Second-line chemotherapy with pemetrexed after gemcitabine failure in patients with advanced pancreatic cancer: a multicenter phase II trial.

BACKGROUND: A standard second-line chemotherapy regimen has yet to be defined for patients with gemcitabine (Gem)-refractory advanced pancreatic cancer (PC). PATIENTS AND METHODS: In this multicenter phase II trial, patients with unresectable or metastatic PC who had progressed on single-agent Gem or a Gem-containing regimen received pemetrexed 500 mg/m(2) as a 10-min infusion every 3 weeks until disease progression or occurrence of unacceptable toxicity. The primary end point was the 3-month survival rate. RESULTS: A total of 192 treatment cycles were given to 52 patients. The overall response rate was 3.8% (two partial responses); 10 patients (19.2%) experienced stable disease, nine of them for >12 weeks. At least one CA 19-9 reduction > or =50% occurred in 12 patients (23.1%). The 3-month survival rate was 75% (95% confidence interval 63.2% to 86.8%), the median time to tumor progression was 7 weeks (range 1-62 weeks) and the median overall survival time was 20 weeks (range 1-84 weeks). Grade 3/4 hematological toxic effects included (percent of patients): neutropenia (17.3%), thrombocytopenia (5.8%) and anemia (3.8%). The most frequent non-hematological toxic effects were diarrhea, nausea and stomatitis/pharyngitis (23.1% each). CONCLUSION: Pemetrexed is a safe treatment option with moderate activity in patients with advanced PC after failure of Gem.

[29-year-old female patient with pneumonia and enlarged abdominal lymph nodes]. / 29-jährige Patientin mit Pneumonie und grossen abdominellen Lymphknoten.

Common variable immunodeficiency (CVID) is the most common clinically manifested primary immunodeficiency disease. A 29-year-old female patient presented with pneumonia and enlarged thoracal and abdominal lymph nodes. Frequently recurring infections, especially in the respiratory tract were observed in the patient's history. A hypogammaglobulinaemia could be detected. By exclusion of other disorders and a complete analysis of the immune status a CVID Ib/B was diagnosed. Regular ambulatory treatment with immune globulin substitution reduced the incidence and severity of infections.

[Dose-reduced conditioning before allogeneic stem cell transplantation: principles, clinical protocols and preliminary results]. / Dosisreduzierte Konditionierung vor allogener Stammzelltransplantation - Grundprinzipien, klinische Protokolle und erste Ergebnisse

BACKGROUND AND OBJECTIVE: In the treatment of leukemia by stem cell transplantation, the immunological effects of allogeneic T-lymphocytes presumably play a greater part than high-dosage total-body irradiation (TBI) and chemotherapy. Using this immunological effect, attempts are currently being made to reduce the dosage of pre-treatment that is toxic to stem cell, such as TBI, thereby making transplantation available for a larger group of patients at high risk for transplantation. This study presents preliminary results of three current studies of this approach. PATIENTS AND METHODS: Elderly patients with chronic myeloid leukemia (CML) have an increased transplantation risk. They were conditioned with TBI that was reduced stepwise (n = 27). Patients with advanced and refractory myeloid leukemia were treated with chemotherapy and dose-reduced TBI (FLAMSA protocol; n = 54). In patients with multiple myeloma, autologous transplantation with high-dose chemotherapy preceded allogeneic transplantation possible after dose-reduced conditioning (Tandem protocol; n = 6). RESULTS: All three protocols of TBI gave results that were not worse than those of previous studies. Relapse ocurred not more frequently in patients with CML. In patients with high-risk AML the FLAMSA protocol gave better results. Autologous-allogeneic tandem transplantation was well tolerated and led to a good response in all patients. CONCLUSION: Allogeneic transplantation after dose-reduced conditioning opens up new possibilities with respect to widening indications for transplantation and improving results in hematological diseases with previously unsatisfactory treatment.

The impact of antithymocyte globulin on short-term toxicity after allogeneic stem cell transplantation.

Antithymocyte globulin (ATG) is commonly used in allogeneic haematopoietic stem cell transplantation (HSCT). Little information is available, however, as to the optimal protocol for use and the side-effects occurring if ATG is administered in high daily doses (10-30 mg/kg). We report our experience with ATG Fresenius (ATG-F) in conditioning for allogeneic HSCT. During a period of 3 days, 47 patients received doses between 10 and 30 mg/kg either over 4 h preceded by 1-1.5 mg/kg prednisolone 30 min before the start of ATG-F (protocol A) or alternatively, over 12 h with 3-4 mg/kg prednisolone being administered before and 6 h after start of ATG (protocol B). During treatment with ATG-F, the side-effects observed included inflammation, disseminated intravascular coagulation, hyperdynamic circulation and renal dysfunction. Although these complications caused substantial morbidity, they were reversible within a few days. Side-effects were significantly more severe in patients treated according to protocol A than in those treated according to protocol B. As prolonged infusion of ATG-F does not reduce T cell clearance due to the long half-life of ATG-F, and since less cytokine release during conditioning might have beneficial long-term effects, we recommend administering ATG-F over 12 h preceded by high-dose steroid treatment.

[Allogeneic transplantation in malignant lymphoma]. / Allogene Transplantation maligner Lymphome.

INTRODUCTION: Allogeneic transplantation of bone marrow and peripheral blood stem cells is a frequently discussed therapeutic option in the treatment of malignant lymphoma. By analysing the results of our own transplant program in patients with advanced lymphoma we tried to evaluate indications for allogeneic transplantations. METHODS: Data from lymphoma patients treated at the Klinikum Grosshadern between 1985 and 2001 were analysed retrospectively. RESULTS: 56 patients were included. 24 patients had low grade Non-Hogdkin's lymphoma (NHL) (follicular lymphoma: n = 8, mantle cell lymphoma: n = 6) or chronic lymphocytic leukemia (CLL: n = 10), 16 patients had high grade NHL (immunoblastic/lymphoblastic: n = 5; large cell/diffuse: n = 5) and 8 patients suffered from Hodgkins's disease. Median age was 41 years, 34 patients were transplanted from an HLA-identical sibling, 19 from an HLA-id. unrelated donor and three from an HLA-mismatched related donor. 30 patients received bone marrow and 26 peripheral blood stem cells. 22 pat. were treated with an intensive 12 Gy TBI containing conditioning regimen, whereas 34 patients were treated with a dose-intensity reduced conditioning procedere. 25 patients are alive between 2 month and 15 years after transplantation. Overall survival after 2 years is 48 % for patients with low grade NHL (incl. CLL), 9.3 % for patients with high grade lymphoma and 25 % for patients with Hodgkin's disease. 1-year-transplant-related mortality (TRM) was 33.9 % in all patients. Dose-intensity-reduced conditioning was not able to reduce TRM. CONCLUSIONS: Allogeneic bone marrow or stem cell transplantation is able to induce long lasting complete remissions in patients with heavily pretreated malignant lymphoma. Results of allogeneic transplantation are encouraging in patients with follicular and other low grade lymphoma. However transplant-related toxicity is high. At present the impact of reducing the intensity of conditioning is not yet clear.

Bcl-2, bax and bcl-xL expression in human sensitive and resistant leukemia cell lines.

With the growing understanding of cytostatic drug-induced programmed cell death new drug-resistance mechanisms based on the altered ability of cells to die by apoptosis have been defined. At first, the sensitive and P-glycoprotein (P-gp)-related resistant cell lines were tested to induce apoptosis by a non-P-gp transported drug, such as cytosine arabinoside (ara-C). It was demonstrated that ara-C induces apoptosis in sensitive as well as in P-gp-related resistant cell lines, as expected. Furthermore, the role of bcl-2 and bcl-xL apoptosis inhibitors as well as bax expression (apoptosis inducer) in human sensitive leukemic cell lines (CCRF-CEM and HL-60) as compared to their resistant variants such as CCRF-CEM/ACT400, CCRF-CEM/VCR1000, HL-60/IDA40, HL-60/DNR250 was evaluated. In addition to the P-gp-related resistance, a possible multidrug resistance-associated protein (MRP) and the lung resistance protein (LRP)-related resistance were assessed by flow cytometry using the monoclonal antibodies 4E3.16, MRPr1 and LRP56. Furthermore, the function of P-gp was determined with the rhodamine-123 (R-123) accumulation test. Bcl-2 and bax were analyzed by both flow cytometry and ECL Western blot, bcl-xL by ECL-Western blot alone. Comparison of the two sensitive cell lines demonstrated different bcl-2, bax and bcl-xL patterns. The common characteristic was the increased expression of one of the apoptosis inhibitor proteins, such as bcl-2 or bcl-xL. The sensitive CCRF-CEM showed a high bax level, where a decrease of about 75% in resistant variants was measured. Compared to their sensitive counterpart HL-60, a low bax expression was analyzed, which increased in the resistant variant. The common characteristic of all resistant cell lines was the decreased expression of bax compared to bcl-2 or bcl-xL. In the P-gp-related resistant HL-60/DNR250 only an increase in bcl-xL was seen, whereas in the LRP-expressing as well as P-gp and MRP negative resistant HL-60/IDA40 both apoptotic inhibitor proteins bcl-2 and bcL-xL showed maximum increase, compared to the other resistant cell lines. The P-gp-related resistant cell lines CCRF-CEM/ACT400 and CCRF-CEM/VCR1000 also showed an increased expression of both bcl-2 and bcl-xL. Summarizing these results, it was shown that the examined sensitive human leukemic cell lines and their resistant variants demonstrated a different pattern of markers for preventing and promoting apoptosis. An association between P-gp and possible LRP-expressing leukemic cells as well as apoptosis-preventing markers (bcl-2, bcl-xL) seems to exist. The clinical relevance of the coexpression of various resistance mechanisms remains to be confirmed in large leukemia patient groups.

In vitro efficacy of known P-glycoprotein modulators compared to droloxifene E and Z: studies on a human T-cell leukemia cell line and their resistant variants.

P-glycoprotein(P-gp)- related resistance is one of the major obstacles in treating leukemia patients. Therefore, it is of clinical interest to find new potential modulators and compare their P-gp-modulating efficacy. The present analysis investigated the influence of P-gp modulators, such as verapamil, tamoxifen, droloxifene E, droloxifene Z, SDZ PSC 833 (PSC 833) and dexniguldipine in a leukemic T-cell line (CCRF-CEM) and its P-gp-resistant counterparts (CCRF-CEM/ACT400 and CCRF-CEM/VCR1000). P-gp expression was assessed with an immunocytological technique using the monoclonal antibody 4E3.16. It was characterized as the percentage of P-gp positive cells and also expressed as a D value by using the Kolmogorov Smirnov statistic. The efficacy of P-gp modulators was determined with the rhodamine-123 accumulation test and the MTT test. An in vitro modulator concentration between 0.1 microM and 3 microM was determined, where no genuine antiproliferative effect was apparent. The modulators PSC 833 and dexniguldipine were the significant (p

Functional P-gp expression in multiple myeloma patients at primary diagnosis and relapse or progressive disease.

In this study, 25 multiple myeloma (MM) patients at primary diagnosis and 18 MM patients at relapse or progressive disease (PD) were examined in order to investigate the incidence of P-glycoprotein (P-gp) expression at initial diagnosis and relapse or PD. Furthermore, P-gp expression in relation to VAD regimen response was determined. P-gp expression in the myeloma cells was determined using monoclonal antibody 4E3.16 and the rhodamine 123 functional test. The percentage of patients with P-gp overexpression at primary diagnosis ranged between 0 and 41% in the literature vs 32% in our study. The percentage of P-gp positive patients at relapse or PD ranged between 29 and 59% in the literature vs 33% in this analysis. All P-gp positive patients had a functional P-gp, ie a pumping P-gp. A significant difference concerning response (50 vs 58.3%) to VAD treatment and median survival (10 vs 12.5 months) between P-gp positive and P-gp negative patients could not be determined. Six of 12 P-gp negative MM patients at relapse or PD developed after VAD therapy a relapse combined with P-gp overexpression. These results do not confirm the suggestions that P-gp overexpression influences response to VAD treatment. However, the results described in the literature and our own emphasize the need for careful accompanying research programmes aimed at detecting the complexity of chemotherapy resistance in the light of developing a risk-adapting therapy for MM patients.

Autoantibodies against p53 are not increased in human ascites and pleural effusions.

Mutated human p53 may give rise to the formation of autoantibodies and may be a marker for a worse prognosis. We speculated that ascites or pleural effusions may enhance the formation of such autoantibodies in cancer patients and, therefore, we measured the presence of autoantibodies in the ascites or pleural effusion of 40 patients with advanced malignancies. As controls, p53 autoantibodies were measured in 15 patients with effusions who did not have a malignancy. Using a specific enzyme-linked immunosorbent assay, p53 autoantibodies could only be detected in the effusions of 5/40 patients (12.5%) with known malignancies. The formation of autoantibodies did not correlate with the presence or absence of tumor cells in the effusion. The effusions of the patients without tumor were all negative for p53 autoantibodies. Our study shows that malignant or reactive effusions do not stimulate the local or systemic production of autoantibodies against p53.

[Expression of transforming growth factor beta-3 (TGF-beta-3) on reactive and malignant cells in ascites and pleural effusion]. / Expression von Transforming-growth-factor-beta-3 (TGF-beta-3) auf reaktiven und malignen Zellen in Aszites und Pleuraergüssen.

PATIENTS AND METHOD: The expression of TGF-beta-3 was examined in 64 patients with reactive and malignant effusion by immunocytochemistry. RESULT: In about half of the patients with malignant effusions (especially breast cancer, gastric cancer, and carcinomas of unknown primary) TGF-beta positive tumor cells could be detected. We could show here for the first time that reactive mesothelial cells could also express TGF-beta. Lymphatic cells were negative in all cases. TGF-beta-3 bioactivity could also be detected in the effusions studied. In our group of patients with far advanced cancer, the expression of TGF-beta had no clear-cut clinical or prognostic correlate. However, the expression of TGF-beta on tumor cells should be interpreted as a marker of tumor progression, taking into account the fibrogenic, angiogenic and immunosuppressive properties of TGF-beta. CONCLUSION: Further research is necessary to answer the question if the 3 isoforms of TGF-beta are coordinately expressed and to elucidate the involvement of this cytokine in tumor progression and metastasis.

[Polyostotic fibrous dysplasia of the spinal column and ribs]. / Polyostotische fibröse Dysplasie der Wirbelsäule und Rippen.

The chest radiograph of a 56-year-old man with pain over the entire region of back, chest and vertebral column revealed chunky swelling over the 7th right rib. Other radiographs and magnetic resonance imaging further showed an infiltrative process in the 12th thoracic and the 2nd as well as 4th lumbar vertebrae. Skeletal scintigraphy was highly suggestive of bone metastases. Results of laboratory tests were within normal limits. Partial rib resection was performed after failure to find the site of a primary tumour. The diagnosis of polyostotic fibrous dysplasia was made histologically. There was no evidence of malignancy and a rare additional endocrinopathy (McCune-Albright syndrome) was excluded.

Successful treatment of patients with hairy cell leukemia (HCL) using a single cycle of 2-chloro-2'-deoxyadenosine (CdA).

2-Chloro-deoxyadenosine (CdA) is a new adenosine-deaminase (ADA) resistant purine analogue with high specificity for lymphoid cells. It was shown that CdA is very effective in hairy cell leukemia (HCL), refractory chronic lymphocytic leukemia and cutaneous T-cell lymphoma leading to lasting remissions in the majority of patients with HCL. We report the successful treatment of five patients with HCL at different stages of their disease using CdA, who were either previously untreated or had received interferon, splenectomy and deoxycoformycin (dCF), an ADA-inhibitor with high therapeutic efficacy in HCL. After one 7-day course of treatment, all patients reached remission. CdA was well tolerated and, only mild side effects such as skin rash, headache, fever, nausea were observed. Aplasia was pronounced in all instances with a slow recovery. The type of histomorphological procedure in preparing and evaluating bone marrow biopsies is emphasized to detect minimal residual infiltration by hairy cells.

Identification of carcinoma cells in ascitic and pleural fluid. Comparison of four panepithelial antigens with carcinoembryonic antigen.

The cell membrane antigens epithelial membrane antigen (EMA), epithelial glycoprotein 34, (egp34), BW-495 and tumor-associated antigen 72 (TAG-72) are present in most benign and malignant epithelial cells and can be demonstrated with the help of monoclonal antibodies. In a study on the identification of carcinoma cells in samples of ascitic and pleural fluid involving 170 patients, we compared the value of immunocytochemical labeling of these antigens with that of immunocytochemical demonstration of carcinoembryonic antigen (CEA). Antibodies to EMA and egp34 occasionally also reacted with reactively proliferating mesothelial cells in benign conditions and thus appear to be inappropriate for diagnostic use. Cells positive for BW-495, TAG-72 and CEA, however, have never been found in benign conditions; the specificity of these antigens thus permits their use in diagnosis. Antigen-expressing cells were found in 85% (BW-495), 62% (TAG-72) and 60% (CEA) of cytologically positive samples from carcinoma patients. Similarly, positive reactions for BW-495, TAG-72 and CEA were observed in, respectively, 36%, 29% and 34% of cytologically negative or suspicious samples. BW-495 thus appears to be a suitable marker for the demonstration of carcinoma cells in samples of pleural and ascitic fluid and to have a higher degree of sensitivity than does either TAG-72 or CEA.