 weeks.

Adult↗
PubMed1987

[Toxicity results of an adjuvant study with intraperitoneal chemotherapy in patients with stomach cancer. Current status and future prospects of intraperitoneal therapy].

The peritoneum is a frequent location of recurrent disease after surgical treatment of carcinoma of the stomach, colon, rectum or ovary. Usually this type of recurrence does not respond very well to systemic chemotherapy. The rational of intraperitoneal (ip) perfusion with cytotoxic drugs is based on a 2- to 3-log-fold increase in ip level over plasma concentration for certain chemotherapeutic agents. Hence, malignant cells in the peritoneal cavity can be exposed to very high concentrations of cytotoxic agents without serious systemic side effects. Remission rates of peritoneal carcinoma after ip perfusion of a range of chemotherapeutic substances varied from between 15 to 50%. Minimal information is available about adjuvant ip perfusion after operation for cure. Toxicity data are presented from our adjuvant trial using ip perfusion after operation for gastric carcinoma for cure with cisplatin in a randomized fashion. Altogether 59 perfusions were performed, with minimal systemic toxicity, no occurrence of peritonitis and only 1 portal infection. Immunological data show that 1 day after ip perfusion the concentration of natural killer cells is increased in 60% of all perfusions, but decreased only in 28%. We conclude that ip perfusion with cisplatin is a safe procedure with limited toxicity. The efficacy of this technique in peritoneal carcinosis is not yet proven in randomized trials. The observation period of our trial in the adjuvant stage after operation for gastric carcinoma is too short as get to assess the usefulness of the procedure.

Antineoplastic Agents↗
PubMed1987

Possible adverse effect of failed adjuvant chemotherapy on the prognosis of women receiving consecutive chemotherapy for recurrent breast cancer.

This study tried to evaluate the impact of adjuvant chemotherapy on the induction of chemoresistance in radically operated upon breast cancer patients. Remission rate, remission duration and survival of a group of women (n = 22) treated with combination chemotherapy (adriamycin and cyclophosphamide, AC) for recurrent breast cancer after failed adjuvant therapy (cyclophosphamide, methotrexate, fluorouracil, vinblastine) were retrospectively compared with the clinical data of non-pre-treated patients (n = 28) receiving the same regimen (AC). The two groups of patients were comparable with regard to their risk factors. In the group of women with prior adjuvant chemotherapy only 3 out of 22 had a partial response, lasting 3, 8, and 16 months; the median survival was 50 months. In the group without prior adjuvant therapy 3 complete and 7 partial remissions with a median remission duration of 15.5 months (range 2-54 months) were found; the median survival was 104 months. The percentage of objective responses among the non-pre-treated patients at 36% was almost significantly higher than that of the pretreated women with 14% (p less than 0.1). Responders to chemotherapy after relapse profited in terms of survival within the first 3 years after radical mastectomy, although no statistically significant difference was observed. The survival data shown assume a "shifting" of women from a group with better prognosis to a group with unfavourable prognosis following failed adjuvant chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Prognostic significance of steroid hormone receptors and histopathological characterization of human breast cancer.

Since breast cancer is a heterogeneous disease, evaluation of prognosis is an obvious problem. The prognostic significance of several pathological criteria including tumor grading according to WHO, steroid hormone receptor status, histological tumor type, tumor size, and axillary lymph node involvement have been investigated. The single parameters with the strongest prognostic significance were axillary lymph node status, tumor grading, and estrogen receptor status. A significant direct correlation exists between tumor grading and steroid hormone receptors, but nevertheless on stratified analysis both factors independently affected the risk of death. Tumor size had weak prognostic importance and histological tumor types failed to show any statistically significant differences with regard to survival.

Adult↗
PubMed1987

Phase-I study of intraperitoneal mitoxantrone--clinical and pharmacokinetic evaluation.

Mitoxantrone, a recent anthracenedione derivative is a potentially useful drug for direct intraperitoneal (i.p.) application because of its high tissue-binding and therapeutic index. We have carried out studies to establish maximum tolerated doses as well as pharmacokinetic studies with i.p. mitoxantrone in 21 patients (5 male, 16 female) with gastrointestinal (9), ovarian (6), unknown (2) and other (4) primary cancers and peritoneal carcinomatosis. Increasing doses (10-40 mg/m2) were given i.p. every 4 weeks. Five partial remissions (2-8+ months) and 7 stable disease courses (2-6+ months) were achieved. A reduction or disappearance of ascites was seen in an additional 3 patients. Severe toxicity (leukopenia) was observed in 4 patients only after 35 mg/m2 and 40 mg/m2 i.p. Pharmacokinetic analysis using high-performance liquid chromatography yielded the following data: The mean ratio of area under curve peritoneal fluid to serum was 1,108. The peritoneal clearance ranged from 2 ml/min to 9,617 ml/min and the disappearance half-life from 0.6-28.9 h. Mean urinary excretion within 24 h was 0.42% of the i.p. dose. These data indicate that mitoxantrone is sequestered in the intraperitoneal tissue compartment and only slowly released. Based on the outcome of this phase-I study we recommend phase-II studies at a dose of 30 mg/m2 i.p., repeated every 3-4 weeks.

Drug Evaluation↗
PubMed1987

[Value of rapid biopsy studies in the intraoperative assessment of axillary lymph node involvement in breast cancer].

In a prospective, randomized trial in breast-cancer patients, the surgical procedure and the adjuvant regimen were determined intraoperatively, depending on the axillary lymph node involvement. Therefore, it was necessary to perform frozen section examinations on axillary lymph nodes. In this context it was important to analyze the value of the frozen section technique of lymph nodes in predicting axillary node involvement. In 162 patients with primary breast cancer we compared the results of the frozen sections and the paraffin histology. In 96% the intraoperative diagnosis was correct and in 4% (7 cases) the results were wrong. In 6 cases we observed a sampling error and in one case a small metastasis was misinterpreted as sinus histiocytosis. In these 7 cases less than 4 lymph nodes were examined in frozen sections and the total axillary node involvement was small (less than 4 involved nodes). There was no false positive report in this series. We conclude that frozen section examinations of axillary lymph nodes are suitable for intraoperative lymph node assessment, if at least 4 of the macroscopically most suspicious lymph nodes are observed. The final histological axillary staging (number of involved lymph nodes) has to be performed on paraffin-embedded material.

Biopsy↗
PubMed1986

[Adjuvant chemotherapy in patients with radical resection of stomach cancer: 5-year results of a prospective randomized study].

102 patients with operable gastric carcinoma were randomly allocated to untreated control, polychemotherapy, chemoimmunotherapy. At a median follow-up of 5 years, chemotherapy did not improve the overall survival rate. However, in certain subgroups, patients with lymphnode metastases and intestinal tumor type showed a significant survival benefit when treated with adjuvant chemotherapy. Furthermore, we found the site of first recurrence very closely related to the type of tumor histology. Regardless of the positive effect of chemotherapy in retrospective subset-analysis, we do not generally recommend the use of polychemotherapy in operable gastric carcinoma.

Aged↗
PubMed1986

[Breast cancer in Austria: epidemiology and risk factors].

The incidence of breast cancer in Austria has been evaluated between 1971 and 1982. The incidence and mortality rates for this disease are comparable to the figures for Western Europe and the United States. A significant increase was observed in the overall incidence of breast cancer, which was, however, restricted to the age group before the 40th and after the 70th year of age. The incidence of breast cancer between 40 and 70 did not change significantly. The evaluation of high risk groups (first parity later than 30 years of age, nulliparity) showed decreasing incidence, whereas the frequency of women with early parity (earlier than 20 years of age)--representing a low-risk group--increased. Therefore, change of risk factors did not show any concordance with increasing breast cancer rate. Changes in diet in Austria over the past 30 years are discussed as a possible risk factor for increasing breast cancer rate.

Adult↗