Biomedical subjects
Publications and source records attributed to C Vogel.
The present consensus manuscript defines evidence-based recommendations for state-of-the-art treatment of metastatic breast cancer depending on disease-associated and biologic variables.
Dieulafoy's lesion was described in 1896 by the French pathologist Georges D. Dieulafoy as a vascular malformation in the stomach. Although usually found in the stomach, the lesion may occur anywhere within the gastrointestinal tract and can cause severe hemorrhage. There is no sex or age predilection. The diagnosis is established endoscopically, and the current therapy of choice is endoscopic hemoclipping. Only rarely is the diagnosis confirmed histologically. We report the case of an elderly female patient who, while hospitalised for a slipped intervertebral disc, presented with lower gastrointestinal bleeding. The source of the bleeding was suspected to be in the right colon by endoscopy. Renewed massive bleeding necessitated surgical treatment with resection of the right hemicolon. The histological work-up of the resected specimen identified a 350-micron large tortuous submucosal artery that had eroded.
The term "pyloric gland adenoma" reflects its etiogenesis from deep mucoid glands in the stomach. The diagnosis can be confirmed by immunohistochemistry. Typically, pyloric gland adenomas are strongly positive for Mucin 6 (deep mucoid gastric glands). These lesions express Mucin 6 over the whole lesion up to the surface often only with a small layer of columnar epithelium expressing Apomucin 5AC. The amount of mucin 5AC which is expressed on normal within the apical foveolar epithelium might vary from case to case. Combination or transdifferentiation with ordinary tubular (intestinal differentiation) adenoma can be observed. The gastric corpus mucosa of elderly female patients with autoimmune gastritis is highly affected. The frequency of pyloric gland adenoma is given in the literature being 2.7% of all gastric polyps. Therefore pyloric gland adenomas are not that rare that one might assume. Only a few publications are available which makes one think that these lesions are frequently misinterpreted. Pyloric gland adenomas can arise in gastric heterotopia and gastric metaplasia in the whole gastrointestinal tract. The clinical significance is given by a 30% rate of malignant transformation. These cases represent for the most well differentiated early adenocarcinomas which are known to have an excellent prognosis after complete polypectomy and limitation to the mucosal layer.
This study investigated the value of both gross features and histological findings for grading of brain swelling. For this purpose, the grooving of the temporal gyri (unci) as well as the extension of the cones at the basal part of the cerebellum were measured in 42 brains obtained at autopsy. Furthermore, the distension of perivascular spaces in tissue samples from seven different regions of the brains was evaluated histologically, assisted by an automatic image processing and analysis system. In each individual, the normal range of brain weight was calculated on the basis of the body height, using the formulae by Röthig and Schaarschmidt. The difference between this calculated (normal) value and the brain weight evaluated at autopsy was considered as a reliable criterion for the grade of brain swelling. There was no statistical evidence of a positive correlation between the various parameters. Hence, it can be concluded that both gross section and histological findings are of minimal significance for grading of brain swelling.
While there is extensive methodological literature analysing the effects of misclassification on the relative risk under various misclassification scenarios, for the attributable risk only the effects of non-differential misclassification either of exposure or disease, and the effects of non-differential independent misclassification of exposure and disease have been discussed for the 2 x 2-situation. The paper investigates the effects of non-differential correlated misclassification of exposure and disease on the attributable risk taking possible correlations of both types of misclassification into account. Furthermore, a comparison with the corresponding effects on the relative risk is drawn. We propose a matrix-based approach to describe the underlying structure of non-differential misclassification. The bias arising from non-differential misclassification in the attributable risk and relative risk is evaluated in four examples assuming under- or overreporting of exposure and disease. In each of the four examples we found scenarios where pronounced differences in degree and, more importantly, in direction of bias occurred. Our results clearly demonstrate the danger lying in the stereotype transfer of findings regarding misclassification effects on the relative risk to other epidemiologic risk measures and underline the necessity of specific analyses of the effects of misclassification on the attributable risk.
The genes Phf5a and Phf5b-ps are the first two members of a novel murine multigene family that is highly conserved during evolution and belongs to the superfamily of PHD-finger genes. The Phf5 gene family contains an active locus on mouse chromosome 15, region E and several processed pseudogenes on different chromosomes. The active locus, Phf5a, is expressed ubiquitously in pre- and postnatal murine tissues and encodes a protein of 110 amino acids. The protein is localized in the nucleus in a non-homogenous pattern as the nucleolar subcompartment is almost free of Phf5a. The molecular and biological functions of Phf5a are unknown up-to-date, but the systematic deletion of its yeast homolog is lethal, pointing out that the protein is required for cell viability. Interpretation of our data and review of the literature suggest both basic and essential cellular functions of the Phf5a protein, possibly acting as a chromatin-associated protein.
OBJECTIVES: Only the effects of isolated nondifferential misclassification of exposure or disease on the estimates of attributable risk have been discussed in the literature. The aim of this paper is to broaden the spectrum of scenarios for which implications of misclassification are available. METHODS: For this purpose, a matrix-based approach allowing a comprehensive, unified analysis of various structures of misclassification is introduced. The relative bias or--in the situation of covariate misclassification--the relative adjustment are presented for the different misclassification scenarios. RESULTS: Under nondifferential misclassification of exposure or disease, the attributable risk is biased towards the null with the only exception of perfect sensitivity of exposure classification or perfect specificity of disease classification both leading to an unbiased attributable risk. From these two marginal effects, the consequences of simultaneous nondifferential independent misclassification of exposure and disease on the attributable risk are derived in the matrix-based approach. Misclassification of a dichotomous covariate leads to partial adjustment. CONCLUSIONS: To a large extent, the results for the attributable risk are in accordance with the well-known results for the relative risk. The algebraic differences between the two risk measures, however, make it necessary to repeat the methodological considerations for the attributable risk.
PURPOSE: The NK1-receptor antagonist MK-869 (L-754,030) has demonstrated antiemetic activity in humans receiving chemotherapy. Objectives of the present trial included the first assessment of oral MK-869 plus dexamethasone compared with a 5HT(3) antagonist plus dexamethasone for prevention of acute and delayed emesis after high-dose cisplatin. Furthermore, the study sought to confirm that addition of MK-869 to a 5HT(3) antagonist plus dexamethasone was more effective than just the 5HT(3) antagonist plus dexamethasone for prevention of acute and delayed emesis. METHODS: This multicenter, double-blind, parallel-group trial in 351 cisplatin-naïve patients evaluated prevention of acute (0 to 24 hours) and delayed emesis (primary efficacy parameter; days 2 to 5) after cisplatin (> or =70 mg/m(2)). Patients were randomized to four groups (I to IV) (n = number randomized; number evaluable): granisetron (10 microg/kg intravenously) pre-cisplatin followed by placebo on days 2 to 5 (group I) (n = 90; 90); granisetron and MK-869 (400 mg PO [by mouth]) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group II) (n = 86; 84); MK-869 (400 mg PO) the evening before and pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group III) (n = 89; 88); or MK-869 (400 mg PO) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group IV) (n = 86; 84). All patients also received dexamethasone (20 mg PO) before cisplatin. Additional medication was available to treat emesis or nausea at any time. RESULTS: In the acute period, 57%, 80%, 46%, and 43% of patients were without emesis in groups I, II, III, and IV, respectively (P <.01 for group II v group I). In the delayed period, the proportion of patients without emesis in groups I, II, III, and IV was 29%, 63%, 51%, and 57%, respectively (P <.01 for groups II, III, and IV v group I). The distribution of nausea scores in the delayed period was lower when comparing group II with group I (P <.05 for days 1 to 5 and days 2 to 5). One serious adverse event (dizziness) was rated as possibly related to MK-869. CONCLUSION: Once daily oral administration of MK-869 was effective in reducing delayed emesis and nausea after high-dose cisplatin. However, the combination of the 5HT3 antagonist plus dexamethasone was numerically superior to MK-869 plus dexamethasone in reducing acute emesis. Confirming and extending previous findings, the triple combination of a 5HT(3) antagonist, MK-869, and dexamethasone provided the best control of acute emesis.
BACKGROUND AND STUDY AIMS: The aim of this study was to examine the occurrence of clinically relevant changes in thyroid function after enteral administration of contrast agent by endoscopic retrograde cholangiopancreatography (ERCP). PATIENTS AND METHODS: In this study 70 patients without a history of thyroid disease who had not recently undergone thyroid-specific or thyroid-influencing therapy were examined. Patients were examined on two or three occasions using a standardized questionnaire regarding symptoms of hypothyroidism and hyperthyroidism. The parameters of thyroid function (TT3, TT4, FT4, thyroid-stimulating hormone (TSH)) and urinary iodine excretion were measured on day 0 and on day 21 post-ERCP, and in 23 patients additionally on day 42 post-ERCP. Based on ultrasonographic results, four groups differing in thyroid morphology were distinguished. RESULTS: The data show that an average amount of only 4.7 g of enterally applied iodine is associated with a lasting decrease of TSH, especially in patients with enlarged organs with nodular transformation. As far as TT3 is concerned, there was a significant increase in all patient groups; regarding FT4 we only observed a marked increase in the group with enlarged, nodular thyroid glands. There was a notable increase in urinary iodine excretion on day 21, and a further increase on day 42 post-ERCP. Clinical symptoms of hyperthyroidism did not occur. CONCLUSIONS: We conclude that before administration of iodine-containing contrast agent for ERCP in patients without a history of thyroid disease, thyroid ultrasonographic examination, rather than TSH measurements, should be performed, in order to identify patients already at risk for hyperthyroidism before diagnostic enteral contrast-medium application.
BACKGROUND: An optimal method for hepatocyte transplantation is not yet determined. With the principles of tissue engineering in vitro conditioning of hepatocytes on biodegradable polymer in a flow bioreactor before implantation forming spheroids may achieve increased cell mass and function to replace lost organ function in vivo. METHODS: Biodegradable poly-L-lactic (PLLA) polymer discs were seeded with rat hepatocytes in a concentration of 10 x 10(6) cells per ml and exposed to a medium flow of 24 ml/min for 1, 2, 4 and 6 days. The number and diameter of spheroidal aggregates was measured by phase-contrast microscopy. H&E histology was performed. Albumin production as hepatocyte specific function was determined by ELISA. RESULTS: Spheroids of viable hepatocytes of 50-200 microm in diameter were formed. Both the number and diameter of the spheroids increased during the first 2 days and then remained constant until day 6. Albumin production was maintained throughout the culture period. CONCLUSION: Short (2- 3 days) pre-transplant conditioning of hepatocytes in a flow bioreactor on biodegradable PLLA resulted in formation of spheroids with a liver-like morphology and preserved specific metabolic function. Tissue engineered hepatocyte spheroids on polymer may represent a functionally active and easy transplantable neotissue and may serve as an in vivo substitute for lost liver function.
The epidemiological problem of risk attribution in the framework of multiple exposures has been the subject of intensive research activities in the last decade. In particular, partitioning methods have been developed to define new multidimensional measures of attributable risk putting the task of quantifying a proportion of disease events in a population that can be ascribed to the adverse health effects of certain risk factors into a multifactorial perspective. The parameters generalize the concept of attributable risk to different multifactorial frameworks in which multiple exposures might be arranged in hierarchically ordered classes or in equally ranking groups. Partitioning methods are reviewed and differences between the multifactorial variants of attributable risk are illustrated by a component causes model.
Following confirmation of the appropriate dosage, safety and potential efficacy of Herceptin(trastuzumab) in small-scale phase I and II trials involving patients with refractory disease, a large trial was conducted in 222 patients with breast cancer who had relapsed after one or two chemotherapy regimens for their metastatic disease. The results showed a positive and durable overall response rate (15% according to a response evaluation committee (REC) assessment) using trastuzumab monotherapy (initial dose 4 mg/kg intravenously (i.v.) followed by 2 mg/kg i.v. weekly). In another recently completed phase II trial, 113 patients were randomised to two dose levels (initial dose of 4 mg/kg i.v. dose followed by 2 mg/kg i.v. weekly, or initial dose of 8 mg/kg followed by 4 mg/kg i.v. weekly) of single-agent trastuzumab as first-line therapy for metastatic disease. The preliminary overall response rate was 23% based on investigator assessment, and tolerability was excellent as in previous trials; efficacy was similar in both dose groups, but the side-effects tended to be more frequent in the higher dose group. The preferred dosage is therefore the same as that currently recommended, i.e. an initial dose of 4 mg/kg i.v. followed by 2 mg/kg weekly i.v. until disease progression.
Following confirmation of the appropriate dosage, safety and potential efficacy of Herceptin(R) (trastuzumab) in small-scale phase I and II trials involving patients with refractory disease, a large trial was conducted in 222 patients with breast cancer who had relapsed after one or two chemotherapy regimens for their metastatic disease. The results showed a positive and durable overall response rate (15% according to a response evaluation committee (REC) assessment) using trastuzumab monotherapy (initial dose 4 mg/kg intravenously (i.v.) followed by 2 mg/kg i.v. weekly). In another recently completed phase II trial, 113 patients were randomised to two dose levels (initial dose of 4 mg/kg i.v. dose followed by 2 mg/kg i.v. weekly, or initial dose of 8 mg/kg followed by 4 mg/kg i.v. weekly) of single-agent trastuzumab as first-line therapy for metastatic disease. The preliminary overall response rate was 23% based on investigator assessment, and tolerability was excellent as in previous trials; efficacy was similar in both dose groups, but the side-effects tended to be more frequent in the higher dose group. The preferred dosage is therefore the same as that currently recommended, i.e. an initial dose of 4 mg/kg i.v. followed by 2 mg/kg weekly i.v. until disease progression.
BACKGROUND: An earlier trial of raloxifene, conducted in women with metastatic breast carcinoma who initially had responded to tamoxifen and subsequently developed disease progression, suggested no antitumor activity for raloxifene in tamoxifen-refractory disease. However, preclinical studies and preliminary clinical data in healthy women suggest that raloxifene antagonizes growth of estrogen-dependent neoplasia. METHODS: Raloxifene HCl 150 mg twice daily was given to 22 postmenopausal women with metastatic (American Joint Committee on Cancer Stage IV) or locoregionally recurrent, initially estrogen receptor positive breast carcinoma. Prior systemic treatment of metastatic disease was not allowed. Prior adjuvant chemotherapy or hormonal therapy was required to have been completed at least 1 year before study entry. Tumor response was evaluated every other month either radiographically or by physical examination. Evaluable disease was defined as bidimensionally measurable lesions. RESULTS: Twenty-one patients were eligible for efficacy analysis; 6 had been treated previously with tamoxifen. There were no complete tumor responses. Four patients (19%; 95% confidence interval [95% CI], 2.2%, 36%) had partial tumor responses lasting 6.3, 17.5, 23.9, and 28.1 months, respectively. Prolonged stable disease (i.e., tumor size stable for > or = 6 months) was observed in 3 patients (14%; 95% CI, 0.0%, 29%) and lasted 7.9, 12.2, and 25.1 months, respectively. Combining partial responses and prolonged stable disease yielded an overall clinical benefit rate of 33% (95% CI, 13%, 53%). Adverse events generally were consistent with the disease state; there were no serious adverse events or laboratory changes believed to be therapy-related. CONCLUSIONS: Raloxifene HCl, 150 mg, administered twice daily was safe, well tolerated, and modestly effective in highly selected postmenopausal women with advanced breast carcinoma. Further study of high dose raloxifene as monotherapy for advanced breast carcinoma most likely is unwarranted.
The prevalence of breast cancer (a hormonally driven neoplasm) in the United States, the potential health benefits of estrogen replacement therapy for postmenopausal women, and the burgeoning research focusing on selective estrogen receptor modulators (SERMs) have resulted in additional complexity in managing breast cancer. In an attempt to clarify existing data, the Society of Surgical Oncology sponsored a symposium entitled "Estrogens and Antiestrogens in Managing the Patient with Breast Cancer" at its 52nd Annual Cancer Symposium. This conference was held in March 1999 and was chaired by Dr. S. Eva Singletary, Professor of Surgery and Chief of the Surgical Breast Section at The University of Texas M. D. Anderson Cancer Center in Houston, Texas. The following is a review of the material presented by the symposium participants.
The tumor promoter 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to increase the expression of prostaglandin endoperoxide H synthase (PGHS)-2. This study focused on the regulatory mechanism of TCDD-mediated transcriptional activation of PGHS-2. Treatment of rat hepatocytes with TCDD led to a dose-dependent induction of PGHS-2 mRNA levels associated with an increased synthesis of prostaglandin E(2), whereas expression of PGHS-1 was not affected. In vitro experiments with c-Src inhibitors, such as herbimycin A and geldanamycin, and in vivo studies with c-Src-deficient mice indicated that up-regulation of PGHS-2 but not the cytochrome P450 gene CYP1A1 by TCDD is mediated via a c-Src-dependent pathway. Transient transfection studies with different reporter constructs of the murine PGHS-2 promoter mutated in the xenobiotic-responsive element (XRE) or CCAAT/enhancer binding protein (C/EBP) element revealed that a C/EBP-binding site is an important regulatory cis-acting factor for trans-activation of the PGHS-2 gene by TCDD. Consistent with transfection studies, gel mobility shift assays showed that TCDD led to an enhanced DNA-binding activity of C/EBP beta transcription factor. The experimental data presented in this article reveal a XRE-independent and c-Src-mediated activation of the PGHS-2 gene by TCDD through the C/EBP response element located in its promoter region.
The metabolism of a xenobiotic is an important stage resulting in its toxification (bioactivation) or detoxification. The most common reaction is the oxidation catalyzed by the cytochrome P450 (CYP) enzyme system. An alternate enzyme for chemical oxidation is the prostaglandin H synthase (PGHS) also known as cyclooxygenase (COX). The PGHS is the initial enzyme in arachidonate metabolism and formation of prostanoids such as prostaglandins (PG), prostacyclins, and thromboxanes. However, 25 years ago it was found that during the reduction of the endogenous substrate, hydroperoxy-endoperoxide (PGG2) to hydroxy-endoperoxide (PGH2), the PGHS enzyme is capable to "co-oxidize" chemicals. In this reaction, a broad spectrum of chemicals can serve as electron donors such as phenolic compounds, aromatic amines, and polycyclic aromatic hydrocarbons. In contrast to numerous CYP enzymes in liver, the PGI is an alternate enzyme for xenobiotic metabolism in extrahepatic tissues. In respect of tissue distribution, PGHS can play an essential role in the bioactivation of e.g. procarcinogenic chemicals in certain target tissues that possess low CYP monooxygenase activity. Two PGHS isozymes have been identified: PGHS-1 and PGHS-2, which have very similar kinetic properties, but differ in regard to expression and regulation. In recent studies it was shown that not only endogenous stimuli but also drugs and environmental chemicals can activate PGHS-2 expression. Therefore the PGHS enzymes provide two interesting aspects for pharmacology and toxicology: a) the co-oxidation of chemicals and b) the altered synthesis of prostanoids after exposure to certain xenobiotics which can be essential for their ultimate toxicity.
A few hours after peripheral axons of cutaneous afferent neurons have been transected, some of their novel endings become excitable by physical or chemical stimuli. It has been assumed that these axon endings preferentially respond to those stimuli which have excited their previous receptive endings. We studied the prevalence of sensory properties among 784 unmyelinated sural nerve fibres which had been axotomized 2-24 h before, by applying mechanical and thermal forces to the nerve lesion site. Among 126 responding C-fibres, the majority was unimodal, responding exclusively to mechanical (31%), cold (23%) or heat (18%) stimuli. The remainder were either mechano-heat sensitive (10%), mechano-cold sensitive (6%) or heat and cold sensitive (12%). The distribution of sensory properties among acutely axotomized sural nerve C-fibres is therefore largely similar to the recently published distribution of receptor types among intact sural nerve C-fibre afferents. Thus, the hypothesis that responses of axotomized afferent fibres reflect their original receptive properties is corroborated. Knowledge of underlying transduction mechanisms may lead to specific pharmacological tools for suppression of ectopic discharges in unmyelinated axotomized afferents, which probably contribute to neuropathic pain states.