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Latest Paper:
From the Departments of *Transplantation and Hepatobiliopancreatic Surgery and daggerDiagnostic and Interventional Radiology, Johannes Gutenberg University of Mainz, Mainz, Germany; and double daggerInstitute of Medical Biostatistics, Epidemiology and Informatics, Johannes Gutenberg University of Mainz, Mainz, Germany.
OBJECTIVE:: Aiming at avoidance of futile surgery, we have tested whether radiofrequency ablation (RFA) may be used as first-line treatment in patients with colorectal metastases (CRLM) occurring within the first year after colorectal surgery. SUMMARY BACKGROUND DATA:: Surgical resection is the standard treatment in patients with CRLM. Major retrospective analyses have identified the interval between colorectal surgery and the occurrence of CRLM to be of prognostic importance. So far, it is unknown whether survival of the respective patients is hampered if RFA is used as first-line treatment. METHODS:: According to a clinical pathway, we have treated patients with CRLM detected within the first year after colorectal surgery preferentially by RFA (n = 28). Resection (n = 82) was performed in patients who were deemed not amenable to RFA due to number, size, or location of metastatic lesions. The diameter of lesions differed between the groups. All other characteristics of patients and lesions were comparable. Local recurrence and new hepatic lesions were treated with repeated RFA or surgery whenever possible. RESULTS:: Local recurrence at the site of ablation or resection occurred in 32% and 4%(P < .001), new metastases apart from the site of previous treatment in 50% and 34%(P = .179), and systemic recurrence in 32% and 37%(P = .820) of the patients after RFA and surgery, respectively. Time to progression was significantly shorter in patients primarily treated with RFA (203 vs. 416 days; P = .017). After primary treatment, 9 RFA patients and 8 surgery patients were amenable to repeated RFA or repeated surgery resulting in identical rates of disease-free patients and identical 3-year overall survival in both treatment groups: 67% and 60%, respectively; P = .93. CONCLUSIONS:: Despite striking differences in local tumor recurrence and shorter time to progression, survival in patients with early CRLM does not depend on the mode of primary hepatic treatment.
Department of Obstetrics and Gynecology, University of Ulm Medical School, Ulm.
BACKGROUND: Standard treatment of patients with breast cancer decreases with age and older persons are mostly excluded from clinical trials. We hypothesized that non-adherence to treatment guidelines occurs for women aged >/=70 years and changes overall survival (OAS) and disease-free survival (DFS). PATIENTS AND METHODS: We enrolled 1922 women aged >/=50 years with histologically confirmed invasive breast cancer treated at the University of Ulm from 1992 to 2005. Adherence to guidelines and effects on OAS and DFS for women aged >/=70 years was compared with that for younger women (50-69 years). RESULTS: Women >70 years less often received recommended breast-conserving therapy (70-79 years: 74%-83%;>79 years: 54%) than women aged </=69 years (93%). Non-adherence to the guidelines on radiotherapy (<70 years: 9%; 70-79 years: 14%-27%;>79 years: 60%) and chemotherapy (<70 years: 33%; 70-79 years: 54%-77%;> 79 years: 98%) increased with age. Omission of radiotherapy significantly decreased OAS [</=69 years: hazard ratio (HR)= 3.29; P < .0001;>/=70 years: HR = 1.89; P = .0005] and DFS (</=69 years: HR = 3.45; P < .0001;>/=70 years: HR = 2.14; P < .0001). OAS and DFS did not differ significantly for adherence to surgery, chemotherapy, or endocrine therapy. CONCLUSION: Our study confirms that substandard treatment increases considerably with age. Omission of radiotherapy had the greatest impact on OAS and DFS in the elderly population.
Jochen Gensichen,
Michael von Korff,
Monika Peitz,
Christiane Muth,
Martin Beyer,
Corina Güthlin,
Marion Torge,
Juliana J Petersen,
Thomas Rosemann,
Jochem König,
Ferdinand M Gerlach
Institute for General Practice, Friedrich Schiller University/University Hospital Jena, Bachstrasse 18, D-07743 Jena, Germany. jochen.gensichen@med.uni-jena.de
BACKGROUND: Case management by health care assistants in small primary care practices provides unclear benefit for improving depression symptoms. OBJECTIVE: To determine whether case management provided by health care assistants in small primary care practices is more effective than usual care in improving depression symptoms and process of care for patients with major depression. DESIGN: Cluster randomized, controlled trial. A central automated system generated the randomization scheme, which was stratified by urban and rural practices; allocation sequence was concealed until groups were assigned. SETTING: 74 small primary care practices in Germany from April 2005 to September 2007. PATIENTS: 626 patients age 18 to 80 years with major depression. INTERVENTION: Structured telephone interview to monitor depression symptoms and support for adherence to medication, with feedback to the family physician. MEASUREMENTS: Depression symptoms at 12 months, as measured by the Patient Health Questionnaire-9 (PHQ-9); secondary outcomes were patient assessment of chronic illness care, adherence to medication, and quality of life. RESULTS: A total of 310 patients were randomly assigned to case management and 316 to usual care. At 12 months, 249 intervention recipients and 278 control patients were assessed; 555 patients were included in a modified intention-to-treat-analysis (267 intervention recipients vs. 288 control patients). Compared with control patients, intervention recipients had lower mean PHQ-9 values in depression symptoms (-1.41 [95% CI,-2.49 to - .33]; P = .014), more favorable assessments of care (3.41 vs. 3.11; P = .011), and increased treatment adherence (2.70 vs. 2.53; P = .042). Quality-of-life scores did not differ between groups. LIMITATION: Patients, health care assistants, family physicians, and researchers were not blinded to group assignment, and 12-month follow-up of patients was incomplete. CONCLUSION: Case management provided by primary care practice-based health care assistants may reduce depression symptoms and improve process of care for patients with major depression more than usual care. PRIMARY FUNDING SOURCE: German Ministry of Education and Research.
Institute of Experimental and Clinical Pharmacology and Toxicology, Clinical Pharmacology and Clinical Toxicology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
Aim: The uptake of drugs from the blood into the renal tubular cells is a key determinant for renal secretion and may influence their systemic plasma concentrations and extrarenal effects. Metformin, used for treatment of type 2 diabetes, is taken up into renal tubular cells by the organic cation transporter 2 (OCT2). Because many patients with type 2 diabetes receiving metformin are concomitantly treated with beta-blockers, we tested whether beta-blockers can inhibit OCT2-mediated drug transport. Method: Using Madin-Darby canine kidney II cells stably expressing the uptake transporter OCT2, we analysed whether the beta-blockers bisoprolol, carvedilol, metoprolol and propranolol inhibit the transport of OCT2 substrates 1-methyl-4-phenylpyridinium (MPP(+)) and metformin. Results: Neither bisoprolol nor metoprolol significantly inhibited the uptake of MPP(+), whereas a significant inhibition was observed for carvedilol und propranolol (half maximal inhibitory concentration IC(50): 26.3 and 67.5 muM) respectively. Moreover, all beta-blockers significantly inhibited OCT2-mediated metformin uptake (IC(50) for bisoprolol: 2.4 muM, IC(50) for carvedilol: 2.3 muM, IC(50) for metoprolol: 50.2 muM and IC(50) for propranolol: 8.3 muM). Conclusion: These in vitro results demonstrate that alterations of uptake transporter function by beta-blockers have to be considered as potential mechanisms underlying drug-drug interactions in the kidney.
Martin Danzer,
Helene Polin,
Johannes Pröll,
Reinhard Haunschmid,
Katja Hofer,
Stephanie Stabentheiner,
Christa Hackl,
Hedwig Kasparu,
Josef König,
Hanns Hauser,
Michaela Binder,
Richard Weiss,
Christian Gabriel,
Otto Krieger
1 Red Cross Transfusion Service of Upper Austria, Linz, Austria. 2 Federal Agency for Water Management, Mondsee, Austria. 3 First Department of Internal Medicine, Elisabethinen Hospital, Linz, Austria. 4 Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
BACKGROUND.: Hematopoietic stem-cell transplantation is a well-established treatment in various hematologic malignancies, but the outcome depends on disease relapse, infections, and the development and severity of acute and chronic graft-versus-host disease. Some evidence has revealed an important role for the nonclassical major histocompatibility complex class I molecules in transplantation, most notably human leukocyte antigen (HLA)-E. This study evaluates the impact of HLA-E alleles on transplantation outcome after HLA-matched allogeneic HSCT. METHODS.: We genotyped DNA for HLA-E polymorphism from 83 recipients and their respective donors by real-time polymerase chain reaction after melting curve analysis and compared the results with clinical outcome. RESULTS.: HLA-E*0103 homozygous patients showed a higher probability of overall survival (P= .003) and disease-free survival (P= .001) in a univariate model. Cox regression analysis confirmed HLA-E*0103, 0103 (P= .006; relative risk 1.12; 95% confidence interval .31-1.94) and early stage of disease (P= .005; relative risk 1.16; 95% confidence interval .45-1.86) as independent factors improving overall survival. Moreover, homozygosity for HLA-E*0103 was associated with a significant decreased incidence of transplant-related mortality (P= .01). CONCLUSIONS.: We found an association between HLA-E*0103 homozygosity and the significant reduction of transplant-related mortality in related and unrelated HSCT. The risk of posttransplant complications was significantly reduced when the donor possesses the HLA-E*0103, 0103 genotype, and this was translated in a better overall survival.
We report on time-resolved measurements of the plasma evolution during metal ablation with ultrashort laser pulses in the range from 200 fs to 3.3 ps. The plasma transmission exhibits two distinctive minima. Almost total attenuation is observed a few nanoseconds after the ablation pulse, while a second decrease of the transmission to approximately 50% is observed after about 150 ns. Images taken with a gated ICCD-camera confirm these data and allow determining the expansion velocity of the plasma plume. The attenuation in the first nanoseconds can be attributed to electrons and sublimated mass emitted from the target surface, while attenuation after several 10 ns is due to particles and droplets after a thermal boiling process. The possibility of a normal or an explosive boiling process, also called phase explosion, is discussed. Despite of the physical insight into the ablation process, these data provide valuable information for scaling the speed of ultrashort pulse laser materials processing in a fluence regime of several J/cm2 since they allow estimating the maximum usable pulse repetition rate.
Friedrich-Alexander-University Erlangen-Nuremberg, Institute of Experimental and Clinical Pharmacology and Toxicology, Department of Clinical Pharmacology and Clinical Toxicology, Fahrstrasse 17, D-91054 Erlangen, Germany +49 9131 8522077 ;+49 9131 8522773 ; joerg.koenig@pharmakologie.med.uni-erlangen.de.
Background: Transport proteins, for example the drug export pump P-glycoprotein, are important for the absorption, distribution and excretion of drugs. Inhibition and induction of P-glycoprotein efflux function is a well-established mechanism of drug-drug interactions. Alteration of transporter-mediated drug uptake by concomitantly administered drugs may also result in a change in drug pharmacokinetics. These uptake transporter-mediated drug-drug interactions are the focus of this review. Objective: To examine the current in vitro evidence on interactions mediated by OATPs (organic anion transporting polypeptides) and OCTs (organic cation transporters). Methods: Comparing data of in vivo observed drug-drug interactions with in vitro analysed alterations in drug transport mediated by the hepatic expressed uptake transporters OATP1B1, OATP1B3 and OCT1 and by the renal expressed OCT2 protein. Results/conclusions: Some of the previously in vivo described drug-drug interactions could be explained by alteration in uptake transporter function demonstrating that inhibition or induction of uptake transporters is a newly recognised mechanism of potential drug-drug interactions.
University of Erlangen-Nuremberg.
The organic cation transporter 2 (OCT2, SLC22A2) plays an important role for renal drug elimination. Recent clinical studies indicate an impact of the frequent non-synonymous c.808G>T (p.270Ala>Ser) polymorphism on renal clearance of metformin and the extent of the metformin-cimetidine interaction. The role of this polymorphism for renal disposition of endogenous compounds and drugs other than metformin has not been investigated. In addition, it is unclear whether the observed genotype-dependence of an OCT2-mediated drug-drug interaction might occur also with other OCT inhibitors. To address these issues we generated HEK cells stably expressing wildtype OCT2 or the p.270Ala>Ser variant. No differences in protein expression levels and membrane incorporation pattern were observed between the two cell lines. The p.270Ala>Ser variant significantly impaired uptake kinetics of MPP(+), dopamine, norepinephrine, and propranolol. Vmax values were significantly reduced for all four compounds mediated by the p.270Ala>Ser variant compared to wildtype OCT2. In addition, a significant difference in the affinity to wildtype and mutant OCT2 was observed for dopamine (Km dopamine: 932+/-77 vs 1285+/-132 microM). Moreover, out of a set of 27 compounds p.270Ala>Ser OCT2 was significantly less sensitive to inhibition by cimetidine, flurazepam, metformin, mexiletine, propranolol, and verapamil than wildtype OCT2 (e.g. for propranolol: IC50 wildtype vs p.270Ala>Ser 189 vs 895 microM, P< .001). Our results indicate that the common OCT2 c.808G>T SNP significantly alters uptake of endogenous compounds and drugs. Moreover, for selected compounds the extent of OCT2-mediated drug interactions could depend on OCT2 c.808G>T genotype.
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Fahrstr. 17, 91054, Erlangen, Germany, zolk@pharmakologie.uni-erlangen.de.
The organic cation transporter 2 (OCT2) provides an important pathway for the uptake of cationic compounds in the kidney, which is the essential step in their elimination from the organism. Although many drugs have been identified which interact with human OCT2, structural elements required for an interaction with OCT2 are not well defined. To address this issue, HEK293 cells stably expressing human OCT2 were generated. IC(50) values of commonly used drugs for inhibition of [(3)H]MPP(+) uptake were determined and correlated with physicochemical descriptors. We found only a significant correlation between the topological polar surface area (TPSA) and IC(50) values (r = .71, p < .0001). Structural alignment of most potent inhibitor drugs of OCT2-mediated MPP(+) uptake was used to construct a two-point pharmacophore consisting of an ion-pair interaction site and a hydrophobic aromatic site separated by 5. A. Taken together, our data identify structural determinants for inhibitor interactions with OCT2.
Department of Obstetrics and Gynecology, Ulm University Medical Center, Prittwitzstrasse 43, 89075, Ulm, Germany, daherr@gmx.de.
Currently the prognostic value of lymphovascular space involvement (LVSI) in patients with cervical cancer is unclear. We evaluated the prognostic impact of different categories of LVSI on overall survival (OAS) and disease-free survival (DFS) in a Middle-European population of women with surgically staged, early cervical cancer. The records of 281 women with clinically and histologically diagnosed early cervical cancer undergoing primary surgical treatment at the University of Ulm School of Medicine between 1992 and 2006 were retrospectively reviewed. LVSI as determined by hematoxylin-eosin staining was topographically categorized as conjoined-LVSI and satellite-LVSI. The effect of LVSI, tumor stage, lymph node metastases, and histology on OAS and DFS was assessed by Cox regression analyses. Tumor size and nodal status could be confirmed as significant prognostic factors for OAS and DFS in early-stage cervical cancer. While no significant effect of LVSI in general (satellite-LVSI or conjoined-LVSI) on OAS and DFS was calculated, the presence of satellite-LVSI was associated with significant decreased rates of both, OAS and DFS. We propose satellite-LVSI as new risk factor for patients with early-stage cervical cancer, in order to better identify the patients urgently needing adjuvant therapy.
