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Biomedical subjects

B Kremer

Publications and source records attributed to B Kremer.

At least 73 records · Page 4Linked to original sources
PubMed1999

Sequential therapy with azelastine in seasonal allergic rhinitis. Deutsche Rhinitis Studiengruppe (German Rhinitis Study Group).

A sequential therapy treatment with azelastine (Allergodil) in seasonal allergic rhinitis is introduced. In the critical early stage, treatment begins with a combination of azelastine tablets (azelastine hydrochloride, CAS 79307-93-0) and azelastine nasal spray (azelastine, CAS 58581-89-8), and after five days only the nasal spray is administered. This sequential therapy model aims at achieving the quickest and most complete effect without reducing the tolerability. The investigation was carried out as a randomized, controlled double-blind phase IV study of parallel group design with 300 patients during 14 days. In the first five days, one group was given one puff (0.14 mg) of azelastine nasal spray twice daily and one 2 mg tablet of azelastine at night. The other group received nasal spray and a placebo tablet. Beginning on day six, both groups received nasal spray only. Both treatments proved to be effective; the combination therapy, however, was significantly more effective beginning as early as the first treatment. The superiority of the combination therapy increased until day five. Thereafter, the two curves grew closer together; however, the superiority of the combination treatment remained. The tolerability of both treatments was similar.

Adolescent↗
PubMed1999

Disseminated tumor cells in pancreatic cancer patients detected by immunocytology: a new prognostic factor.

Using an immunocytological approach, we previously showed that disseminated cancer cells are frequently found in peritoneal cavity and bone marrow samples of gastrointestinal and pancreatic cancer patients. Recently, we demonstrated that the detection of isolated tumor cells could serve as a new prognostic factor in gastric and colorectal cancer. Thus far, no conclusive data concerning the clinical implication of minimal residual disease in pancreatic cancer exist. In this study, we investigated peritoneal lavage and bone marrow samples of 80 pancreatic cancer patients to determine the predictive value of immunocytologically detected disseminated tumor cells. Therefore, immunocytological findings were correlated with the clinical follow-up data (median observation time, 10.7 months; range, 2-61 months), and the findings in peritoneal cavity and bone marrow samples were compared. Fifty-two % of the patients showed minimal residual disease at least in one compartment (39% positive lavage and 38% positive bone marrow samples). The detection rate of isolated tumor cells increased in parallel to the tumor stage. The presence of tumor cells in the peritoneal cavity significantly correlated with the survival time of the patients (P = 0.0035). In bone marrow samples, a strong trend was seen (P = 0.06). The evaluation of both compartments increased the number of positive patients and resulted in a highly significant correlation: all patients who were positive in at least one compartment died within 18 months, whereas negative patients showed a 5-year survival rate of 30% (P<0.0001). We recommend immunocytological investigation of peritoneal cavity and bone marrow samples as a new prognostic marker in pancreatic cancer patients.

Bone Marrow↗
PubMed1999

Surgical possibilities for pancreatic cancer: extended resection.

DESIGN: It was the aim of this study to investigate the influence of extended retroperitoneal tissue clearance on long-term survival in patients with ductal adenocarcinoma of the head of the pancreas. PATIENTS AND METHODS: From 10/1988 to 3/1998 a prospective observation study was initiated in 108 patients with malignant growth in the head of the pancreas to compare patients with regional lymphadenectomy (RLA) versus extended retroperitoneal tissue clearance (ELA). In 36 patients other tumors than ductal adenocarcinomas were found, so that 72 patients with a partial pancreaticoduodenectomy and a histologically established diagnosis of ductal adenocarcinoma were included. Pancreaticoduodenectomy was combined with RLA in 26 cases and with ELA in 46 patients. RESULTS: Comparing only R0-resected patients (n = 58) no significant difference in long-term survival rates between the RLA and the ELA group was found. Hospital mortality was 3.8% in the RLA group and 6.5% in the ELA group. Significant or nearly significant results were shown for the following parameters: STAGE OF THE DISEASE: Patients after partial pancreaticoduodenectomy of a stage I/II cancer of the head of the pancreas showed a 63% 5-year survival rate compared to 15% in patients in stage III or IV (p = 0.0087). GRADING: No patient with a poorly differentiated ductal adenocarcinoma of the head of the pancreas survived the first year in comparison to 55% of patients with well or moderately differentiated tumors (p = 0.0022). N-STAGE: 5-year survival of patients in NO stage was 46.9% and 15% for N1 stage patients (p = 0.081). PORTAL VEIN INFILTRATION: No patient with a R0-resection and histologically proven tumor infiltration of the portal vein survived the first year whereas 63% of patients did so after curative resection without portal vein involvement (p = 0.0063). CONCLUSION: Our data indicate that extensive retroperitoneal tissue clearance does not improve long-term survival rates compared to regional lymphadenectomy restricted to the right side of the mesenteric artery.

Aged↗
PubMed1998

Human pancreatic adenocarcinomas express Fas and Fas ligand yet are resistant to Fas-mediated apoptosis.

The Fas system, comprising the Fas receptor (Fas, CD95, APO-1) and its ligand, Fas ligand (FasL), is a central mediator of programmed cell death in various physiological and pathological processes. Recent evidence indicated that tumor cells can exploit this system to their benefit in the dialogue with the host immune system. We have shown that all human pancreatic adenocarcinoma cell lines tested by fluorescence-activated cell sorting analysis (6 of 6) and immunocytochemistry (12 of 12) were positive for Fas expression, as were normal and malignant duct cells in pancreatic tissue sections. However, despite Fas expression, pancreatic tumor cells have become largely resistant toward recombinant FasL- or anti-APO-1 agonistic antibody-induced apoptosis. This resistance correlated with high levels in pancreatic tumor cells of mRNA for FAP-1, a Fas-associated phosphatase that can block the apoptotic function of Fas. Using a variety of methodological approaches, we also present evidence for the production of FasL by pancreatic tumor cells because 6 of 6 pancreatic tumor cell lines were found to contain FasL mRNA as well as the Mr 40,000 and Mr 26,000 forms of the FasL protein. Likewise, pancreatic tissue revealed FasL-specific immunostaining in pancreatic tumor cells but not in the surrounding stroma. In coculture experiments, pancreatic tumor cells displayed a cytotoxic effect toward the Fas-sensitive Jurkat T-cell line, which could be inhibited by a FasL-specific neutralizing antibody. Together, these results support the recently proposed "counterattack model" for local deletion of tumor-reactive T-cells by tumor cell-derived FasL.

Adenocarcinoma↗
PubMed1998

Clinical validation of a new olfactory test.

A new approach to clinical olfactometry is presented using nasal sprays. A special dosage valve was used to standardize an aerosol size to 40 microns. For evaluation a 6 x 6 matrix (substance/olfactory quality) with verbal associative clues was used according to test psychological findings. Validation took place in three steps after determining smell-associated thresholds in preliminary examinations. Recognition of different aromas administered either by spraying into the open mouth from a distance of 5 cm using nasal sprays or sniffing opened bottles was compared in 50 subjectively normosmic subjects. Findings showed that the correspondence between the two procedures was relatively high, with global identification of odorous substances as high as 98.4% in the spray test. The number of substances used was next reduced to those six substances providing the most reproducible results in an investigation with 56 normosmic and 55 hyposmic subjects. Verbal associative clues were also tested. In a last step 50 patients with hyposmia of various origin and 110 normosmic subjects were tested, allowing previous results to be reproduced regardless of the cause of hyposmia. The spray test was shown to be easily performed and was suitable as a screening test, with a sensitivity of 88% and a specificity of 100%.

Administration, Intranasal↗
PubMed1998

Growth inhibition of pancreatic tumor cells by modified antisense oligodeoxynucleotides.

INTRODUCTION: Pancreatic adenocarcinomas are largely resistant to apoptosis. More than 50% of pancreatic tumors reveal mutations in the p53 tumor suppressor gene. METHODS: We investigated the growth of pancreatic tumor cells after downregulation of p53 protein expression by antisense oligodeoxynucleotides. RESULTS: Proliferation and p53 expression of PancTu-I cells overexpressing mutant p53 protein were inhibited by antisense oligodeoxynucleotide treatment. When analyzed, two of three other pancreatic tumor cell lines with mutated p53 were also inhibited in their growth. Two of two wild-type (wt) p53 pancreatic tumor cells were not significantly influenced by p53 expression and were, only to a lesser extent, affected in their proliferation. K562 cells (lacking p53 mRNA) and normal human skin fibroblasts used as a target mismatch control showed no changes in proliferation rates with treatment. The different biological effects in the various cells were not caused by differences in the uptake of the oligodeoxynucleotides as monitored by confocal laser-scanning microscopy. CONCLUSIONS: Truncation and 5'- and 3'-lipophilic modifications of the oligodeoxynucleotides drastically enhanced the growth inhibition of PancTu-I cells, which were resistant to apoptosis-inducing agents. Furthermore, a higher sequence-specificity of the observed effects was achieved with these compounds.

Adenocarcinoma↗
PubMed1998

A human carcinoma model in athymic rats reflecting solid and disseminated colorectal metastases.

We studied the metastatic properties of human tumor cells and tumor cell dissemination in a xenograft tumor model for human colorectal carcinoma in athymic rats which shows a reproducible pattern of metastases similar to the clinical situation. Such a model is also attractive for evaluating several therapeutic approaches. The tumor cell lines HT-29 and WiDr which are derived from the same colorectal tumor and exhibit a similar tumorigenic potential after subcutaneous injection were injected into the portal venous system of 4-week-old male nude rats. After injection of WiDr cells no liver metastases were observed; however, 50% of the rats developed liver metastases 4-12 weeks after injection of HT-29. Immunostaining of the liver cryosections at different times after injection revealed a total disappearance of WiDr cells within the first 12 h. A subpopulation of HT-29 (HT29-b) with increased metastatic activity was isolated by double selection and recultivation of cells from induced liver metastases. After a 6- to 12-week period rats injected with HT-29b showed a pattern of metastases with additional lung metastases and in some cases peritoneal carcinosis. In addition to immunohistochemistry cytokeratin 20 reverse transcriptase-polymerase chain reaction was confirmed to be a sensitive and specific tool for the detection of disseminated tumor cells in different compartments.

Animals↗
PubMed1998

The retroperitoneal resection margin and vessel involvement are important factors determining survival after pancreaticoduodenectomy for ductal adenocarcinoma of the head of the pancreas.

The prognosis of ductal adenocarcinoma of the pancreas is still poor. We analysed the factors that have a major influence on the survival of patients. Surgical specimens from 51 patients with ductal adenocarcinoma of the head of the pancreas were examined for tumour size, histological type, grade and local extension. In 7 patients the retroperitoneal resection margin was involved either macroscopically or histologically. Their mean survival was 10.6 months (1-17 months), compared with 22.7 months for the 44 patients with curative R0 resection. In 10 patients large vessels (portal and/or mesenteric vein) had to be resected; they survived for only 2-11 months, with a mean of 5 months (P<0.05). Non-R0-resected patients and patients in whom tumour-invaded vessels had to be resected constitute a high-risk group with a significantly shorter mean survival of 8.8 months, compared with 24.3 months for R0 resected patients without vessel invasion (P<0.05). Lymph node metastases were seen in 35 of 51 patients. Survival analysis based on nodal status revealed a mean survival of 33 months for patients staged as N0, 21.4 for N1a patients and 14 month for N1b patients. The differences were not statistically significant, however. Our data suggest that tumour invasion of the retroperitoneal resection margin and large vessel involvement are the major factors determining survival in patients with pancreatic cancer.

Aged↗
PubMed1998

WOFIE augments the immunosuppressive potency of FK-506. Window of opportunity for immunological engagement.

UNLABELLED: Bidirectional recognition of donor- and recipient-derived immunocompetent cells has been proven to play a pivotal role for the induction of long-term unresponsiveness to allogeneic grafts. This study investigated the fate of heterotopic heart grafts with respect to the timing of subtherapeutic doses of FK-506 and with respect to the time point and type of donor antigen application, leaving space for mutual adaptation of alloreactive lymphocytes, designated as the 'WOFIE-concept' (window of opportunity for immunological engagement), originally described by R Calne. METHODS: Heterotropic heart transplantation was performed using male DA (RT1.a) donor and LEW (RT1.1) recipient rats in the following groups (n = 6). FK-506 was applied intramuscularly (i.m.) using doses of 2 mg/kg x body weight per day. Donor antigen application was performed either by DA blood transfusion, 2 ml intravenously (i.v.), or by i.v. transfusion of 5 x 10(7) DA splenocytes. (i) LEW --> LEW, untreated; (ii) DA --> LEW, untreated; (iii) DA --> LEW, FK-506 days 0, 4-7; (iv) DA --> LEW, FK-506 as group (iii) plus 2 ml of DA blood 6 h post-Tx; (v) same as group (iv) but DA blood transfusion 24 h post-Tx; (vi) DA --> LEW, FK-506 as group (iii) plus DA splenocytes 6 h post-Tx; (vii) same as group (vi) but DA splenocyte transfusion 24 h post-Tx; (viii) DA --> LEW, FK-506 days 0-4 and (ix) DA --> LEW, FK-506 as group (viii) plus DA blood 6 h post-Tx. Immunohistochemical stainings (APAAP-method) of the allografts and flow cytometric analysis of recipient spleens were performed electively 3, 7 and 14 days after organ reperfusion. RESULTS: The mean graft survival differed significantly between groups and comprised (mean +/- SD days): (i) >100, (ii) 6.5 +/- 1.0, (iii) 31.6 +/- 12.1, (iv) 44.8 +/- 10.1, (v) 29.8 +/- 14.2, (vi) 27.2 +/- 4.7, (vii) 14.6 +/- 4.2, 17.5 +/- 4.2, (viii) 17.5 +/- 4.2 and (ix) 18.8 +/- 2.8 days. Prolongation of graft survival and long-term unresponsiveness (group iv) revealed a substantially different pattern of graft infiltration. CONCLUSIONS: Effective treatment with unspecific immunosuppressants like FK-506 can be substantially improved if (i) mutual antigen recognition between donor and recipient immunocompetent cells is warranted, (ii) donor-derived blood-borne antigens are given immediately after graft reperfusion, and (iii) the type of inoculated donor antigen has a strong impact on graft survival as splenocytes which contain a large population of professional antigen-presenting cells failed to prolong graft survival after interrupted FK-506 treatment.

Animals↗
PubMed1998

Clear cell carcinoma of the pancreas: an adenocarcinoma with ductal phenotype.

AIMS: Primary clear cell carcinoma of the pancreas resembling metastatic renal carcinoma has only rarely been described. To date it has been poorly characterized as a distinct tumour entity. METHODS AND RESULTS: We report a case of clear cell carcinoma in a 53-year-old man involving the head of the pancreas and which had a small intraductal papillary component. The clear cell portion comprised about 90% of the tumour mass. It showed predominantly a solid growth pattern with a few scattered tubular structures. Immunocytochemically the tumour cells stained positively for cytokeratins 7, 8, 18 and 19, whereas the reaction for vimentin and neuroendocrine markers was negative. K-ras analysis revealed a point mutation at codon 12 with mutation of GGT to GAT. CONCLUSION: The intraductal tumour component of this clear cell carcinoma as well as the cytokeratin pattern and the K-ras mutation suggest that this rare type of pancreatic cancer has a ductal phenotype.

Adenocarcinoma, Clear Cell↗
PubMed1998

Isolated tumor cells are frequently detectable in the peritoneal cavity of gastric and colorectal cancer patients and serve as a new prognostic marker.

OBJECTIVE: To evaluate the prognostic significance of isolated tumor cells detected by a panel of various monoclonal antibodies. SUMMARY BACKGROUND DATA: Previously, we showed by using immunocytology that cancer cells are frequently found in bone marrow and peritoneal cavity samples of gastrointestinal cancer patients. METHODS: Findings in bone marrow and peritoneal cavity samples were compared and correlated with the 4-year survival rate of 84 gastric and 109 colorectal patients with cancer. RESULTS: Although positive results in the bone marrow showed little prognostic significance, the peritoneal cavity results correlated with the 4-year survival rate (gastric cancer: p = 0.0038; colorectal cancer: p = 0.0079). Additionally, in subgroups of patients with early (gastric cancer: p = 0.02, colorectal cancer: p = 0.48) and advanced (gastric cancer: p = 0.02, colorectal cancer: p < 0.0001) tumor stages, a correlation of immunocytologic findings and the survival rate was seen. CONCLUSIONS: The detection of minimal residual disease in the peritoneal cavity serves as a new prognostic marker.

Colorectal Neoplasms↗
PubMed1998

Tumor necrosis factor-alpha hyporesponsiveness of rat intestinal mononuclear cells and whole portal venous blood after hemorrhagic shock.

OBJECTIVE: To determine the effect of hemorrhagic shock on spontaneous and endotoxin-induced cytokine release from intestinal mononuclear cells compared with whole portal venous blood and splenic macrophages. DESIGN: Random assignment to either unmanipulated control group, sham operation group, or hemorrhagic shock group. SETTING: University animal laboratory. SUBJECTS: Male Wistar rats, weighing between 300 and 350 g. INTERVENTIONS: Rats were bled to 30 mm Hg for 30 mins by withdrawal/reinfusion of shed blood and Ringer's lactate equivalent to the shed blood volume. MEASUREMENTS: Rats were killed immediately, 4 hrs, or 24 hrs after reperfusion. Portal venous blood, splenic macrophages, and small bowel mononuclear cells were obtained and spontaneous (unstimulated) and endotoxin-induced supernatant tumor necrosis factor (TNF)-alpha (WEHI 164 subclone 13) and interleukin (IL)-6 (B 13-29 clone 9) release was measured by bioassay. MAIN RESULTS: Increased endotoxin-induced TNF release from gut mononuclear cells and portal venous blood was suppressed 4 and 24 hrs after reperfusion compared with sham operated animals (p < .05). TNF release from splenic macrophages could be significantly increased (p < .05) by addition of endotoxin in all groups with no difference between control, sham, and shock animals. In shock animals, endotoxin-stimulated IL-6 release was significantly greater (p < .05) than control and sham operated rats 4 hrs after reperfusion in portal blood and from splenic macrophages. In contrast to splenic macrophages, gut mononuclear cells and portal venous blood demonstrated high spontaneous IL-6 concentrations without further stimulation by endotoxin. CONCLUSIONS: Hemorrhagic shock induced a hyporesponsiveness from gut mononuclear cells and whole portal venous blood 4 and 24 hrs after reperfusion. Spontaneous and endotoxin-induced stimulation of IL-6 indicates a different modulation of cytokines in gut, portal vein and spleen. The differences of gut mononuclear cells and portal blood compared with the splenic macrophages indicate a compartmentalized cytokine response.

Animals↗
PubMed1998

[CD95 resistance and Fas ligand synthesis as mechanism of defense by immunocompetent cells in pancreatic tumors].

Tumor cells have developed a variety of passive and active strategies to escape surveillance by the host immune system. In the present work we have investigated the role of the CD95 system comprising the CD95 receptor (Fas, CD95, APO-1) and its ligand Fas-ligand (FasL) in the dialogue between pancreatic tumor cells and tumor-reactive/cytotoxic T cells. Despite abundant expression of CD95 in pancreatic tumor cells from tumor tissue and in various pancreatic tumor cell lines, we found all (6/6) pancreatic tumor cell lines to be largely resistant to CD95-mediated apoptosis when compared to the CD95-sensitive T cell line Jurkat. Intriguingly, all pancreatic tumor cell lines tested synthesized FasL. In coculture experiments it was shown that two were capable of increasing Jurkat cell apoptosis in a FasL-dependent manner. These data suggest that pancreatic tumor cells have exploited the CD95 system to their benefit in order to protect themselves against tumor-reactive T cells.

Cell Survival↗
PubMed1998

[Significance of allopeptide-induced expression of Fas ligand (FasL) in parenchyma of allogenic heart transplants as the cause of donor-specific tolerance induction].

This study proves the tolerogenicity of polymorphic allopeptides. Combined administration of peptides derived from the alpha 1 (intrathymal) and the alpha 2 (intraperitoneal) helical region of the donor RT1.A(a) molecule induced specific tolerance in a rat model of cardiac allotransplantation. The underlying tolerance mechanism was mediated by selective depletion of alloreactive T cells within the thymus and Fas-L-induced apoptosis within the graft.

Animals↗