Georg Weinländer

Two consecutive phase II studies of 5-fluorouracil/leucovorin/mitomycin C and of gemcitabine in patients with advanced biliary cancer.

Introduction: Carcinoma of the biliary system is a rare tumor entity, and patients with advanced disease face a dismal prognosis. Because of the absence of standard chemotherapy for advanced biliary carcinoma, we have performed two consecutive studies to evaluate the clinical potential of 5-fluorouracil, leucovorin and mitomycin C as well as the novel antimetabolite gemcitabine in this disease. Patients and Methods: A total of 39 consecutive patients suffering from locally inoperable or metastatic biliary cancer were enrolled in the study between March 1994 and October 1997. Twenty patients were treated with leucovorin 200 mg/m2 and 5-FU 400 mg/m2, both given as intravenous bolus on days 1–4, and mitomycin C 8 mg/m2 on day 1 (group A). Treatment cycles were repeated every 28 days. The second cohort included 19 patients, who received gemcitabine 1200 mg/m2 on days 1, 8 and 15 with a 2-week interval before the next treatment cycle (group B). Treatment was continued for a maximum of 6 cycles in the absence of progressive disease in both groups, and endpoints of the study were responses rates, survival and toxicity. Results: In group A, 5 patients (25%) had a partial response (PR), 6 additional patients (30%) had stable disease (SD) and 9 patients (45%) progressed during treatment. The median survival was 9.5 months (range, 3–14.5) with the median time to progression being 4 months (range, 3–9). In group B, 3 patients achieved a PR (16%), 4 showed SD (21%), while the remaining 12 patients had progressive disease. A median survival of 6.5 months (range, 2–11.5) was obtained, and the median time to progression was 2.5 months (range, 1–6+). Toxicity was generally mild in both treatment arms, 6 patients in group A required dose reductions, while no dose adaptation had to be performed for gemcitabine. Conclusion: Our data suggest that treatment of advanced biliary cancer is feasible and can be safely performed with both regimens applied in our study. While administration of gemcitabine has resulted in only mild toxicities, its exact impact on the management of advanced biliary cancer should be evaluated in a controlled trial.

High levels of eosinophil cationic protein in wheezing infants predict the development of asthma

BACKGROUND In association with respiratory tract infections, infants may have episodes of wheezing, which represent the onset of asthma in some of them. Activated eosinophils play a central part in asthmatic inflammation. OBJECTIVE We investigated whether, in infants experiencing their first episode of wheezing, eosinophil activation is present and can predict the development of asthma. METHODS In a prospective trial, eosinophil activation was measured by eosinophil cationic protein (ECP) concentrations in serum from 33 nonatopic infants with their first episode of wheezing, 15 nonatopic infants with upper respiratory tract infection without wheezing, and 18 healthy nonatopic infants. One year later, the children were re-evaluated for a diagnosis of infantile asthma. RESULTS Wheezing infants had higher median serum ECP levels (13.4 micrograms/L) than children with nonwheezy respiratory tract infection (7.6 micrograms/L, p < 0.005) or healthy subjects (7.1 micrograms/L, p < 0.005). In addition, wheezing infants (n = 13) with serum ECP concentrations greater than 20 micrograms/L were more likely to have asthma within 1 year than patients with ECP levels less than 20 micrograms/L (odds ratio = 12.4; confidence interval, 4.6-33.5). CONCLUSION Eosinophil activation measured by serum ECP is present in infants with their first episode of wheezing illness, especially in those infants in whom asthma subsequently develops within 1 year. These data may indicate a predictive value of serum ECP measurements in children with wheezing to identify those patients in whom infantile asthma is developing. These findings probably also indicate that serum ECP may be used to identify the children who need early antiinflammatory treatment.

Combined Irinotecan and Oxaliplatin Plus Granulocyte Colony-Stimulating Factor in Patients With Advanced Fluoropyrimidine/Leucovorin-Pretreated Colorectal Cancer

PURPOSE To evaluate the efficacy and tolerance of combined irinotecan and oxaliplatin in patients with advanced colorectal cancer pretreated with leucovorin-modulated fluoropyrimidines. PATIENTS AND METHODS Thirty-six patients with metastatic colorectal cancer, who progressed while receiving or within 6 months after discontinuing palliative chemotherapy with fluoropyrimidines/leucovorin, were enrolled onto this study. Treatment consisted of oxaliplatin 85 mg/m2 on days 1 + 15 and irinotecan 80 mg/m2 on days 1 + 8 + 15 every 4 weeks. Depending on the absolute neutrophil counts (ANC) on the day of scheduled chemotherapeutic drug administration, a 5-day course of granulocyte colony-stimulating factor (G-CSF) 5 microg/kg/d was given. RESULTS The overall response rate was 42% for all 36 assessable patients (95% confidence interval, 26% to 59%), including two complete remissions (6%). Thirteen additional patients (36%) had stable disease, and only eight (22%) progressed. The median time to treatment failure was 7.5 months (range, 1 to 13.5+ months). After a median follow-up time of 14 months, 19 patients (53%) are still alive. Hematologic toxicity was commonly observed, although according to the ANC-adapted use of G-CSF (in 31 patients during 81 of 174 courses), it was generally mild: grade 3 and 4 granulocytopenia occurred in only five and two cases, respectively. The most frequent nonhematologic adverse reactions were nausea/emesis and diarrhea, which were rated severe in 17% and 19%, respectively. CONCLUSION Our data suggest that the combination of irinotecan and oxaliplatin with or without G-CSF has substantial antitumor activity in patients with progressive fluoropyrimidine/leucovorin-pretreated colorectal cancer. Overall toxicity was modest, with gastrointestinal symptoms constituting the dose-limiting side effects. Further evaluation of this regimen seems warranted.

Treatment of advanced breast cancer with gemcitabine and vinorelbine plus human granulocyte colony-stimulating factor.

AbstractPurpose. A phase II trial was performed to investigate the efficacy and tolerance of gemcitabine, vinorelbine, and recombinant human granulocyte colony‐stimulating factor (G‐CSF) in advanced breast cancer. Patients and methods. Between April 96 and August 97, 60 patients entered this trial. Forty‐five patients were previously untreated and 15 patients had failed previous palliative chemotherapy with (n = 10) or without anthracyclines (n = 5). Therapy consisted of gemcitabine 1000 mg/m2 on days 1 + 15 + 21 and vinorelbine 40 mg/m2 on days 1 + 21, both diluted in 250 ml saline and infused over 30 min. G‐CSF was administered at 5 μg/kg/day subcutaneously from days 2–6 and 22–26. Courses were repeated every 5 weeks. Treatment was continued in case of response or stable disease until a total of six courses. Results. The overall response rate was 55.5% for patients who had not received prior palliative chemotherapy (95% confidence interval, 40%–70.3%), including 5 CR (11.1%) and 20 PR (44.4%) 12 patients (27%) had stable disease (SD), and 8 (18%) progressed. Second‐line treatment with this regimen resulted in 6/15 (40%) objective remissions, 5 had SD, and 4 PD. The median time to progression was 9.5 months (range, 1.5–28) in previously untreated patients, and 7.0 months (range, 2–23) in those who had failed prior chemotherapy. After a median follow‐up time of 15 months, 44 patients (73%) are still alive with metastatic disease. Myelosuppression was commonly observed, though WHO 3 and 4 neutropenia occured in only 9 (l5%) and 2 patients (3%), and was never complicated by septicaemia; grade 3 anemia was noted in 2 patients. Severe (WHO grade 3) nonhematologic toxicity was rarely observed, and included nausea/emesis in 3 and constipation in 2 patients. Conclusions. Our data suggest that gemcitabine and vinorelbine plus G‐CSF is an effective and tolerable first‐ as well as second‐line combination regimen for treatment of advanced breast cancer.

Stabilization of a progressive hemangioblastoma under treatment with thalidomide.

After the second recurrence of spinal seeding in hemangioblastoma not associated to von-Hippel–Lindau disease, we treated an adult female patient with thalidomide 200 mg orally/day at night for longer than 1 year. The patient reported subjective relief of symptoms after 1 month. Magnetic resonance imaging (MRI) controls 1, 6 and 11 months after begin of thalidomide treatment did not show further tumor progression. She remained wheelchair-bound, but mobility of her arms continuously improved. There was no thalidomide associated side-effect in this patient until her death from pneumonia due to legionnaires disease.Antiangiogenic treatment with interferon (IFN) α-2a and IFN α-2b and with SU 5416 has been reported to be effective and well tolerated in several patients with previously progressive angioblastomas and hemangioblastomas. This case adds further evidence of the efficacy of an antiangiogenic treatment concept in a progressive hemangioblastoma.

Generation of dendritic cells from human chronic myelomonocytic leukemia cells in fetal calf serum-free medium.

It is generally believed that the immune system plays a role not only in the acquisition of malignant diseases but also in the rejection of microscopic as well as established tumor cells. Failure of the immune system to eliminate tumor cells may be, among other factors, due to an insufficient presentation of tumor antigens. Dendritic cells (DCs), as professional antigen-presenting cells, therefore, may be therapeutically used to initiate or enhance immune responses in patients with malignancies. In this study we demonstrate that peripheral blood cells of patients with chronic myelomonocytic leukemia (CMML) can be induced to acquire DC characteristics. Upon culture with granulocyte-macrophage colony-stimulating factor (GM-CSF) plus interleukin-4 (IL-4) plus tumor necrosis factor α (TNFα), CMML cells develop DC morphology and acquire the phenotypic characteristics of DCs. When a CD14+ cell population is used for DC generation, a homogeneous differentiation towards the DC lineage occurs similar to that, observed in normal peripheral blood monocytes. CMML-derived DCs are potent stimulators of the allogeneic mixed lymphocyte reaction (MLR) when compared with uncultivated cells. The demonstration of a deletion of the long arm of chromosome 7, del(7)(q22), in 86% of highly enriched CD1a+ cells by fluorescence in situ hybridization (FISH) indicates the leukemic origin of generated DCs. In addition, we present data that generation of CMML-derived DCs is also possible under fetal calf serum-free conditions for a potential clinical use. These DCs may be used as a cellular vaccine to induce anti-tumor immunity in patients with CMML.

Mitomycin C, Vinorelbine, Carboplatin plus Granulocyte-Macrophage Colony-Stimulating Factor for Treatment of Advanced Non-Small Cell Lung Carcinoma

Background: The therapeutic potential of chemotherapy in the treatment of recurrent or metastatic non-small cell lung carcinoma (NSCLC) seems modest. Thus, the search for novel agents and combination regimens with a superior therapeutic index has a high priority. The present combination regimen consisting of mitomycin C, vinorelbine, carboplatin and granulocyte-macrophage colony-stimulating factor (GM-CSF) was chosen because of the known activity of these agents in NSCLC and their potential drug synergism without (nonhematologic) cross-toxicity. To prevent/counteract neutropenia that was assumed to represent the dose-limiting toxicity, the hematopoietic growth factor GM-CSF was routinely adminstered. The objective of our trial was to determine the antitumor efficacy and tolerance of this combination regimen in patients with advanced NSCLC. Patients and Methods: Forty consecutive patients with nonresectable, measurable NSCLC (stage IIIB, 7; stage IV, 33) were treated with an intravenous combination chemotherapy regimen consisting of mitomycin C 8 mg/m2 on day 1, vinorelbine 40 mg/m2 on days 1 and 21, and carboplatin 250 mg/m2 on days 1 and 21; GM-CSF 5 µg/kg was administered subcutaneously on days 2–8 and 22–28. Treatment cycles were repeated every 6 weeks. All patients are evaluable in terms of toxicity and response assessment. A total of 123 courses was administered. Results: Objective tumor response was notes in 16 patients (40%; 95% confidence interval 24.9–56.7%), including 3 (7.5%) complete and 13 partial responses. There was no change in 12 (31.5%) patients, and 12 had progressive disease. Median duration of response was 6 (range 3–15) months, the median time to progression for all patients was 6.2 (range 1–17.5) months, and the projected median survival time was 8.7 (range 1–23.3) months; the 1-year survival rate was 27.5%. Myelosuppression was the most frequently encountered adverse reaction; WHO grade 3 or 4 granulocytopenia and/or thrombocytopenia occurred in 42.5 and 12.5%, respectively. Other toxicities were generally mild to moderate, and always fully reversible. Conclusion: With a 40% major response rate and disease stabilization in one additional third of our patients, this drug combination seems to have significant activity against advanced metastatic NSCLC. Due to its subjective tolerance and ease of administration, further investigation of this regimen in the palliative-intent care setting seems warranted.

Impaired hemorheology in patients with postmastectomy lymphedema

Lymphedema of the arm is one of the most disabling and serious complications of breast cancer. Apart from tumor infiltration or fibrosis of lymphatic pathways, little is known about factors favoring the development of lymphedema. In the present study, we investigated the impact of rheologic parameters, e.g. red cell aggregation (EA) and plasma viscosity (PV), and of capillary morphology and capillary flow in patients with breast cancer with (n = 18) and without (n = 18) lymphedema. Patients with lymphedema showed a significant increase of red cell aggregation (p < 0.001) that indicates a systemic component of lymphedema and might offer a possibility of prevention and therapy of this condition. A hitherto unclassified protein factor favoring red cell aggregation and lymphedema might be postulated.

Cytogenetic analysis and fluorescence in situ hybridization in a case of IgD multiple myeloma

Immunoglobulin D multiple myeloma (IgD MM) is a subentity of MM occurring in fewer than 2% of patients with distinct clinical pattern, dismal prognosis, and very little information about genetic abnormalities. The karyotype and the results of fluorescent interphase in situ hybridization analysis of a 62-year-old female patient with IgD MM are presented and show a complex hypodiploid karyotype with loss of an X chromosome and monosomy 13--very well known adverse prognostic factors in MM--but, in addition, several deletions of chromosomes 1, 6, 11, and 12, as well as translocations involving chromosomes 4, 9, 10, 15, 16, and 21 that underline the singularity of IgD MM.