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Lars Fischer

Publications and source records attributed to Lars Fischer.

15 recordsLinked to original sources
PubMed2006

Relapse of primary central nervous system lymphoma: clinical features, outcome and prognostic factors.

Data on relapsed primary central nervous system lymphoma (PCNSL) are limited. We have evaluated the clinical characteristics and outcome of relapsed PCNSL patients from two German trials. Patients with relapsed disease after primary treatment were studied. Primary therapy consisted of high-dose methotrexate-based chemotherapy in all patients. Treatment for relapse was not predetermined. After a median follow-up of 22.5 months, 52 (36%) patients with relapse were identified among 143 patients with complete remission (CR) after primary treatment. The median disease-free survival was 10.25 (3-47.5) months. The median age at relapse was 59 years. Forty-four of 51 evaluable patients relapsed within the CNS, 6 systemically and one both cerebrally and systemically. The median survival time after first relapse was 4.5 (0.5-40.5) months. Karnofsky performance status (KPS) at relapse (P = 0.004), site of relapse (isolated systemic versus other, P = 0.049) and treatment for relapse (versus no treatment, P = 0.001) were independent prognostic factors for survival after relapse in multivariate analysis. Survival of patients with relapsed PCNSL is poor despite high response rates to salvage therapy. Good KPS, isolated systemic relapse and treatment for relapse were significantly associated with longer survival.

Adult↗
PubMed2006

Skewed expression of natural-killer (NK)-associated antigens on lymphoproliferations of large granular lymphocytes (LGL).

Killer-immunoglobulin-like receptors (KIR) or C-type lectin-like receptors are heterogeneously expressed on NK cells and small subsets of T cells and might provide a new diagnostic tool for LGL lymphoproliferations (LGLL). We investigated the diagnostic impact of these cell surface molecules in T- and NK-type LGLL. Using three-color flow cytometry we examined the expression patterns of KIR (CD158a/b/e/i), CD85j, lectin-like receptors (CD94, CD161, NKG2A/D) and natural cytotoxicity receptors (NKp30/44/46) in 13 patients with LGLL (10 T-, 3 NK-LGLL) and compared them to those of the corresponding lymphocyte subsets in 20 control subjects. The presence of clonal TCR-gamma rearrangements and of Epstein Barr virus- (EBV) DNA were evaluated by PCR. All patients exhibited an altered expression of NK-associated markers. KIR were either lacking (6/13) or overexpressed (7/13). CD94 expression was significantly higher in all LGLL. NKG2A expression was significantly higher in NK-LGLL. Absence or overexpression was observed for NKG2A in T-LGLL and CD161 in most T/NK-LGLL. In NK-LGLL expression of NKp30 and NKp46 was significantly decreased, whereas CD85j was overexpressed. We consistently found a skewed expression pattern of novel NK markers as a pathological feature of LGLL. These antigens should be included in the diagnostic workup of this rare disease.

Adult↗
PubMed2006

The anti-lymphoma effect of antibody-mediated immunotherapy is based on an increased degranulation of peripheral blood natural killer (NK) cells.

BACKGROUND: In patients treated with rituximab and alemtuzumab for lymphomas or CLL, antibody-dependent cellular cytotoxicity (ADCC) is a major mechanism of action. Therefore, assessment of ADCC is mandatory to understand the complex mechanisms leading to the anti-lymphoma effects of monoclonal antibodies (mAb). Due to methodical difficulties, little is yet known about the relevant cell subpopulations and effector mechanisms leading to tumor lysis in ADCC. METHODS: We used a novel flow cytometric assay that detects CD107a as a marker for NK-cell degranulation to characterize and quantify peripheral blood natural killer (NK) cells mediating ADCC in vitro and in vivo. RESULTS: We observed specific and dose-dependent NK-cell activation after administration of rituximab and alemtuzumab. The number of degranulating NK cells was closely related to the concentration of mAb and the effector:target ratio. We were able to quantify and characterize the peripheral blood NK cells mediating ADCC. The majority of degranulating NK cells had the phenotype: CD56(dim), CD69(+), NKG2D(+), NKp30(-), NKp46(-), and CD94(-). Furthermore, we found that the CD107a assay can also visualize ADCC under clinical conditions as we observed increased numbers of NK cells degranulating in response to CD20(+) lymphoma cell lines in patients with non-Hodgkin's lymphoma treated with rituximab. CONCLUSIONS: We were able to quantify and characterize NK cells mediating ADCC with a new and feasible method. The CD107a assay may be useful for predicting treatment responses of individual patients and may help find the optimal dosage and timing for treatment with mAb.

Antibodies, Monoclonal↗
PubMed2006

Cell death in pancreatitis: effects of alcohol.

Pancreatitis is a severe and frequently lethal disorder, a major cause of which is alcohol abuse. Parenchymal cell death is a major complication of pancreatitis. In experimental models of (non-alcoholic) acute pancreatitis, acinar cells have been shown to die through both necrosis and apoptosis, the two principal pathways of cell death. The severity of experimental acute pancreatitis correlates directly with the extent of necrosis and inversely with apoptosis. Thus, understanding the regulation of apoptosis and necrosis, and whether it is possible to manipulate the pattern of death responses, is becoming exceedingly important in investigations of the pathogenesis and treatment of pancreatitis. The effects of alcohol on cell death responses of pancreatitis, and the mechanisms that may mediate these effects, are just starting to be explored. This paper reviews the signaling pathways mediating the balance between apoptosis and necrosis in acute pancreatitis, and alcohol's effects on cell death responses in pancreatitis.

Animals↗
PubMed2006

The diagnostic value of cerebrospinal fluid pleocytosis and protein in the detection of lymphomatous meningitis in primary central nervous system lymphomas.

The exact rate of lymphomatous meningitis in primary central nervous system lymphomas (PCNSL) is uncertain. In this prospective multicenter study, cerebrospinal fluid (CSF) from 116 immunocompetent patients with newly diagnosed PCNSL was evaluated. Lymphoma cells were found in 18.1%, protein elevation (>45 mg/dL) in 65%, and CSF pleocytosis (>5/microL) in 36% of patients. Pleocytosis correlated with positive cytology, whereas CSF protein did not (specificity cell count vs. protein 74% vs. 34% [p<0.001], sensitivity 86% vs. 62% [p=0.18]).

Central Nervous System Neoplasms↗
PubMed2005

Extracellular matrix stimulates reactive oxygen species production and increases pancreatic cancer cell survival through 5-lipoxygenase and NADPH oxidase.

The extracellular matrix (ECM) facilitates pancreatic cancer cells survival, which is of central importance for pancreatic adenocarcinoma that is highly fibrotic. Here, we show that reactive oxygen species (ROS) mediate the prosurvival effect of ECM in human pancreatic cancer cells. Fibronectin and laminin stimulated ROS production and NADPH oxidase activation in pancreatic cancer cells. Both pharmacological and molecular approaches show that fibronectin stimulated ROS production through activation of NADPH oxidase and NADPH oxidase-independent pathways and that 5-lipoxygenase (5-LO) mediates both these pathways. Analyses of the mechanisms of ROS production by ECM proteins and growth factors indicate that activation of NADPH oxidase (Nox4) is a common mechanism employed both by ECM proteins and growth factors to increase ROS in pancreatic cancer cells. We also found that Nox4 is present in human pancreatic adenocarcinoma tissues and that these tissues display membrane NADPH oxidase activity. ECM proteins and growth factors activate NADPH oxidase through different mechanisms; in contrast to ECM proteins, growth factors activate NADPH oxidase through 5-LO-independent mechanisms. Inhibition of 5-LO or NADPH oxidase with pharmacological inhibitors of these enzymes and with Nox4 or 5-LO antisense oligonucleotides markedly stimulated apoptosis in cancer cells cultured on fibronectin. Our results indicate that ROS generation via 5-LO and downstream NADPH oxidase mediates the prosurvival effect of ECM in pancreatic cancer cells. These mechanisms may play an important role in pancreatic cancer resistance to treatments and thus represent novel therapeutic targets.

Adenocarcinoma↗
PubMed2005

The segments of the hepatic veins-is there a spatial correlation to the Couinaud liver segments?

PURPOSE: To investigate and describe the volume, position and shape of venous segments within the human liver and define their spatial correlation to the Couinaud segments (CS) and to the portal vein segments (PVS). MATERIAL AND METHODS: This study was based on 64 routinely acquired CT scans of patients undergoing hepatic surgery. The final analysis included 19 patients. All 19 CT data sets were transformed into 3D liver models. Three venous segments were postulated reflecting the left, middle, and right hepatic vein. Each venous segment was furthermore divided in two venous subsegments. Volume, position and shape of these venous segments/subsegments were calculated and, finally, compared with the volume, position and shape of the Couinaud segments and the portal vein segments. RESULTS: The right hepatic vein covers with 539.8 +/- 119.5 ml (47.1%) the largest part of total liver volume followed by the middle hepatic vein 372.7 +/- 151.1 ml (32.5%) and the left hepatic vein 248 +/- 75.9 ml (20.4%). The Couinaud liver segments and portal vein segments 2, 3, 5, 7, and 8 have consistent positional assignments within the three venous segments. Only the CS 4a, 4b, and 6 showed significantly different positions compared to the PVS 4a, 4b, and 6 (P < 0.03). The venous subsegments have a broad volumetric distribution reaching from 79 to 337 ml. There is no positional correlation of venous subsegments compared to Couinaud segments or portal vein segments at all (kappa < 0.75). In contrast, the venous segments/subsegments which can be assigned to either liver halve and either liver lobe have an identical volume, shape and position compared to the corresponding Couinaud liver segments (kappa > 0.75). CONCLUSION: The venous segments distinguish liver areas divided by the left and middle hepatic vein in exactly the same pattern as Couinaud segments and portal vein segments do. However, the comparison of shape and position of venous subsegments showed no correlation with both liver segmental approaches.

Adult↗
PubMed2005

Response to chemotherapy and treating institution predict survival in primary central nervous system lymphoma.

The majority of the available data on primary central nervous system lymphoma (PCNSL) derive from small unicentric or oligocentric studies. In this multicentre study, we evaluated the response, survival and toxicity in PCNSL patients after carmustine, methotrexate 1.5 g/m2, procarbazine and dexamethasone (BMPD) chemotherapy and searched for prognostic factors. Fifty-six patients received the BMPD protocol (dexamethasone was given only in course 1). The overall complete response rate to chemotherapy was 61% (34/56). Ten complete responders received whole-brain irradiation and 24 were not irradiated. Responders to chemotherapy had significantly longer median overall survival than non-responders (18.2 vs. 9.9 months, P = 0.02). Median survival was significantly longer at institutions accruing at least four patients than at those with fewer patients (31.5 vs. 9.5 months, P = 0.03).

Adult↗
PubMed2004

Treatment of primary intraocular lymphoma with oral trofosfamide: report of two cases and review of the literature.

BACKGROUND: The prognosis of primary intraocular lymphoma (PIOL) is poor. Due to frequent ocular and/or CNS relapses, the optimal treatment for PIOL has not yet been defined. This is the first report of PIOL treatment with trofosfamide. METHODS: The first patient with a newly diagnosed PIOL was not considered eligible for high-dose methotrexate-based systemic chemotherapy due to comorbidities. The second patient had a primary central nervous system lymphoma, which was resistant to three chemotherapy regimens and responded to whole-brain irradiation. A tumor relapse in the eye was treated with local radiotherapy with initial success; however, the tumor subsequently recurred. The first patient received oral trofosfamide 150 mg daily, the second 400 mg daily (reduced after 5 months of therapy to 300 mg daily) over 5 consecutive days, followed by a 5-day drug-free interval. RESULTS: In both patients, complete remission was achieved, which lasted for 8+ and 18 months, respectively. Except for a temporary asymptomatic decrease in hemoglobin in the first patient, no toxicity was observed. CONCLUSIONS: Trofosfamide may offer an alternative treatment option for PIOL with a very favorable side effect profile. The exact role of trofosfamide in the treatment of PIOL remains to be defined.

Administration, Oral↗
PubMed2004

Phosphatidylinositide 3-kinase gamma regulates key pathologic responses to cholecystokinin in pancreatic acinar cells.

BACKGROUND & AIMS: Early events in the pancreatic acinar cell critical for development of pancreatitis include activation of the transcription factor nuclear factor kappa B (NF-kappa B), abnormal Ca(2+) responses, and trypsinogen activation. Mechanisms underlying these responses, which can be studied in isolated pancreatic acini stimulated with supraphysiologic doses of cholecystokinin (CCK-8), remain poorly understood. We here report that these responses are regulated by phosphatidylinositide 3-kinase (PI3K) gamma. METHODS: To inactivate PI3K, we used mice deficient in the catalytic PI3K gamma subunit p110 gamma as well as the PI3K inhibitors LY294002 and wortmannin. We measured Ca(2+) responses by using Fura-2, NF-kappa B-binding activity by electromobility shift assay, I kappa B degradation by Western blotting, and trypsinogen activation by fluorogenic assay. RESULTS: CCK-induced intracellular Ca(2+) mobilization, Ca(2+) influx, trypsinogen, and NF-kappa B activation were all diminished in pancreatic acini isolated from p110 gamma(-/-) mice. Both in mouse and rat acini, these responses were inhibited by the PI3K inhibitors. The Ca(2+) signal and trypsinogen activation were similarly reduced in acini isolated from p110 gamma(-/-) and p110 gamma(+/-) mice compared with wild-type mice. By contrast, NF-kappa B activation was inhibited in p110 gamma(-/-) acini but not in p110 gamma(+/-) acini. These differences indicate that the mechanism of NF-kappa B regulation by PI3K gamma differs from those for the Ca(2+) and trypsinogen responses. CCK-induced responses in p110 gamma(-/-) acini were all further inhibited by LY294002, indicating the involvement of other PI3K isoform(s), in addition to PI3K gamma. CONCLUSIONS: The results show that key pathologic responses of the pancreatic acinar cell are regulated by PI3K gamma and suggest an important role for this PI3K isoform in pancreatitis.

Animals↗
PubMed2003

Effects of STI571 (gleevec) on pancreatic cancer cell growth.

BACKGROUND: Pancreatic cancer is an aggressive malignancy characterized by low responsiveness to chemotherapy and radiotherapy. This resistance is partly due to the overexpression of several tyrosine kinase receptors and their ligands. STI571 has specific activity in inhibiting c-kit, PDGF and Abl receptor tyrosine kinases and has proven successful in the treatment of CML and GIST patients. Here, we investigated the potential role of STI571 in pancreatic cancer. RESULTS: The GI50 of STI571 as well as the effects of STI571 on growth factor actions in pancreatic cell lines were analyzed using the MTT assay. FACS analysis using Annexin and PI staining was performed to study cell cycle, apoptosis, and cell death. Western blot analysis was carried out to investigate MAP kinase and receptor tyrosine kinase phosphorylation. STI571 inhibited cell proliferation in pancreatic cancer cell lines with GI50 concentrations ranging from 17 to 31.5 microM. EGF, IGF-1, and FGF-2 but not PDGF exerted growth stimulatory effects in pancreatic cancer cell lines. STI571 only partly blocked these effects on cell growth, and did not abrogate growth factor-induced receptor and MAPK phosphorylation. CONCLUSION: Our data demonstrate that STI571 inhibits pancreatic cancer cell growth with high GI50 concentrations through tyrosine-kinase receptor independent pathways. The clinical application of STI571 in pancreatic cancer is therefore rather doubtful.

Antineoplastic Agents↗
PubMed2002

Longitudinal analysis of Epstein-Barr viral load in plasma and peripheral blood mononuclear cells of transplanted patients by real-time polymerase chain reaction.

BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) is a significant cause of morbidity and mortality in transplant recipients and is caused by iatrogenic suppression of T cell function. Elevations in the Epstein-Barr viral (EBV) load in plasma (>1000 EBV copies/100 microL plasma) or peripheral blood mononuclear cells (PBMC) (>5000 EBV copies/microg PBMC DNA) as determined by real-time quantitative polymerase chain reaction (RQ-PCR) have been shown to be sensitive indicators for the development of PTLD in patients. METHODS: The diagnostic value of frequent monitoring of EB viral load in peripheral blood from 46 patients after heart transplantation was investigated compared with 21 healthy controls in a prospective longitudinal study. EB viral load was detected in PBMC and plasma using real-time quantitative (RQ)- polymerase chain reaction (PCR)-based assays and compared with serological parameters of EBV infection or with the occurrence of CMV reactivations. RESULTS: EB viral load was significantly increased in PBMC and in plasma from transplanted patients compared with healthy controls. Regarding levels and fluctuations of EB viral load in PBMC, patients were grouped in three distinct categories with high, intermediate, or low EB viral load. Although in one patient without PTLD, the EB viral load exceeded the threshold value for PTLD of 5000 EBV copies/microg PBMC DNA, all patients had an EB viral load in plasma of less than 1000 EBV copies/100 microL plasma. No correlation was found between the level of EB viral load and serological parameters of EBV reactivations in patients or in healthy control individuals. EBV and cytomegalovirus reactivations occurred independently in the majority of patients. CONCLUSIONS: EB viral load measurements in plasma and PBMC of patients using RQ-PCR are superior to serology and are a powerful tool for monitoring transplanted patients.

Adolescent↗
PubMed2002

The stem cell factor-c-kit system and mast cells in human pancreatic cancer.

Stem cell factor (SCF) and its receptor c-kit take part in the regulation of developmental processes of mast cells, hematopoietic stem cells, and melanocytes, as well as in the growth control of human malignancies. To explore the possible role of the SCF-c-kit system and of mast cells in pancreatic cancer, the concomitant expression and distribution of the two molecules were examined in 17 normal and 26 cancerous human pancreatic tissues and in 6 cultured pancreatic cancer cell lines. Mast cell distribution was also evaluated in the same tissue samples. In addition, the effects of SCF and of the c-kit tyrosine-kinase inhibitor STI571 on the growth of the cancer cell lines and of the normal pancreatic ductal cell line TAKA-1 were assessed. SCF immunoreactivity was absent in acinar, ductal, and islet cells of the normal pancreas and faint in pancreatic cancer tissues and cell lines. In contrast, c-kit was clearly present in some normal and hyperplastic ducts of the normal pancreas, in the cancer cells of 73% of the tumor samples, and in all the cell lines tested. Mast cells, identified by tryptase and chymase immunostaining on consecutive tissue sections, showed immunoreactivity for SCF and c-kit in both normal and cancerous specimens and their number was significantly increased (p = 0.03) in pancreatic cancer compared with the normal pancreas. SCF showed a dose-dependent growth inhibitory effect on TAKA-1 cells (p < 0.001), whereas pancreatic cancer cells were resistant to the SCF-induced growth inhibition. Nonetheless, the growth of TAKA-1 cells and pancreatic cancer cells was inhibited by the c-kit tyrosine kinase inhibitor STI571. In conclusion, the SCF-c-kit system, possibly with the contribution of mast cells, may have a growth-regulating role in the normal pancreas, which is altered during malignant transformation.

Adolescent↗
PubMedDate not supplied

Limits of Couinaud's liver segment classification: a quantitative computer-based three-dimensional analysis.

PURPOSE: Traditionally, liver surgery relies on Couinaud's liver segment classification. As the position and shape of these segments are variable and their borders are hidden within the homogeneous liver mass, the accuracy of segment identification methods needs computer-aided reevaluation. METHOD: The segmental liver anatomy of 23 patients receiving diagnostic helical CT scans because of suspected intrahepatic lesion was analyzed with the aid of a computer-based operation-planning system. We compared the standard Couinaud classification, which depends particularly on the main stems of portal and hepatic veins, with a method that calculates the segment borders by analyzing the complete portal venous tree. Volume, shape, and position of the liver segments found by each method were compared. RESULTS: With reference to the portal vein-based method, segmental volumes were overestimated by the classic Couinaud method by up to 24% and underestimated to 13%. Volumes of Couinaud segments 4a, 7, and 8 were generally larger compared with those obtained by the portal vein-based method, whereas segments 3 and 6 were smaller. Gross variations were found in segments 5, 7, and 8. When shape and position were considered, poor correlation was found for five segments (median kappa = 0.35-0.45). Only segments 2, 7, and 8 had kappa values clearly above 0.45 in the majority of cases. The plane that divides the two hemilivers along the middle hepatic vein and the border between the left sector (segments 2 and 3) and the medial sector (4a and 4b) were found in both methods with very good conformity (kappa > 0.75). CONCLUSION: Couinaud's method of dividing the liver into eight autonomous liver segments has to be accepted as a good approximation. Nevertheless, the volume, position, and shape of these segments and their segmental borders show significant variability.

Adult↗