Biomedical subjects
Publications and source records attributed to W J Köstler.
The present consensus manuscript defines evidence-based recommendations for state-of-the-art treatment of metastatic breast cancer depending on disease-associated and biologic variables.
Proteolytic cleavage of the Her-2/neu extracellular domain (ECD) has been shown to initiate receptor phosphorylation representing Her-2/neu activation in vitro. The present investigation was performed to evaluate the clinical relevance of ECD cleavage for Her-2/neu activation and the consequences of active intracellular Her-2/neu signalling reflected by tyrosine kinase phosphorylation in patients treated with the anti-Her-2/neu antibody trastuzumab. Sera from 62 patients receiving trastuzumab-based treatment for Her-2/neu overexpressing metastatic breast cancer were assessed for pretreatment ECD levels using an enzyme-linked immunosorbent assay. In parallel, Her-2/neu activation status of tumour specimens was assessed by immunohistochemistry using a Her-2/neu phosphorylation state specific antibody (PN2A) and correlated with the patients' ECD levels and clinical course of disease. Serum ECD levels were significantly higher in 15 (24%) patients with tumours exhibiting activated Her-2/neu as compared to those without detectable Her-2/neu phosphorylation (median 148.2 vs 28.5 ng ml(-1), P=0.010). Whereas response rate only showed a trend to be higher in patients with Her-2/neu-phosphorylated breast cancer (47 vs 34%, P=0.197), both uni- and multivariate analyses revealed that the median progression-free survival under trastuzumab-based treatment was significantly longer in patients with Her-2/neu-phosphorylated breast cancer-11.7 (95% CI 5.2-18.3) months-when compared to the progression-free survival of 4.5 (95% CI 3.4-5.6) months observed in patients with tumours lacking phosphorylated Her-2/neu (P=0.001). Proteolytic cleavage of the ECD represents a biologically relevant ligand-independent mechanism of Her-2/neu activation in vivo. The influence of Her-2/neu activation status upon the outcome of trastuzumab-based therapies merits further investigation in larger prospective trials.
BACKGROUND: Medical information to oncologic patients about their disease as well as regularly updated information about the course of their disease and the therapeutic success are essential components of a comprehensive treatment in cancer patients. STUDY GOAL: The quality of the patient-doctor-interaction as well as the hospital preference of oncologic patients were evaluated by a questionnaire at the Oncologic Out-Patient Clinic of the University Hospital of Vienna. METHODS: 350 questionnaires containing 12 questions about medical information, anti-cancer therapy, suggestions for improvement and hospital preference were distributed. The questions were correlated with the patients' demographic and medical data. RESULTS: Out of 350 questionnaires, 234 (67%)--160 (68%) by women and 74 (32%) by men--were returned. 75% of the patients were satisfied with the provided medical information. In contrast, 12% of patients felt incompletely informed about their particular cancer and 19% were unsatisfied with their state of information about the actual status of their disease. Our institution was mostly visited for quality-associated reasons and only in 3% for pragmatic reasons. 58% of the patients had no suggestions for improvement of medical care, although 28% of the patients wanted to spend more time with their doctors, 10% asked for more psychological care and 8% for additional alternative therapeutic modalities. CONCLUSION: The Oncologic Out-Patient Clinic is frequented mainly for quality-associated reasons. Although satisfaction with medical management is very high, there remains space for improvement of information about the underlying disease and its current status.
OBJECTIVES: In previous experiments, we demonstrated a decreased expression of intercellular adhesion molecule I (ICAM-1) on both tumour cells and antigen-presenting cells derived from patients with breast cancer, resulting in an abrogation of antigen presentation and tumour cell lysis. Recently, increased levels of a soluble isoform of ICAM-1 (sICAM-1) have been detected in the sera of breast cancer patients. The present investigation was performed in order to investigate the biological relevance of serum concentrations and the effects of sICAM-1 in patients with breast cancer. PATIENTS AND METHODS: sICAM-1 was determined using a sandwich enzyme immunoassay on sera from 88 patients with various stages of breast cancer and correlated with clinical parameters. The effect of sICAM-1 present in the sera of patients with breast cancer upon unspecific and anti-Her-21/neu antibody-mediated cytotoxicity (ADCC), as well as upon antigen presentation, was determined using a 51Cr-release assay and [3H]thymidine-uptake of T cells after co-incubation with tetanus-toxoid-pulsed antigen-presenting cells. RESULTS: In patients with early breast cancer, serum levels of sICAM-1 were significantly lower compared to patients with metastatic disease, but did not correlate with usual clinical parameters. In patients with metastatic breast cancer, a significant correlation of sICAM-1 with tumour markers CEA and CA 15-3 was observed. No influence of sICAM-1 upon unspecific cytotoxicity, ADCC, or the ability to present antigen was observed. DISCUSSION: The origin of sICAM-1 in the sera of patients with breast cancer remains unknown. In contrast to its membrane-bound isoform, sICAM-1 was increased in the sera of patients with various stages of breast cancer, but its presence did not influence unspecific cytotoxicity, ADCC, or antigen-induced T cell proliferation.
We have conducted a prospective controlled randomised clinical study testing for the efficacy of topical GM-CSF (molgramostim), as compared to the combined topical use of an antiseptic agent (povidone-iodine) and amphotericin B (AA) in patients with chemotherapy-induced mucositis World Health Organization (WHO) grades I-III. 31 patients (17 females, 14 males) developing oral mucositis following the administration of 5-fluorouracil (5-FU)-based chemotherapy were entered into the present trial. 15 patients were randomised to receive GM-CSF mouthwashes, whereas 16 patients were randomised into the control arm to receive AA. Reported history (P=0.6109) and grading of oral mucositis (2.1+/-0.7, respectively; P=0.9867) were balanced and equally distributed between the two groups. The mean size of lesions of oral mucositis was 1.5+/-0.6 cm (range: 0.7-2.5 cm) in the GM-CSF group and 1.2+/-0.5 cm (range: 0.5-2.5 cm) in the AA group (P=0.08), respectively. The mean number of oral mucositis lesions was 1.9+/-1.1 (range: 1-4) in the GM-CSF group and 2.1+/-1.2 (range: 1-4) in the AA group (P=0.63), respectively. None of the patients had previously received colony stimulating factors either topically or systemically. Treatment for oral mucositis was initiated on day 2.7+/-1.2 (range: day 1-8) after onset of symptoms in the GM-CSF group and on day 1.8+/-1.4 (range: day 1-3; P=0.11) in the AA group. The topical application of GM-CSF resulted in a significantly shorter duration and quicker resolution of oral mucositis, as compared to AA including both, pretreatment plus treatment periods (5.3+/-2.5 versus 8.1+/-1.5 days; P=0.0008) as well as the necessary duration of treatment needed until complete remission of lesions (2.8+/-0.7 versus 6.3+/-1.1 days; P<0.0001). A systemic effect of topical GM-CSF upon the number of peripheral blood leukocytes or granulocytes was excluded. We conclude that the topical application of GM-CSF by mouthwash significantly abbreviated the duration and relieved patients from symptoms of chemotherapy-induced mucositis and was superior to the topical application of AA.
BACKGROUND: Metastatic soft tissue sarcoma not amenable to curative surgery has a dismal prognosis. Aggressive treatment with anthracyclines and ifosfamide represents the current therapeutic mainstay in these patients, most of whom succumb to relapses. Thus, the efficacy of subsequent therapeutic approaches has to be weighed against toxicity caused by palliative treatment. PATIENTS AND METHODS: Patients with locally advanced or metastatic soft tissue sarcoma refractory to treatment with anthracyclines and ifosfamide were enrolled into the present phase II study. Patients were assigned to receive docetaxel at 100 mg/m2 every three weeks. In case of severe toxicity, patients were switched to a weekly schedule of docetaxel (40 mg/m2). RESULTS: A total of 106 cycles (80% at the scheduled 100 mg/m2 dose level) were administered in 27 patients. Partial response was observed in 4 (15%) patients and 4 (15%) patients experienced disease stabilization. Median progression free survival and overall survival were 2.4 (range: 0.9-23.9) and 7.7 (range: 1.0-44.3) months, respectively. Upon renewed progression, three patients initially responsive to treatment with docetaxel were successfully reinduced by treatment with docetaxel. The safety profile of docetaxel was tolerable and the administration mostly manageable on an outpatient basis. CONCLUSIONS: Our results suggest that docetaxel represents an efficacious and tolerable treatment in a minority of patients refractory to standard treatment. There is a need for better identification of patients most likely to benefit from salvage treatment with docetaxel.
Previous experiments from our laboratory have shown that immune mechanisms aiming at the destruction of tumour cells including the recognition of target cells and their elimination via the expression of intercellular adhesion molecule-1 (ICAM-1; CD54), the production of tumour necrosis factor-alpha (TNF-alpha) by monocytes and appropriate function of lymphocyte subpopulations were defective in breast cancer. Previous observations were extended to assess expression levels and regulatory mechanisms of costimulatory molecules CD54, CD80 and CD86 on monocytes derived from patients with early breast cancer (EBC). In addition, antigen presentation by antigen-presenting cells (APC) was analyzed within this context. We report that monocytes derived from patients with EBC exhibited significantly decreased expression levels of CD54 (p = 0.0002), CD80 (p = 0.009) and CD 86 (p = 0.002) compared with monocytes derived from healthy females. Simultaneously, lipopolysaccharide (LPS)-induced TNF-alpha production of monocytes was found to be defective in patients with EBC. Finally, T-cell proliferation in response to tetanus toxoid (TT) was significantly decreased in patients with EBC compared with healthy control females (p < 0.0001). Furthermore, T-cell proliferation in response to TT-pulsed APC derived from healthy controls was significantly inhibited in the presence of anti-CD54 and/or anti-CD80 antibodies in a dose-dependent manner, thus corroborating the necessity of the presence of CD54 and CD80 as costimulatory molecules in the present setting. We conclude that monocytes derived from patients with EBC showed a simultaneous defect of expression of CD54 and its regulation via TNF-alpha, CD80 and CD86 as well as T-cell proliferation following exposure to TT-pulsed APC. Based upon these findings, it is speculated that defects in costimulatory molecule expression might contribute to tolerance of the immune system towards the presence of malignant cells in patients with EBC.
The present phase II trial was performed to assess the efficacy and toxicity of polychemotherapy with gemcitabine and cisplatin in patients with locally advanced or metastatic carcinoma of the pancreas. Sixteen patients received six courses of an i.v. cytotoxic regimen consisting of gemcitabine (1000 mg/m2, days 1, 8 and 15) and cisplatin (35 mg/m2, days 1, 8 and 15) administered in 28-day intervals. Complete remission (CR) occurred in one patient (6%), partial remission (PR) in four patients (25%) and stable disease in seven patients (44%), whereas four patients (25%) developed progressive disease resulting in an overall response rate of 31%. Mean duration of responses (CR+PR) was 3.6 (range 0.7-8.5) months and mean time to progression was 7.4 (range 3.8-12.6) months. After a mean observation period of 11.5 months the overall survival was 9.6 months with 12 patients (75%) still being alive, which compares favorably with historical data of the administration of gemcitabine alone. The performance status improved in three (19%) and stabilized in eight (50%) out of 16 patients for 4 weeks or longer. Treatment-associated toxicity included alopecia of WHO grade III in all cases, leukopenia of WHO grades I and II in 10 patients (63%), grade III in five patients (31%), and thrombocytopenia grades I and II in four patients (25%), and grades III and IV in 10 patients (63%). We conclude that the administered dosage and schedule of gemcitabine and cisplatin in patients with locally advanced or metastatic cancer of the pancreas constitutes an active cytotoxic regimen associated with moderate toxicity.
The aim of this phase II study was to investigate the therapeutic value of second-line treatment with oxaliplatin, irinotecan (CPT-11) and mitomycin C (MMC) in patients with metastatic colorectal cancer pretreated with 5-fluorouracil (5-FU)-based chemotherapy. A total of 10 patients with metastatic colorectal cancer, all of whom had developed progressive disease from advanced or metastatic colorectal cancer while receiving or within 6 months after discontinuing first-line chemotherapy with 5-FU and leucovorin, were entered in this study. At the time of relapse, cytotoxic chemotherapy consisting of oxaliplatin 80 mg/m2 plus CPT-11 80 mg/m2 given i.v. on therapeutic day 1, and MMC 6 mg/ m2 given i.v. on day 15, respectively, was initiated. Treatment courses were repeated every 4 weeks for a total of six courses unless there was prior evidence of progressive disease. The overall response rate was 30% with three partial responses for all 10 assessable patients. Two additional patients (20%) had stable disease and five patients (50%) progressed. The median overall survival duration has not been reached yet and is longer than 7.1 months (range 2-23.5+) from the beginning of second-line therapy. Four patients are currently alive with progressive disease. The tolerance of second-line treatment was generally mild to moderate and easy to treat. Our data suggest that the combination of oxaliplatin, CPT-11 and MMC in patients with metastatic colorectal cancer pretreated with 5-FU-based chemotherapy is feasible and has substantial antitumor activity. Further evaluation of this regimen seems warranted.
The issue of minimal residual disease (MRD) manifesting itself by the presence of undetected disseminated isolated tumor cells in both tissues and hematopoietic autografts from patients with early-stage malignancies or from patients in clinical complete remission has been discussed widely during the last decade. Based on the current understanding of the pathogenesis of malignancy, disseminated tumor cells persisting after conventional oncologic treatment modalities or after reinfusion of contaminated autologous hematopoietic cells constitute the source of subsequent recurrence of disease. Accordingly, much emphasis is placed on the detection and characterization of disseminated isolated tumor cells in both basic and clinical research. This effort is aimed at a better understanding of the processes of metastasis and tumor dormancy and, ultimately, the estimation of prognosis, molecular monitoring, and the design of new therapeutic agents in oncology. In our review, we used computerized (MEDLINE, Embase) and manual searches to summarize laboratory and clinical data concerning MRD focusing on the issue of MRD in solid malignancies. We give a detailed overview of the methods used for the detection and molecular characterization of disseminated tumor cells and of the prevalence and prognostic significance of the detection of MRD in patients and hematopoietic autografts. Finally, we discuss the emerging therapeutic consequences of the detection of disseminated tumor cells, with special emphasis on the therapeutic potential of antibodies. We conclude that the detection of MRD represents a hallmark for the diagnosis, monitoring, and treatment of malignant conditions in future clinical trials.
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Chemotherapy- and radiotherapy-induced oral mucositis represents a therapeutic challenge frequently encountered in cancer patients. This side effect causes significant morbidity and may delay the treatment plan, as well as increase therapeutic expenses. The pathogenesis of this debilitating side effect can be attributed to the direct mucosal toxicity of cytotoxic agents and ionizing radiation and to indirect mucosal damage caused by a concomitant inflammatory reaction exacerbated in the presence of neutropenia, and the emergence of bacterial, mycotic, and viral infections. The prophylactic and therapeutic armamentarium for the treatment of oral mucositis consists of locally and systemically applied nonpharmacological measures and pharmacotherapeutics.
BACKGROUND: VIP acts as a neuroendocrine mediator under physiological conditions, with an important role in water and electrolyte secretion in the gut. Recent findings suggest that VIP also promotes growth and proliferation of normal as well as malignant cells. We have investigated the VIP-serum levels in patients with pancreatic cancer and colonic adenocarcinoma as compared to healthy controls. This was accompanied by immunohistochemical investigations and in vitro experiments to further define the role of the peptide in pancreatic and colorectal cancer. MATERIALS AND METHODS: Serum levels of VIP were evaluated under standardized conditions in a total of 135 patients; 45 patients had metastatic colorectal cancer, 45 suffered from metastatic pancreatic cancer, and 45 healthy volunteers served as controls. Human pancreatic and colorectal carcinoma cell lines were incubated over 5 days with VIP in increasing concentrations. RESULTS: In healthy controls, a median VIP-serum level of 42.44 +/- 2.540 pg/ml (range, 12.9-98.5 pg/ml) was found, while patients with pancreatic cancer had a median level of 40.58 +/- 3.013 pg/ml (range, 6.9-102.4 pg/ml). In patients with cancer originating in the colon, however, a median serum level of 116 +/- 10.14 pg/ml (range, 51.6-487 pg/ml) was found. While no difference between healthy controls and patients with pancreatic cancer could be detected (p = 0.6381), a significant difference between patients with colorectal cancer and healthy controls (p < 0.0001) and patients with pancreatic cancer (p < 0.0001) was demonstrated. The median VIP-concentrations found in the patients sera for pancreatic and colonic tumor patient groups, 40 pg/ml and 115 pg/ml respectively, had no significant effect on the proliferation of PANC-1 and HT29, inhibited ASPC-1, BxPC3, COLO201 and HCT-15 cells, and stimulated the growth of one pancreatic (CAPAN-1) and one colonic (COLO320DM) cell line under these conditions. CONCLUSIONS: As opposed to pancreatic cancer and healthy controls, patients in our series had elevated serum VIP-levels. Further studies are warranted to evaluate whether VIP can be used as a tumor marker in this disease.