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Biomedical subjects

M Schröder

Publications and source records attributed to M Schröder.

At least 19 recordsLinked to original sources
PubMed2000

Treatment of iliac artery aneurysms by percutaneous implantation of stent grafts.

BACKGROUND: Iliac artery aneurysms have traditionally been treated by direct surgical reconstruction. Endovascular stent grafts have been developed to provide an effective but less invasive treatment option for patients with peripheral arterial aneurysms. METHODS AND RESULTS: In 48 patients, a total of 53 endoprostheses (mean length 7. 3 cm, mean diameter 8.1 mm) were implanted into the iliac arteries (common iliac artery n=29, external iliac artery n=19) for percutaneous exclusion of aneurysmal lesions. The technical success of complete exclusion of the aneurysm was achieved in 47 of 48 cases (97.9%). In 1 case, persistent perfusion through a collateral branch was detected; however, this aneurysm thrombosed spontaneously within 2 weeks. In all patients, graft patency was monitored by clinical examination, which included the standardized treadmill test with calculation of the ankle-brachial Doppler index and color-coded duplex ultrasound. Forty-two of the 48 patients (87.5%) underwent follow-up angiography. According to Kaplan-Meier life-table calculations, primary patency rates were 100% after 1 year, 97.9% after 2 years, 94.9% after 3 years, and 87.6% after 4 years. Serial contrast-enhanced spiral CT scans were performed to rule out late procedural failures and to assess growth progression of the lesions. No secondary leaks were observed. Furthermore, the aneurysm diameter had reduced from 24.8+/-8.0 mm to 23.1+/-6.6 mm at the last follow-up (P:=NS). CONCLUSIONS: Stent grafts are a safe and effective treatment option for iliac artery aneurysms and provide good long-term patency of the graft.

Aged↗
PubMed2000

Ligand-independent dimerization activates the stress response kinases IRE1 and PERK in the lumen of the endoplasmic reticulum.

IRE1 and PERK are type I transmembrane serine/threonine protein kinases that are activated by unfolded proteins in the endoplasmic reticulum (ER) to signal adaptive responses. IRE1 is present in all eukaryotic cells and signals the unfolded protein response through its kinase and endoribonuclease activities. PERK signals phosphorylation of a translation initiation factor to inhibit protein synthesis in higher eukaryotic cells but is absent in the Saccharomyces cerevisiae genome. The amino acid sequences of the amino-terminal ER luminal domains (NLDs) from IRE1 and PERK display limited homology and have diverged among species. In this study, we have demonstrated that the NLD of yeast Ire1p is required for signaling. However, the NLDs from human IRE1alpha and murine IRE1beta and the Caenorhabditis elegans IRE1 and PERK function as replacements for the S. cerevisiae Ire1p-NLD to signal the unfolded protein response. Replacement of the Ire1p-NLD with a functional leucine zipper dimerization motif yielded a constitutively active kinase that surprisingly was further activated by ER stress. These results demonstrate that ER stress-induced dimerization of the NLD is sufficient for IRE1 and PERK activation and is conserved through evolution. We propose that ligand-independent activation of IRE1 and PERK permits homodimerization upon accumulation of unfolded proteins in the lumen of the ER.

Amino Acid Sequence↗
PubMed2000

[Prognostic value of hemoglobin level for primary radiochemotherapy of head-neck carcinomas].

The pretherapeutic hemoglobin level (Hb) has been postulated to constitute a prognostic marker for outcome after primary chemoradiation of patients with advanced cancer of the head and neck. However, this hypothesis has not been tested systematically in large study samples. In the years 1992-1997, 125 patients with advanced head and neck cancer (stages III/IV UICC) were treated with primary chemoradiation in two different prospective multicentric trials, 62 patients in trial A (phase II, 1992-1995), and 63 in trial B (phase III, 1995-1997). Beside initial Hb, other pretherapeutic parameters with potential prognostic relevance were assessed and correlated with clinical outcome after 43-months follow-up: total tumor volume (TTV; calculated in initial CT scans), tumor oxygenation (polarographic measurements with Eppendorf histography), TNM, tumor localization, age, and performance status. The evaluation of the clinical end points (progression-free and overall survival and local tumor control) revealed that Hb and TTV were independent parameters with strong predictive character of outcome after primary chemoradiation in both trials (n = 125). Bivariate analysis showed < median (13.5 g/dl) a hazard ratio of 2.1 (P = 0.002) for Hb; and > median (98 ml) a Hazard ratio of 2.0 (P = 0.006) for TTV. Severe anemia (Hb < 10 g/dl) was an adverse factor in three patients. Hypoxia was associated with poorer initial therapeutical response but was not predictive of clinical outcome. Furthermore, tumor oxygenation showed no correlation with Hb. The other parameters examined failed to show prognostic significance. Our results indicate a high prognostic value of initial Hb for outcome after primary chemoradiation in advanced head and neck cancer and imply a therapeutic benefit of Hb substitution or erythropoietin administration. We propose to test this in randomized clinical trials.

Adult↗
PubMed2000

[Mechanical properties of suture materials for anchoring cruciate ligament transplants].

The fixation of hamstring grafts in ACL reconstruction requires a connector device. During the process of ingrowing the graft stability depends entirely on the fixation. The following study focused on the mechanical conditions of no 6 Ethibond, 5 mm Mersilene tape and 5 mm Polylene tape. The material were tested as loops with a length of 30 mm including the knot similar to intraoperative conditions. The ultimate tension load and elongation of the conditioned and unconditioned loops were investigated under cyclic load of 50 N and 100 N using a tension load machine. The ultimate tension load increased significantly only for Mersilene from 416 N to 462 N. However, the highest ultimate tension load showed Polylene with 479 N. The oscillating load up to 100 N revealed for unconditioned loops an elongation of 4.1 mm for Ethibond, 2.9 mm for Polylene and 5.4 mm for Mersilene. The elongation decreased significantly for the conditioned loops to a maximum of 1.4 mm. Concerning the amplitude during the period of oscillating load there was found a significant reduction as well. Based on our results Polylene showed the best mechanical properties. Regardless the intraoperatively used material we advocate the conditioning of the loops before anchoring the hamstring graft in ACL reconstruction.

Anterior Cruciate Ligament↗
PubMed2000

High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study.

Sporadic inclusion body myositis (s-IBM) is an acquired inflammatory muscle disease of unknown cause. In general, s-IBM presents with slowly progressive, asymmetric weakness, and atrophy of skeletal muscle. There is a mild transitory or nil responsiveness to standard immunosuppressive treatment. A controlled cross-over study of 22 s-IBM patients over 3 months showed a partial improvement in those treated with high-dose intravenous immunoglobulin therapy (IVIG) versus placebo. The present study included 22 patients aged 32-75 years and with a mean duration of disease of 5.2+/-3.6 years. They were randomized by a double-blind, placebo-controlled, cross-over design to monthly infusions of 2 g/kg bodyweight IVIG or to placebo for 6 months each, followed by the alternative treatment. After 6 and 12 months the response to treatment was evaluated, using a modified Medical Research Council scale, Neuromuscular Symptom Score (NSS), the patient's own assessment of improvement, arm outstretched time, and electromyography. No serious side effects were seen, in particular no viral infection and no major cardiac or neurological complications. Overall there was no progression of the disease in 90% of patients, unlike that which might have been expected in untreated patients. A mild and significant improvement (11%) in clinical symptoms was found using NSS, but not with other test procedures. There was a trend to mild improvement in treated patients when using other tests. Individual responses to treatment was heterogeneous. The validity of this study may be reduced by mismatch of groups with regard to age at onset and variability in disease expression. The findings of this study largely confirm those of a previous IVIG trial. Treatment with IVIG may be mildly effective in s-IBM by preventing disease progression or inducing mild improvement. Long-term studies are needed to evaluate further the benefit of IVIG therapy in s-IBM.

Adult↗
PubMed2000

13-cis retinoic acid exerts its specific activity on human sebocytes through selective intracellular isomerization to all-trans retinoic acid and binding to retinoid acid receptors.

Despite its potent biologic effect on human sebocytes, 13-cis retinoic acid exhibits low binding affinity for cellular retinoic acid binding proteins and nuclear retinoid receptors. Hence, 13-cis retinoic acid may represent a pro-drug possibly acting through all-trans isomerization. In this study, marked isomerization of 13-cis retinoic acid has been confirmed in cultured SZ95 sebocytes showing 2- to 15-fold higher levels of all-trans retinoic acid at 12-72 h, as measured by high performance liquid chromatography. In contrast, only low amounts of all-trans retinoic acid were converted intracellularly to its 13-cis isoform. 9-cis retinoic acid was not detected after either 13-cis retinoic acid or all-trans retinoic acid treatment. The rapid isomerization of 13-cis retinoic acid to high levels of all-trans retinoic acid was a sebocyte-specific event, as no significant isomerization of 13-cis retinoic acid to all-trans retinoic acid occurred in HaCaT keratinocytes. De novo mRNA expression of cytochrome P450 1A1, a major xenobiotic metabolizing enzyme, in SZ95 sebocytes was induced by all-trans retinoic acid, but not by 13-cis retinoic acid. In addition, mRNA levels of cellular retinoic acid-binding protein II, which is supposed to regulate the concentration of intracellular all-trans retinoic acid, rapidly increased under all-trans retinoic acid treatment (30 min-6 h), whereas the 13-cis retinoic acid effect was markedly weaker and delayed. Both 13-cis retinoic acid and all-trans retinoic acid suppressed mRNA expression of cytochrome P450 1A2. In parallel experiments, 13-cis retinoic acid significantly reduced SZ95 sebocyte proliferation at 10-7 M, show- ing 30-40% inhibition after 9 d. All-trans retinoic acid and 9-cis retinoic acid exhibited similar anti-proliferative effects. AGN 193109, a pan-antagonist of the retinoic acid receptors, antagonized the anti-proliferative activity of all retinoic acid isomers tested in a concentration-dependent manner with complete abolishment at ratios of 1:10 13-cis retinoic acid and 1:1 all-trans retinoic acid. Coincubation of SZ95 sebocytes with 13-cis retinoic acid and AGN 193109 did not alter the intracellular concentration of 13-cis retinoic acid and its isomerization profile. In contrast, the retinoid X receptor antagonist CD 3507 did not affect the inhibition of SZ95 sebocyte proliferation induced by retinoic acids. Our findings indicate: (i) a selective 13-cis retinoic acid isomerization to all-trans retinoic acid in the intracellular compartment of SZ95 sebocytes; (ii) a reduced all-trans retinoic acid inactivation process after 13-cis retinoic acid treatment as compared with treatment with all-trans retinoic acid; and (iii) a retinoic acid receptor-mediated inhibition of SZ95 sebocyte proliferation. These data explain the sebocyte-specific activity of 13-cis retinoic acid and support a pro-drug/drug relation between 13-cis retinoic acid and all-trans retinoic acid.

Cell Division↗
PubMed2000

Treatment of catheter-induced iliac artery injuries with self-expanding endografts.

PURPOSE: To evaluate the efficacy of fabric-covered endoprostheses for percutaneous repair of traumatic iliac artery lesions. METHODS: Among 47 patients treated for catheter-induced iliac artery injuries, 20 (42%) patients (13 men; mean age 58 +/- 10 years, range 41-76) presented with acute (n = 7) or subacute (n = 13) lesions considered inappropriate for bare stent implantation (17 dissecting aneurysms, 2 perforations, and 1 traumatic arteriovenous fistula). The self-expanding Cragg EndoPro System I or Passager devices were deployed percutaneously to exclude the defects. RESULTS: Immediate exclusion of the lesion was achieved in all 20 cases; there were no major procedural complications. However, within 24 hours after implantation, fever (n = 11, 55%) and elevations in white blood cell count (n = 10, 50%) and C-reactive protein (n = 13, 65%) were seen in the majority of patients, which prolonged hospitalization in this group (8.4 versus 4.2 days). During a median 21-month follow-up (range 5-31), 2 angiographically documented restenoses at the outlet of the endografts were treated successfully with balloon angioplasty, achieving primary and secondary patency rates of 87% and 100%, respectively. CONCLUSIONS: Early model stent-grafts provided a safe and effective endovascular treatment for iliac perforations and large arterial dissections, showing a high mid-term patency rate. However, postimplantation syndrome appears to occur frequently with this type of Dacron-covered nitinol device.

Adult↗
PubMed2000

[Percutaneous therapy of catheter-induced traumatic vascular lesions with Dacron coated nitinol stents].

OBJECTIVE: Percutaneous peripheral interventional procedures as well as coronary interventions can be complicated by dissections and traumatic lesions of peripheral arteries. The aim of this study was to evaluate the efficacy of fabric covered endoprostheses for percutaneous repair of traumatic peripheral arterial lesions. PATIENTS AND METHODS: In this study we used the EndoPro 1/Passager device (Boston Scientific, USA), which is a self-expanding nitinol stent covered by an ultrathin layer of dacron fabric. In 27 patients a total number of 31 endoprostheses (mean length 7.3 cm) were implanted in iliac (n = 20), femoral (n = 6) and popliteal arteries (n = 1). Indications for stenting were large dissections (n = 24), arterial perforations (n = 2) and one traumatic arterio-venous fistula. RESULTS: An immediate exclusion of the lesion could be achieved in all cases. There were no major procedural complications. However, within 24 hours after implantation 14 patients (51.9%) developed fever. WBC and CRP were elevated in 13 (48.1%) and 17 (63%) patients, respectively. Repeated blood cultures could not show any bacterial growth. The primary patency after a mean follow-up of 19 (5 to 31) months was 85.2%. In two cases with markedly impaired peripheral run-off subacute graft occlusions occurred. In 2 other cases the angiography revealed relevant restenoses (> 75%). The patency could be restored in 2 of these 4 cases leading to a secondary patency rate of 92.6%. CONCLUSIONS: The EndoPro 1/Passager endoprosthesis seems to be safe and effective to seal large dissections and traumatic lesions of peripheral arteries, showing a high long-term patency rate.

Adult↗
PubMed2000

UFT/leucovorin plus weekly paclitaxel in the treatment of solid tumors.

The palliation of symptoms and improvement of quality of life are important aspects of therapy in patients with incurable metastatic cancer. This article describes the preliminary results of a phase I study of uracil and tegafur, an orally available fluorouracil (5-FU) derivative combined with oral leucovorin plus weekly intravenous paclitaxel. While the daily oral dose of UFT is fixed at 300 mg/m2 plus 90 mg leucovorin on days 1 to 28, paclitaxel is escalated in 10 mg/m2 steps starting with 50 mg/m2 weekly as a 1-hour infusion. To date, 26 patients with a median age of 57 years have been entered into the protocol and have received a median 2.2 cycles of therapy. Dose level 4 (paclitaxel 80 mg/m2) has been recently completed. Major dose-limiting toxicities were fatigue syndrome (two patients) and diarrhea (five patients). Preliminary responses have been observed in three of 14 currently evaluable patients. This protocol is taking the development of protracted 5-FU administration--given orally as UFT--in combination with paclitaxel one step further, using paclitaxel in a dose-dense, weekly schedule. It is hoped that an active regimen for the outpatient treatment of solid tumors will be developed.

Administration, Oral↗
PubMed1999

Stent-supported reconstruction of the aortoiliac bifurcation with the kissing balloon technique.

BACKGROUND: Bilateral iliac artery obstructions involving the aortic bifurcation or high-grade stenosis of the abdominal aorta are not usually considered an indication for percutaneous treatment. The purpose of the present study was to evaluate the initial and long-term results of primary stent implantation for reconstruction of the aortic bifurcation. METHODS AND RESULTS: In 48 patients with obstructions of the aortoiliac segment, primary stent implantation was performed with the "kissing balloon technique." Preinterventional angiography showed bilateral stenoses (>85%) of the proximal common iliac arteries in 25 patients, unilateral occlusions and contralateral stenosis in 22 patients, and bilateral occlusion in 1 patient. In 7 cases, stents were placed for the treatment of high-grade infrarenal aortic stenoses. After excimer laser-assisted recanalization of the common iliac artery obstructions, the aortic bifurcation was reconstructed with the bilateral simultaneous implantation of Palmaz stents (diameter, 7 to 8 mm). Stents used for the treatment of aortic stenoses (Palmaz, n=6; Gianturco, n=1) had a diameter ranging from 20 to 25 mm. In all patients, stents were placed successfully (residual stenosis <30%) and without complications. A clinical improvement of +2 to +3 according to American Heart Association criteria was observed in 41 and 7 patients, respectively. Follow-up was performed clinically (standardized treadmill testing and color-coded Doppler ultrasound) and angiographically. The primary angiographic patency rate (24-month follow-up) was 86.8%. In 3 patients, angiography revealed significant restenoses, which were successfully treated with percutaneous transluminal angioplasty. CONCLUSIONS: Primary stent implantation with the kissing balloon technique is safe and effective for the treatment of aortoiliac obstructions involving the aortic bifurcation and represents a true endovascular alternative to surgery.

Angioplasty, Balloon↗
PubMed1999

EEG burst suppression is not necessary for maximum barbiturate protection in transient focal cerebral ischemia in the rat.

Barbiturates have been demonstrated to reduce the cerebral metabolic rate (CMR) in a dose-dependent manner but investigations of a dose-response relationship for their neuroprotective efficacy are scant. It has been suggested that barbiturates possess other mechanism of action that may be critical to their protective effect. If so, it is conceivable that the peak effect of such mechanisms does not parallel the reduction in CMR. Thus, maximal neuroprotection may be achieved with a substantially lower dose of the drug. Thirty Sprague-Dawley rats were subjected to 2 h of middle cerebral artery occlusion while either anesthetized with (1) halothane (control) or (2) intravenous thiopental titrated to cause mild EEG suppression or (3) thiopental titrated to maintain EEG burst suppression. Cortical blood flow was recorded by continuous bilateral laser Doppler flowmetry (LDF). Infarct volume was assessed after 3 h of reperfusion. Low-dose thiopental decreased blood flow to 80% of baseline and high-dose thiopental to 70% of baseline. LDF did not indicate improvement of blood flow by thiopental in the ischemic area. Compared to controls, low-dose thiopental significantly decreased infarct volume by 28% and high-dose thiopental by 29%. The results of this study and a review of literature indicate that barbiturates provide cerebral protection but that the magnitude of this effect has been overestimated. Other mechanisms than CMR reduction seem to contribute to their beneficial effects, and high doses administered to the point of burst suppression may not be required to obtain maximal protection.

Animals↗
PubMed1999

[Nasal T-cell lymphoma of the lethal midline type. Case report and current aspects in the literature].

A case of nasal T-cell lymphoma as a cause of lethal midline granuloma in a 41-year-old woman is described. Primary chemotherapy as management failed, and tumor control was achieved thereafter by local radiotherapy to a dose of 52 Gy. Fourteen months after diagnosis the patient died in multiorgan failure with involvement of her skin, lung and liver. Present studies give strong evidence that lethal midline granuloma is very often a type of T-cell lymphoma that might be caused by Epstein-Barr virus. According to the literature our findings support the hypothesis that tumors are best treated by local high-dose irradiation.

Adult↗
PubMed1999

[Results of a prospective randomized trial with induction chemotherapy for cancer of the oral cavity and tonsils].

Although induction chemotherapy administered prior to local therapy produces encouraging initial response rates in head and neck cancer, randomized studies have failed to demonstrate an improvement in survival rates. All randomized studies included only patients with advanced stage III and IV disease. In our opinion, this is the main reason for the low rate of complete responses demonstrated in the randomized trials (maximum 18%). Frei et al. estimate that a 40%-50% complete response rate is necessary before improved survival rates are seen. To date, such complete response rates with induction chemotherapy have only been attainable in resectable T2-T3, N0-N2 disease. Therefore, we initiated a prospective randomized trial including only patients with the mentioned disease stages. Patients (pts) were randomized to receive either induction chemotherapy with three cycles of carboplatin/5-FU prior to surgery and radiotherapy (arm A, 70 pts) or standard treatment with surgery and radiotherapy (arm B, 74 pts). Patients were classified according to primary tumour site and neck disease. The observed remission rate after chemotherapy confirmed the primary estimated rate for this subgroup of patients with head and neck cancer (CR: 43%, PR: 37%, NR: 15%, PD: 5%). After a follow-up of 12-96 months overall survival was 58% in arm A and 45% in arm B (n.s.). Disease-free survival in arm A (61%) is statistically significantly better than in arm B (43%, P=0. 03). Therefore, we recommend further controlled trials to investigate the role of induction chemotherapy in patients with primary resectable carcinomas of the oral cavity and tonsils and stage T2-T3 and N0-N2 disease prior to surgery.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Structural properties of sutures used in anchoring multistranded hamstrings in anterior cruciate ligament reconstruction: a biomechanical study.

Sutures are frequently used in anchoring hamstring or quadriceps tendon grafts in cruciate ligament reconstruction. Trumpet like widening of the femoral bone canal was found in patients having had anterior cruciate ligament reconstruction with hamstring autograft. We investigated 5-mm Polylene tape (Genzyme, Boston, MA) and Mersilene tape (Ethicon, Somerville, NJ) as well as No. 6 Ethibond sutures (Ethicon) for ultimate load, stiffness, and elongation under tension of 50 N, 150 N, 250 N, and ultimate load. The Mersilene and Polylene tapes were tested in single loops and Ethibond in double loops having a length of 30 mm. The length is similar to that used intraoperatively for the graft fixation. The suture materials were loaded using a material testing machine at a strain rate of 60 mm/min. The ultimate loads of the loops with knots were 474 N +/-24.7 N for Polylene, 437 N +/-38.2 N for Mersilene, and 338 N +/-16.8 N for Ethibond, and was statistically significant (analysis of variance [ANOVA], P<.05). The elongation under a tension load of 50 N was similar for Ethibond (1.2+/-0.216 mm) and Polylene (1.3+/-0.32 mm). Mersilene (1.7+/-0.34 mm) showed an increased elongation (ANOVA, P=.03). The stiffness for Ethibond was 37.1+/-2.7 N/mm, for Mersilene 38.4+/-3.8 N/mm, and for Polylene was 47+/-3.1 N/mm. The Polylene tape appears to be the most suitable material in terms of strength and stiffness. Nevertheless, the stiffness of all the tested materials is greatly inferior to the stiffness of the commonly used grafts. We believe that a stiffer graft construct might reduce motion during the early period of ingrowing.

Anterior Cruciate Ligament↗
PubMed1999

Importance of the fraction of microcrystalline cellulose and spheronization speed on the properties of extruded pellets made from binary mixtures.

The aim of the study was to prove the importance of the binary mixture composition and spheronization speed on pellet properties. Extrudates from different binary mixtures of microcrystalline cellulose (MCC) and dicalcium phosphate dihydrate were prepared with a power-consumption-controlled extruder and spheronized at different speeds. The water content of the extrudate for the production of spherical pellets was evaluated. The pellets were characterized in terms of size, shape, porosity, mechanical properties, and disintegration. The fraction of MCC in the binary mixtures had the highest impact on the pellet properties. With an increasing fraction of MCC more water was required for successful pelletization, size and porosity of the pellets decreased, and the surface tensile stress increased. These observations were evaluated using the "sponge" and the "crystallite--gel" models for MCC. The latter led to the conception that an extrudate consists of two phases: a percolating crystallite--gel phase formed by MCC and water during extrusion and a filler phase formed by the second component of the binary mixture. This two-phase concept provides explanations for the extent of shrinking during drying and for the disintegration behavior. The spheronization speed had an influence on the size but not on porosity or surface tensile stress of the pellets. The best results were obtained at intermediate spheronization velocities of 10 and 13.4 m/sec. Fundamental properties of extrudates and pellets can be described by applying a two-phase concept of the crystallite--gel model.

Algorithms↗
PubMed1999

Analysis of the inhibition of N-nitroso-dimethylamine activation in the liver by N-nitro-dimethylamine using a new non-linear statistical method.

N-nitro-dimethylamine (NTDMA) is carcinogenic to rats: it induces nasal cavity tumours. It can be demethylated to N-nitromethylamine and formaldehyde and reduced to N-nitroso-dimethylamine (NDMA): a potent liver carcinogen and also of the nasal cavity if activation in the liver is blocked. To explain the mechanism of NTDMA carcinogenicity we compared its demethylation with that of NDMA in liver microsomes from female and male rats, untreated, fasted or treated with ethanol to induce cytochrome P450 2E1 (CYP2E1). Kinetic parameters were analysed by nonlinear statistical methods, which yielded unbiased parameter estimates for the calculated Km and Vmax values. Km for both compounds was very similar in females (24-47 microM) whereas Vmax for NTDMA was consistently higher than for NDMA as substrate: 1.07-4.70 nmol formaldehyde/mg microsomal protein x min and 0.52-2.76 nmol, respectively. In liver microsomes from induced male rats NTDMA was found to be a much more effective inhibitor of NDMA activation (KEI 39.6-73.6 microM) than NDMA of NTDMA demethylation (KEI 224-286 microM). Nasal microsomes can demethylate both NDMA and NTDMA but the kinetics are vastly different. NTDMA is demethylated at a linear rate and approximately 10-fold more effectively than NDMA. The mechanism of carcinogenicity of ingested NTDMA, we propose, is a partial reduction to NDMA in the liver and inhibition of NDMA activation in the liver by residual NTDMA, which enables NDMA to reach the nasal mucosa where it is activated to DNA-alkylating species and the observed tumours are formed.

Animals↗
PubMed1999

Growth factor receptors are differentially expressed in cancers of the papilla of vater and pancreas.

OBJECTIVE: To compare growth factor receptor expression in papilla of Vater cancer and pancreatic cancer. SUMMARY BACKGROUND DATA: Cancer of the papilla of Vater has a much better prognosis than pancreatic cancer. Earlier symptoms may result in earlier diagnosis, but different biologic growth behaviors and genetic alterations might also be explanations. PATIENTS AND METHODS: Surgical specimens from papilla of Vater cancers (24 patients) and pancreatic cancers (80 patients), normal papilla of Vater tissues (20 patients), and normal pancreatic tissues (24 patients) were frozen and fixed. The authors compared the expression of the epidermal growth factor receptor (EGFR) and c-erbB2 and c-erbB3 by Northern blot, in situ hybridization, and immunohistochemistry. RESULTS: In papilla of Vater cancer, Northern blots showed comparable EGFR and c-erbB2 mRNA expression but significantly lower c-erbB3 mRNA levels than in normal papilla. In pancreatic cancer, mRNA expression was enhanced compared with normal controls for EGFR (4-fold), c-erbB2 (2.5-fold), and c-erbB3 (5.2-fold). In situ hybridization confirmed this and showed mRNA expression only in cancer cells. EGFR immunohistochemical staining scores were comparable in papilla of Vater cancer (1.17 +/- 0.22) and normal papilla (1.42 +/- 0.25). Staining scores for c-erbB2 (2.72 +/- 0.40 vs. 3.89 +/- 0.37) and c-erbB3 (2.78 +/- 0.35 vs. 3.89 +/- 0.53) were slightly lower than controls in papilla of Vater cancer. In pancreatic cancer, immunostaining scores for EGFR, c-erbB2, and c-erbB3 were significantly higher than controls. CONCLUSION: Members of the EGFR family show similar or lower expression in papilla of Vater cancer than in normal controls. In pancreatic cancer, these receptors are upregulated. This supports the hypothesis that papilla of Vater cancer and pancreatic cancer have biologic differences that may contribute to the different growth of these tumors.

Adult↗