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Biomedical subjects

R Raab

Publications and source records attributed to R Raab.

At least 55 records · Page 3Linked to original sources
PubMed1996

Antibody-based immunotherapeutic strategies in colorectal cancer.

Monoclonal antibodies may well be on their way to becoming an integral part of therapy after the most recent success in prolonging overall and recurrence-free survival in patients with stage III colorectal cancer after potentially curative surgery. After a median follow-up of 5 years, antibody treatment reduced the overall death rate by 30% and decreased the recurrence rate by 27%. These results are similar with regard to efficacy but there is less toxicity with those obtained in contemporary and more recent chemotherapy trials. The key to success with high-molecular-weight substances such as immunoglobulines lies in the careful selection of the appropriate target population, i.e., patients with minimal residual disease, where only isolated tumor cells which are readily accessible to therapy are present. An argument for combining immunotherapy with chemotherapy can be made on the basis of the phenotype of individual disseminated tumor cells, which by immunocytochemistry were found to only rarely express proliferation-associated antigens and therefore are independent of the cell cycle. Further efforts to improve immunotherapy have also led to the combined clinical use of antibodies with biologic response modifiers which are known to enhance effector cell-mediated antibody-dependent cytotoxicity. Additional rationally designed clinical trials are ongoing in which specific immunotherapy is directed towards known, readily accessible, and abundant cell target structures, either alone or combined with treatment modalities which employ different action mechanisms.

Animals↗
PubMed1996

In vitro selection of peptides acting at a new site of NMDA glutamate receptors.

Oligomeric N-methyl D-aspartate receptor (NMDAR) in brain is a ligand-gated ion channel that becomes selectively permeable to ions upon binding to ligands. For NMDAR channel, the binding of glutamate and glycine results in opening of the calcium permeable channel. Because the calcium influx mediated by NMDAR is important for synaptic plasticity and excitotoxicity, the function of NMDA receptors has been implicated in both health and disease. Native NMDA receptors are thought to be heteromeric pentamers with a central ion conduction pathway. There are five genes (NR1, 2A, 2B, 2C, and 2D) encoding various subunits that have been cloned, and NR1 is thought to be the essential subunit since it forms a functional channel by itself. To study NMDAR structure and function, we have searched for peptide modulators of NR1 using random peptide bacteriophage libraries. The peptides were identified based on their specific association with a purified receptor fusion protein that contains the putative ligand binding domain. We report the identification of one group of cyclic peptides (Mag-1) with a consensus sequence of CDGLRHMWFC. Using biochemical binding analysis and patch clamp electrophysiological recording, we show that the synthetic Mag-1 peptides cause noncompetitive inhibition of the receptor channel activity.

Amino Acid Sequence↗
PubMed1996

Effect of c-kit ligand, stem cell factor, on mediator release by human intestinal mast cells isolated from patients with inflammatory bowel disease and controls.

The regulation of mediator release in human intestinal mast cells is largely unknown. Apart from IgE receptor crosslinking no secretagogues have been described so far. This study examined the effect of two cytokines (c-kit ligand and interleukin 3) and other agonists on human intestinal mast cell function. Cells were isolated from surgery specimens of 47 patients undergoing intestinal resection because of tumours or inflammatory bowel disease. Cell suspensions contained 3.6% mast cells (mean of 50 experiments). After preincubation without or with c-kit ligand or interleukin 3, cells were stimulated by IgE receptor crosslinking, C5a or formyl-methionyl-leucyl-phenylalanine (fMLP). Histamine and sulphidoleukotriene release was measured in supernatants. The sequential stimulation of the cells with c-kit ligand and IgE receptor crosslinking induced the release of high amounts of histamine and leukotrienes, whereas each agonist by itself induced only marginal mediator release. Interleukin 3 induced no release by itself, but enhanced the IgE receptor dependent release, possibly by an indirect mechanism. No significant mediator release was seen in response to C5a and fMLP, even if the cells were pretreated with c-kit ligand. The mediator release, particularly that of leukotrienes, was higher in cells isolated from actively inflamed tissue from patients with inflammatory bowel disease compared with controls. In conclusion, it was found that, apart from IgE receptor crosslinking, c-kit ligand and interleukin 3 regulate mediator release in human intestinal mast cells. The enhancement of mediator release by cytokines may be of particular relevance in the pathogenesis of inflammatory bowel diseases and food intolerance reactions.

Adult↗
PubMed1996

[Liver metastases in breast carcinoma. Results of partial liver resection].

Within 11 years we performed 35 liver resections in 34 patients with liver metastases of breast cancer. The median age was 47 years. The median interval between the primary operation and the liver resection was 27.3 months. 59% of the patients had a solitary metastases. A curative (R0) resection was possible in 86%. Operative mortality was 3% (n = 1). Overall 5-year survival was 18.4% (median 27 months). Prognosis was significantly (p < 0.001) better following R0-resection (22%, median 41.5 months) than after R1/2-resection (maximum 20 months, median 5 months). Beside the radicality an unfavorable influence on the prognosis could be demonstrated only for a prior local recurrence of the primary tumor (p < 0.05). If a R0-resection was possible stage of the primary tumor, number and size of the metastases, and extension of the operative procedure were without prognostic significance. We conclude that patients with isolated liver metastases of breast cancer can have a long lasting benefit from liver resection. In individual cases even cure may be possible.

Adult↗
PubMed1996

Efficacy and safety of topical calcitriol (1,25-dihydroxyvitamin d3) for the treatment of psoriasis.

Plaque-type psoriasis has been successfully treated with topical calcitriol, but there has been no long-term follow-up study of the safety and efficacy of this calciotropic hormone. In a single-centre study, patients with plaque or erythrodermic psoriasis were enrolled in a double-blind, right/left comparison, placebo-controlled study, and received 1.5 micrograms of calcitriol (15 micrograms/g of Vaseline) per day, or a placebo consisting of Vaseline alone. A subset of these patients (n = 22), with at least 25% involvement, applied 0.1 g of calcitriol ointment/50 cm2 on an area of from 2,500 to 5,000 cm2. Of the 84 patients enrolled in the double-blind control study, 96.5% responded to topical calcitriol therapy, compared with 15.5% whose lesions improved with Vaseline alone, after 2.4 months. After completion of the double-blind study, 22 patients applied calcitriol ointment (15 micrograms/g Vaseline) to all of their lesions (up to 10 g of calcitriol ointment; 150 micrograms calcitriol lesions showed either excellent or moderate clearing in 90.9% of all cases. The remaining 9.1% of cases showed slight improvement of their lesions. No abnormalities in calcium metabolism were noted in any of the patients using topical calcitriol. None of the patients experienced any local cutaneous side-effects, including six patients who applied calcitriol ointment to the face. Topical calcitriol is safe and effective for the treatment of psoriasis.

Administration, Cutaneous↗
PubMed1996

Safety and efficacy of oral calcitriol (1,25-dihydroxyvitamin D3) for the treatment of psoriasis.

Plaque-type psoriasis has been successfully treated with oral calcitriol, but there has been no long-term follow-up on the safety and efficacy of this calciotropic hormone for psoriasis. In a single centre study, patients were enrolled in an open trial to evaluate the efficacy and safety of oral calcitriol for psoriasis. Of the 85 patients who received oral calcitriol, 88.0% had some improvement in their disease; 26.5, 36.2 and 25.3%, had complete, moderate and slight improvement in their disease, respectively. The mean baseline psoriasis area severity index score (PASI) of 18.4 +/- 1.0 was reduced to 9.7 +/- 0.8 and 7.8 +/- 1.3 after 6 and 24 months on oral calcitriol therapy. Serum calcium concentrations and 24 h urinary calcium excretion increased by 3.9% and 148.2%, respectively, but were not outside the normal range. Bone mineral density remained unchanged. The clearance of creatinine decreased by 13.4% from baseline during the first 6 months of treatment, and thereafter, remained unchanged after 3 years of follow up. An evaluation of creatinine, inulin and paraaminohypurate (PAH) clearance was performed in eight patients. After 6 months on oral calcitriol, there was a 22.5% decline in creatinine clearance but no significant changes were observed in either inulin or PAH clearance, suggesting that calcitriol alters creatinine metabolism or secretion but does not affect renal function. Oral calcitriol is effective and safe for the treatment of psoriasis.

Administration, Oral↗
PubMed1996

[What is the advantage of free microvascular tissue transfer after pelvic exenteration? A argument for delayed primary management].

Locoregional pelvic recurrences are amenable to re-resection even if musculoskeletal fixation is present. This report updates our experience with pelvic composite resections and microsurgical closure of the perineal cavity by nine latissimus dorsi flaps, one as a bilobed type combined with a scapula flap. All flaps survived. There was one rupture of the vascular pedicle following repositioning of the patient. Another flap healed completely, but presented a wound rupture with secondary healing in the area of the rima ani. Three major advantages to this method have been proven: (1) Healing and hospitalization could be reduced compared to conservative treatment; (2) The latissimus dorsi transfer allows stable perineal coverage and closure of dead space, preventing any pelvic herniation; (3) Performed as a delayed procedure the free tissue transfer is well tolerated by the patient.

Adult↗
PubMed1995

[Ergotamine-induced anorectal lesions].

During the past 10 years several reports on perianal ulcerations secondary to chronic use of ergotamine suppositories were published. The present case reports deal with 2 female patients who used ergotamine suppositories for treatment of sick head aches for several years. In both cases the suppositories were used chronically. The first patient, a 60 year old woman has been treated repeatedly because of recurrent perianal ulcerations. An infection and a carcinoma could be excluded. The diagnosis of ergotamine induced ulcerations could be suspected only after a detailed work up of the patients past medical history and interview of family members. The ulcerations healed within a few months after broad excision and withdrawal of the medication. The second patient, a 51 year old woman complained of severe obstipation which occurred within a few months. The investigations showed a circular stenosis in the lower third of the rectum. The patient was treated successfully by bougienage under general anaesthesia. These case reports demonstrate the difficulties in diagnosis such lesions and emphasize the importance of a close medical follow-up when ergotamine suppositories are used for treatment of migraine. Whenever possible, a continuous treatment should be avoided.

Anal Canal↗
PubMed1995

[Diagnostic measures before laparoscopic cholecystectomy].

Successful use of laparoscopic cholecystectomy requires good cooperation between surgeon and gastroenterologist. Standard preoperative workup includes detailed history of the patient, blood chemistry of serum bilirubin and liver enzymes as well as sonography for the detection of common bile duct stones. Intravenous cholangiography can be performed to diagnose anatomic variations of the bile ducts. In case of common bile duct stones "therapeutic splitting" by endoscopic retrograde cholangiography with sphincterotomy and gallstone extraction preoperatively may help to avoid unnecessary conventional open cholecystectomy.

Cholangiography↗
PubMed1994

Randomised trial of monoclonal antibody for adjuvant therapy of resected Dukes' C colorectal carcinoma. German Cancer Aid 17-1A Study Group.

Over the past decade various clinical trials have used monoclonal antibodies as therapeutic agents against solid tumours. No consistent pattern of response or improved survival has yet emerged although antigenic heterogeneity and insufficient accessibility of cells in advanced tumours have been offered as explanations for these failures. We designed a study in which a monoclonal antibody was used to target minimal residual disease in an early stage of tumour cell dissemination in patients with colorectal cancer. Only patients in Dukes' stage C who had undergone curative surgery and were free of manifest residual tumour were admitted. 189 patients with colorectal cancer of stage Dukes' C were randomly assigned to an observation regimen or to postoperative treatment with 500 mg of 17-1A antibody, followed by four 100 mg infusions each month. A balance of risk factors in the two groups was achieved by dynamic randomisation procedure. After a median follow-up of 5 years, antibody treatment reduced the overall death rate by 30% (Cox's proportional hazard, p = 0.04, log-rank p = 0.05) and decreased the recurrence rate by 27% (p = 0.03, p = 0.05). The effect of antibody was most pronounced in patients who had distant metastasis as first sign of a relapse (p = 0.0014, p = 0.002), an effect that was not seen for local relapses (p = 0.74, p = 0.67). Toxic effects of 17-1A antibody were infrequent, consisting mainly of mild constitutional and gastrointestinal symptoms. During 371 infusions four anaphylactic reactions were seen, all controllable by intravenous steroids and none necessitated admission to hospital. Adjuvant therapy with 17-1A antibody extends life and prolongs remission in patients with colorectal cancer of Dukes' stage C.

Antibodies, Monoclonal↗
PubMed1994

Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20.

Murine monoclonal antibody 2B8 specifically recognizes the CD20 phosphoprotein expressed on the surface of normal B lymphocytes and B-cell lymphomas. The light- and heavy-chain variable regions of 2B8 were cloned, after amplification by the polymerase chain reaction, into a cDNA expression vector that contained human IgG1 heavy chain and human kappa-light chain constant regions. High-level expression of chimeric-2B8 antibody (C2B8) was obtained in Chinese hamster ovary cells. Purified C2B8 exhibited antigen binding affinity and human-tissue reactivity similar to the native murine antibody. In vitro studies showed the ability of C2B8 to bind human C1q, mediate complement-dependent cell lysis of human B-lymphoid cell lines, and lyse human target cells through antibody-dependent cellular cytotoxicity. Infusion of macaque cynomolgus monkeys with doses ranging from 1.6 mg/kg to 6.4 mg/kg resulted in greater than 98% depletion of peripheral blood (PB) B cells and 40% to 70% depletion of lymph node B cells. Recovery of PB B cells usually started at 2 weeks after treatment and required 60 to greater than 90 days to reach normal levels. As much as 95% depletion of B cells in peripheral lymph nodes and bone marrow was observed following weekly injections of 16.8 mg/kg antibody. No toxicity was observed in any of the animals. These results offer the possibility of using an "immunologically active" chimeric anti-CD20 antibody as an alternative approach in the treatment of B-cell lymphoma.

Amino Acid Sequence↗
PubMed1994

Decreasing the risk of pulmonary artery rupture with a pressure relief balloon.

A pressure relief balloon has been recommended as one way to decrease catheter-related pulmonary artery rupture (PAR). There are approximately 1 to 2 PARs per 1,000 pulmonary artery catheter (PAC) insertions, resulting in significant morbidity and mortality. A new pressure relief balloon (PRB) introduced by Biosensors International (Singapore) was studied for its efficacy in increasing safety during PAC flotation balloon (FB) inflations. Ten human placentae were used for the experiment. The Biosensors PACs and the commonly used Baxter-Edwards (Irvine, CA) catheters were placed in placental veins and their FBs were gradually inflated with a maximum of 1.5 mL of air. Data revealed that PRBs consistently inflated when resistance was met by FBs and inflation pressure reached 1,000 mmHg. When PRBs were removed, the FBs inflated asymmetrically and distended beyond the catheter lumen or protruded through the vessel wall, causing bleeding upon deflation. Without the PRB, pressures reached up to 1,700 mmHg. In addition, the PRB gave visual evidence of resistance to the FB. In conclusion, the PRB is a safety device that limits overinflation of the distal PAC balloon, thus preventing vessel rupture. The device deserves serious consideration and outcome analysis.

Catheterization↗
PubMed1992

Architectural design of the human intrinsic hand muscles.

The architectural features of twenty different muscles (18 intrinsics and 2 thumb extrinsics, n = 180 total muscles) were studied. Muscle length, mass, fiber pennation angle, fiber length, and sarcomere length were determined. From these values, physiologic cross-sectional area and fiber length/muscle length ratio were calculated. Intrinsic muscle lengths were relatively similar to one another, which we interpreted as representing a space constraint within the hand. However, several specialized architectural designs were observed: lumbrical muscles had an extremely high fiber length/muscle length ratio, implying a design toward high excursion. The first dorsal interosseous and adductor pollicis had physiologic cross-sectional areas comparable to those of extrinsic muscles and much greater than those of the other intrinsic muscles. The interosseous muscles had relatively high physiologic cross-sectional areas with low fiber length/muscle length ratios, suggesting their adaptation for high force production and low excursion. Taken together, these observations illustrate the underlying structural basis for the functional capacities of the intrinsic muscles.

Hand↗
PubMed1992

"Primatization" of recombinant antibodies for immunotherapy of human diseases: a macaque/human chimeric antibody against human CD4.

Immunoglobulin variable region genes from non-human primates, cynomolgus macaques, were shown to have 85%-98% homology with human immunoglobulin sequences and yet macaques are phylogenetically distant enough to respond against conserved human antigens. Immunoglobulin genes were isolated from monkeys immunized with human CD4 antigen and a human/monkey chimeric anti-CD4 antibody with 91-92% homology to human immunoglobulin framework regions was cloned and expressed. The antibody has an apparent affinity of 3.2 x 10(-11) M and exhibits potent immunosuppressive properties in vitro.

Animals↗