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Purpose: Introduction of lenalidomide has expanded the therapeutic options for refractory and recurrent multiple myeloma (MM) patients. However, the application of the approved doses may be difficult in some patients due to adverse effects. Experimental design: Therefore, we evaluated the efficacy and safety of lenalidomide in 10 patients with relapsed and refractory MM who received a reduced dose due to leukopenia (4), polyneuropathy (1), muscle cramps (1), thrombocytopenia (1), renal insufficiency (1), at the request of patient (1), as continuous therapy (1), either from the beginning (2) or during treatment (8). They received lenalidomide at a mean (median) daily dose of 14 (15) mg/d once a day (days 1–21 every 28 days) in combination with dexamethasone at a mean (median) dose of 17.6 (28) mg per day (4–40 mg) on days 1–4, 9–12 and 17–20. Results: Mean (median) duration of treatment with lenalidomide was 15.1 (15) months. Partial response or better was reported in seven and minimal response or better was reported in eight patients. Mean (median) values for time-to-progression (TTP) and for progression-free survival (PFS) were 8.7 (4) months. Mean overall survival (OS) has not been reached, all patients are still alive. Conclusion: In conclusion, dose-reduced lenalidomide is an effective and well tolerated treatment for patients with recurrent or refractory MM who cannot tolerate full doses.

Background: The highly vascular nature of renal carcinoma cells suggests that inhibition of angiogenesis may be beneficial in this disease. Thalidomide has been described as inhibitor of the fibroblast growth factor (FGF) and the vascular endothelial growth factor (VEGF). Therefore and in consideration of the promising response rates of the combination of IL-2, IFN-alpha and 5-FU [1] in metastatic renal cancer, we found it reasonable to test the combination of 5-FU and thalidomide. Thus, we conducted a phase I trial to determine safety, side effects and responses to such a treatment. Methods: Patients with metastasized renal cell cancer after nephrectomy and progress after IL-2 and interferon treatment, received oral 5-FU at a dose of 1250 mg/qm2 twice a day for two weeks, then after pausing a week, the oral application was restarted. In addition, oral thalidomide was applied constantly at a maximum dose of 400 mg/d. The combined therapy was given for three months. The primary endpoint was duration until disease progression, the secondary endpoint the response to treatment. Response was determined by CT scans three months after the end of treatment. Results: In total, 12 male patients participated in the trial and received the combined oral therapy. Concerning clinical response, one mixed response (8%), a stable disease in 4/12 patients (33%) and progression was seen in 7 patients (58%). The survival from the start of the therapy showed a median of 21 months with three patients being alive. At present, the longest survival after the therapy is 51 months. Conclusions: The combination of oral 5-FU and thalidomide showed clinical response with tolerable side effects. Further studies will be required to assess the outcome of this treatment regimen.

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Abstract Background Neutropenic enterocolitis is a life-threatening complication most frequently occurring after intensive chemotherapy in acute leukaemias. Gramnegative bacteria constitute the most important group of causative pathogens. Fungi have also been reported, but their practical relevance remains unclear. The guidelines do not address concrete treatment recommendations for fungal neutropenic enterocolitis. Methods Here, we conducted a metaanalysis to answer the questions: What are frequency and mortality of fungal neutropenic enterocolitis? Do frequencies and microbiological distribution of causative fungi support empirical antimycotic therapy? Do reported results of antimycotic therapy in documented fungal neutropenic enterocolitis help with the selection of appropriate drugs? Following a systematic search, we extracted and summarised all detail data from the complete literature. Results Among 186 articles describing patients with neutropenic enterocolitis, we found 29 reports describing 53 patients with causative fungal pathogens. We found no randomised controlled trial, no good quality cohort study and no good quality case control study on the role of antifungal treatment. The pooled frequency of fungal neutropenic enterocolitis was 6.2% calculated from all 860 reported patients and 3.4% calculated from selected representative studies only. In 94% of the patients, Candida spp. were involved. The pooled mortality rate was 81.8%. Most authors did not report or perform antifungal therapy. Conclusion In patients with neutropenic enterocolitis, fungal pathogens play a relevant, but secondary role compared to bacteria. Evidence concerning therapy is very poor, but epidemiological data from this study may provide helpful clues to select empiric antifungal therapy in neutropenic enterocolitis.

Purpose: Introduction of lenalidomide has expanded the therapeutic options for refractory and recurrent multiple myeloma (MM) patients. However, the application of the approved doses may be difficult in some patients due to adverse effects., Experimental Design: Therefore, we evaluated the efficacy and safety of lenalidomide in 10 patients with relapsed and refractory MM who received a reduced dose due to leukopenia (4), polyneuropathy (1), muscle cramps (1), thrombocytopenia (1), renal insufficiency (1), at the request of patient (1), as continuous therapy (1), either from the beginning (2) or during treatment (8). They received lenalidomide at a mean (median) daily dose of 14 (15) mg/d once a day (days 1-21 every 28 days) in combination with dexamethasone at a mean (median) dose of 17.6 (28) mg per day (4-40 mg) on days 1-4, 9-12 and 17-20., Results: Mean (median) duration of treatment with lenalidomide was 15.1 (15) months. Partial response or better was reported in seven and minimal response or better was reported in eight patients. Mean (median) values for time-to-progression (TTP) and for progression-free survival (PFS) were 8.7 (4) months. Mean overall survival (OS) has not been reached, all patients are still alive., Conclusion: In conclusion, dose-reduced lenalidomide is an effective and well tolerated treatment for patients with recurrent or refractory MM who cannot tolerate full doses.

Background: In a large number of patients with multiple myeloma, chemotherapy is the only therapeutic option. During recent years, major effort has been put into immunotherapeutic approaches for this malignancy., Materials and Methods: In this study, wild-type (wt) myeloma cells (5x10(5)) were injected subcutaneously into Balb/c mice. CD40L-transfected myeloma cells (5x10(5)) were subsequently injected intratumorally into the established (>100 mm(3)) wt tumor nodules. Overall survival and tumor growth were measured., Results: Out of eight animals receiving wt tumor cells, one died prior to the formation of a solid tumor nodule. Following the CD40L-transfected myeloma cell injection, stable complete remission at day 60 with all the animals surviving resulted. On day 60, a re-challenge was performed with wt myeloma cells. No tumor growth was observed after 120 days out of seven remaining animals, one died., Conclusion: Intratumoral injection of CD40L-transfected myeloma cells induces complete tumor remission and long lasting immunity against tumor recurrence.

Background: The highly vascular nature of renal carcinoma cells suggests that inhibition of angiogenesis may be beneficial in this disease. Thalidomide has been described as inhibitor of the fibroblast growth factor (FGF) and the vascular endothelial growth factor (VEGF). Therefore and in consideration of the promising response rates of the combination of IL-2, IFN-alpha and 5-FU [1] in metastatic renal cancer, we found it reasonable to test the combination of 5-FU and thalidomide. Thus, we conducted a phase I trial to determine safety, side effects and responses to such a treatment., Methods: Patients with metastasized renal cell cancer after nephrectomy and progress after IL-2 and interferon treatment, received oral 5-FU at a dose of 1250 mg/qm(2) twice a day for two weeks, then after pausing a week, the oral application was restarted. In addition, oral thalidomide was applied constantly at a maximum dose of 400 mg/d. The combined therapy was given for three months. The primary endpoint was duration until disease progression, the secondary endpoint the response to treatment. Response was determined by CT scans three months after the end of treatment., Results: In total, 12 male patients participated in the trial and received the combined oral therapy. Concerning clinical response, one mixed response (8%), a stable disease in 4/12 patients (33%) and progression was seen in 7 patients (58%). The survival from the start of the therapy showed a median of 21 months with three patients being alive. At present, the longest survival after the therapy is 51 months., Conclusions: The combination of oral 5-FU and thalidomide showed clinical response with tolerable side effects. Further studies will be required to assess the outcome of this treatment regimen.

In a wide range of solid tumors, overexpression of CD137L has been shown to induce tumor immunity partly due to the stimulation of CD8+ CTL, which was even increased when immunotherapy with interleukin-12 (IL12) was additionally employed. However, little in known regarding hematologic neoplasias in this respect. Of the 8 animals receiving IL12-secreting tumor cells, 2 died. Animals treated with CD137L-expressing tumor cells and the combination group, all animals survived. Interestingly, re-challenge with wild-type tumor cells was rejected by all animals in the CD137L group and all remaining animals in the IL12 group, while these in the control group died. IL12- and CD137L-transfected plasmocytoma cells prevented tumor growth and induced long-lasting immunity. Our results warrant follow-up for future clinical use in patients with myeloma.

Viral and plasmid vectors may cause immunological side-effects resulting from the expression of therapeutically unwanted genes and from CpG motifs contained in their sequence. A new vector type for minimalistic, immunological-defined gene expression (MIDGE) may overcome these problems. MIDGE is a minimal size gene transfer unit consisting of the expression cassette, including promotor, gene and RNA-stabilizing sequences, flanked by two short hairpin oligonucleotide sequences. DNA not encoding the desired gene is reduced to a minimum. To compare transfection efficiencies in vivo hydrodynamics-based, systemic transfection was performed in BALB/c mice with MIDGE vectors and corresponding plasmids. The transfection efficiencies of the MIDGE vectors as measured by luciferase expression were significantly higher in liver (2.5-fold), lung (3.5-fold), kidneys (3.9-fold) and heart (17-fold) as compared to plasmids. The mean numbers of MIDGE vector molecules per cell as measured by quantitative PCR were also significantly higher. These advantages suggest the preferential use of this new vector type for clinical gene therapy studies.

Standard chemotherapy for pancreatic carcinoma is based on the use of gemcitabine. The clinical benefit of interferon-alpha (IFN-alpha) in advanced pancreatic cancer has been shown. However, it has been demonstrated that to be effective, there is a need for a constant amount of IFN-alpha at the site of the tumor. Therefore, we examined transfection of the human pancreatic cancer cell line DAN-G with a retrovirus encoding for IFN-alpha and the effect of IFN-alpha gene expression alone or in combination with gemcitabine on growth inhibition of DAN-G pancreatic cancer cells in vitro and in vivo in orthotopically implanted DAN-G cells in nude mice. DAN-G cells could be efficiently transfected retrovirally by the human IFN-alpha gene and significantly enhanced the levels of IFN-alpha mRNA. In vitro gemcitabine led to an alteration of G1/S phase progression in transduced as well as untransduced cells, whereas IFN-alpha led to a significant decrease in cell viability in the transduced cells via delay in the progression of the S phase but no alteration of G1/S phase progression. In vivo, tumor volume in mice was reduced significantly with gemcitabine combined with IFN-alpha (76% +/- 8.3%) compared with gemcitabine alone (62.9% +/- 7.3%) or IFN-alpha alone (24.4% +/- 5.2%) compared with untreated animals. We conclude that gemcitabine and IFN-alpha concomitantly inhibited tumor cell proliferation significantly.

Pancreatic tumors lack adequate recruitment of immunocompetent cells, especially dendritic cells (DCs). We have shown previously that coculturing of natural killer-like T cells with DCs transfected with pancreatic tumor cell line-derived RNA reverses pancreatic carcinoma cell resistance by directly triggering natural killer-like T lymphocytes in vitro. In the present study, we tested triggering of specific T lymphocytes in vivo by using an immunocompetent mouse strain (C57BL/6). Syngenic, bone marrow-derived DCs were pulsed with tumor RNA derived from the pancreatic cell line PANC02. This cell line is a ductal pancreatic adenocarcinoma and shows high resistance to every known class of clinically active antitumor agent. PANC02 cells were implanted orthotopically via ultrasound guidance and led to pancreatic tumor formation in all of the mice. Thereafter, tumor RNA-pulsed DCs were injected intratumorally. Intratumoral administration of tumor RNA-pulsed DCs induced significantly more potent protective immunity than s.c. or i.v. administration. It was significantly more effective than administration with unpulsed DCs or DCs pulsed with a control tumor RNA derived from a lymphomatous cell line (EL4). The antitumor effect was caused by induction of antigen-specific T lymphocytes as shown by additional in vitro studies. These results favor intratumoral injection of tumor RNA-pulsed DCs for immunotherapy of pancreatic cancer.

Background and Objectives: High-dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT) has proven to be superior to conventional chemotherapy in patients with chemosensitive relapse of aggressive non-Hodgkin's lymphoma (NHL). Therefore, HDT/ASCT was evaluated as part of first-line therapy. Several trials generated conflicting results. This meta-analysis summarizes the available evidence from all suitable studies., Design and Methods: Prospective, randomized trials with HDT/ASCT as first-line therapy of aggressive lymphoma were included in this meta-analysis. The primary outcome was overall mortality. Statistical analysis applied the odds ratio (OR) and a fixed effects model., Results: Eleven trials with 2228 patients were eligible for meta-analysis. Overall mortality was comparable in the HDT/ASCT and in control arms (OR=0.97, 95% CI: 0.69;1.36, p=0.9), with statistically significant heterogeneity between the trials. To resolve this, we tried to identify variables that could explain this heterogeneity. Among a range of methodological, patient- or treatment-related factors, subgroups formed by the proportion of bulky disease in treated patients, the type of therapy prior to HDT/ASCT, the drop-out rate from the HDT/ASCT arm, and the presence of high or high-intermediate risk IPI showed significant benefit for any of the treatment modalities. However, such post-hoc subgroup analysis may be considerably influenced by random or systemic biases., Interpretation and Conclusions: Overall, the analysis of published evidence reveals very heterogeneous results and no overall survival benefit. Therefore, HDT/ASCT cannot be recommended as standard first line treatment for patients with aggressive NHL. However, the exploratory analyses presented here may help to design new trials for this treatment modality.

To determine the feasibility and safety of multiple sequential courses of high-dose chemotherapy with peripheral blood progenitor cells (PBSCs) followed by thoracic irradiation (54 Gy) and prophylactic cranial irradiation (PCI 30 Gy) in patients with limited disease (LD) small cell lung cancer (SCLC), six patients received one cycle of conventional-dose chemotherapy followed by four cycles of high-dose chemotherapy with stem cell support. Neither significant adverse side-effects nor treatment mortality were observed. CR and almost CR (> 90%) was obtained in five out of six patients while one patient had a partial response (PR). The median survival was 21.3 months (range 8-34). However, the benefit of the high CR rate and prolonged survival did not result in cure even in these favorable circumstances, because all the patients died of recurrence in the cerebral nervous system. According to our data we stopped this chemotherapy regime because it was not able to prevent cerebral disease.