OBJECTIVE::ablation Aiming at avoidance of futile surgery, we have tested whether radiofrequency ablation (RFA) may be used as first-line treatment in and patients with colorectal metastases (CRLM) occurring within the first year after colorectal surgery. SUMMARY BACKGROUND DATA:: Surgical resection is the the standard treatment in patients with CRLM. Major retrospective analyses have identified the interval between colorectal surgery and the occurrence of (n CRLM to be of prognostic importance. So far, it is unknown whether survival of the respective patients is hampered if mode RFA is used as first-line treatment. METHODS:: According to a clinical pathway, we have treated patients with CRLM detected within patients the first year after colorectal surgery preferentially by RFA (n = 28). Resection (n = 82) was performed in patients hepatic who were deemed not amenable to RFA due to number, size, or location of metastatic lesions. The diameter of lesions whenever differed between the groups. All other characteristics of patients and lesions were comparable. Local recurrence and new hepatic lesions were the treated with repeated RFA or surgery whenever possible. RESULTS:: Local recurrence at the site of ablation or resection occurred in not 32% and 4%(P < .001), new metastases apart from the site of previous treatment in 50% and 34%(P as = .179), and systemic recurrence in 32% and 37%(P = .820) of the patients after RFA and surgery, respectively.treatment Time to progression was significantly shorter in patients primarily treated with RFA (203 vs. 416 days; P = .017). After of primary treatment, 9 RFA patients and 8 surgery patients were amenable to repeated RFA or repeated surgery resulting in identical metastases 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 not depend on the mode of primary hepatic treatment.

BACKGROUND:years: Standard treatment of patients with breast cancer decreases with age and older persons are mostly excluded from clinical trials. We < .0001; hypothesized that non-adherence to treatment guidelines occurs for women aged >/=70 years and changes overall survival (OAS) and disease-free survival We (DFS). PATIENTS AND METHODS: We enrolled 1922 women aged >/=50 years with histologically confirmed invasive breast cancer treated at the aged University of Ulm from 1992 to 2005. Adherence to guidelines and effects on OAS and DFS for women aged >/=70 in years was compared with that for younger women (50-69 years). RESULTS: Women >70 years less often received recommended breast-conserving therapy breast (70-79 years: 74%-83%;>79 years: 54%) than women aged </=69 years (93%). Non-adherence to the guidelines on radiotherapy (<70 years:elderly 9%; 70-79 years: 14%-27%;>79 years: 60%) and chemotherapy (<70 years: 33%; 70-79 years: 54%-77%;> 79 years: 98%) increased years: with age. Omission of radiotherapy significantly decreased OAS [</=69 years: hazard ratio (HR)= 3.29; P < .0001;>/=70 years: HR in = 1.89; P = .0005] and DFS (</=69 years: HR = 3.45; P < .0001;>/=70 years: HR = 2.14; P (50-69 < .0001). OAS and DFS did not differ significantly for adherence to surgery, chemotherapy, or endocrine therapy. CONCLUSION: Our study confirms the that substandard treatment increases considerably with age. Omission of radiotherapy had the greatest impact on OAS and DFS in the persons elderly population.

BACKGROUND:249 Case management by health care assistants in small primary care practices provides unclear benefit for improving depression symptoms. OBJECTIVE: To to determine whether case management provided by health care assistants in small primary care practices is more effective than usual care assistants in improving depression symptoms and process of care for patients with major depression. DESIGN: Cluster randomized, controlled trial. A central interview automated system generated the randomization scheme, which was stratified by urban and rural practices; allocation sequence was concealed until groups Ministry were assigned. SETTING: 74 small primary care practices in Germany from April 2005 to September 2007. PATIENTS: 626 patients age concealed 18 to 80 years with major depression. INTERVENTION: Structured telephone interview to monitor depression symptoms and support for adherence to and medication, with feedback to the family physician. MEASUREMENTS: Depression symptoms at 12 months, as measured by the Patient Health Questionnaire-9 management (PHQ-9); secondary outcomes were patient assessment of chronic illness care, adherence to medication, and quality of life. RESULTS: A total German of 310 patients were randomly assigned to case management and 316 to usual care. At 12 months, 249 intervention recipients the and 278 control patients were assessed; 555 patients were included in a modified intention-to-treat-analysis (267 intervention recipients vs. 288 control 74 patients). Compared with control patients, intervention recipients had lower mean PHQ-9 values in depression symptoms (-1.41 [95% CI,-2.49 to OBJECTIVE: - .33]; P = .014), more favorable assessments of care (3.41 vs. 3.11; P = .011), and increased treatment adherence (2.70 automated vs. 2.53; P = .042). Quality-of-life scores did not differ between groups. LIMITATION: Patients, health care assistants, family physicians, and included researchers were not blinded to group assignment, and 12-month follow-up of patients was incomplete. CONCLUSION: Case management provided by primary (2.70 care practice-based health care assistants may reduce depression symptoms and improve process of care for patients with major depression more family than usual care. PRIMARY FUNDING SOURCE: German Ministry of Education and Research.

Aim:bisoprolol The uptake of drugs from the blood into the renal tubular cells is a key determinant for renal secretion and muM) may influence their systemic plasma concentrations and extrarenal effects. Metformin, used for treatment of type 2 diabetes, is taken up renal into renal tubular cells by the organic cation transporter 2 (OCT2). Because many patients with type 2 diabetes receiving metformin beta-blockers are concomitantly treated with beta-blockers, we tested whether beta-blockers can inhibit OCT2-mediated drug transport. Method: Using Madin-Darby canine kidney II in cells stably expressing the uptake transporter OCT2, we analysed whether the beta-blockers bisoprolol, carvedilol, metoprolol and propranolol inhibit the transport transporter of OCT2 substrates 1-methyl-4-phenylpyridinium (MPP(+)) and metformin. Results: Neither bisoprolol nor metoprolol significantly inhibited the uptake of MPP(+), whereas a the significant inhibition was observed for carvedilol und propranolol (half maximal inhibitory concentration IC(50): 26.3 and 67.5 muM) respectively. Moreover, all (MPP(+)) 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 interactions muM and IC(50) for propranolol: 8.3 muM). Conclusion: These in vitro results demonstrate that alterations of uptake transporter function by canine beta-blockers have to be considered as potential mechanisms underlying drug-drug interactions in the kidney.

BACKGROUND.:regression Hematopoietic stem-cell transplantation is a well-established treatment in various hematologic malignancies, but the outcome depends on disease relapse, infections, and factors the development and severity of acute and chronic graft-versus-host disease. Some evidence has revealed an important role for the nonclassical infections, major histocompatibility complex class I molecules in transplantation, most notably human leukocyte antigen (HLA)-E. This study evaluates the impact of polymorphism HLA-E alleles on transplantation outcome after HLA-matched allogeneic HSCT. METHODS.: We genotyped DNA for HLA-E polymorphism from 83 recipients and a their respective donors by real-time polymerase chain reaction after melting curve analysis and compared the results with clinical outcome. RESULTS.:antigen 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 overall 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 (P= .001) 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 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 real-time transplant-related mortality in related and unrelated HSCT. The risk of posttransplant complications was significantly reduced when the donor possesses the evaluates HLA-E*0103, 0103 genotype, and this was translated in a better overall survival.

We surface, report on time-resolved measurements of the plasma evolution during metal ablation with ultrashort laser pulses in the range from 200 an fs to 3.3 ps. The plasma transmission exhibits two distinctive minima. Almost total attenuation is observed a few nanoseconds after in the ablation pulse, while a second decrease of the transmission to approximately 50% is observed after about 150 ns. Images taken taken with a gated ICCD-camera confirm these data and allow determining the expansion velocity of the plasma plume. The attenuation pulse in the first nanoseconds can be attributed to electrons and sublimated mass emitted from the target surface, while attenuation after pulse, several 10 ns is due to particles and droplets after a thermal boiling process. The possibility of a normal or repetition an explosive boiling process, also called phase explosion, is discussed. Despite of the physical insight into the ablation process, these emitted data provide valuable information for scaling the speed of ultrashort pulse laser materials processing in a fluence regime of several pulse J/cm2 since they allow estimating the maximum usable pulse repetition rate.

Background:of Transport proteins, for example the drug export pump P-glycoprotein, are important for the absorption, distribution and excretion of drugs. Inhibition OATP1B1, and induction of P-glycoprotein efflux function is a well-established mechanism of drug-drug interactions. Alteration of transporter-mediated drug uptake by concomitantly absorption, administered drugs may also result in a change in drug pharmacokinetics. These uptake transporter-mediated drug-drug interactions are the focus of drug-drug this review. Objective: To examine the current in vitro evidence on interactions mediated by OATPs (organic anion transporting polypeptides) and potential OCTs (organic cation transporters). Methods: Comparing data of in vivo observed drug-drug interactions with in vitro analysed alterations in drug by transport mediated by the hepatic expressed uptake transporters OATP1B1, OATP1B3 and OCT1 and by the renal expressed OCT2 protein. Results/conclusions:interactions. Some of the previously in vivo described drug-drug interactions could be explained by alteration in uptake transporter function demonstrating that transporters). inhibition or induction of uptake transporters is a newly recognised mechanism of potential drug-drug interactions.

The mediated organic cation transporter 2 (OCT2, SLC22A2) plays an important role for renal drug elimination. Recent clinical studies indicate an impact Moreover, 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 the role of this polymorphism for renal disposition of endogenous compounds and drugs other than metformin has not been investigated. In we addition, it is unclear whether the observed genotype-dependence of an OCT2-mediated drug-drug interaction might occur also with other OCT inhibitors.on To address these issues we generated HEK cells stably expressing wildtype OCT2 or the p.270Ala>Ser variant. No differences in protein In expression levels and membrane incorporation pattern were observed between the two cell lines. The p.270Ala>Ser variant significantly impaired uptake kinetics c.808G>T of MPP(+), dopamine, norepinephrine, and propranolol. Vmax values were significantly reduced for all four compounds mediated by the p.270Ala>Ser variant significantly compared to wildtype OCT2. In addition, a significant difference in the affinity to wildtype and mutant OCT2 was observed for depend dopamine (Km dopamine: 932+/-77 vs 1285+/-132 microM). Moreover, out of a set of 27 compounds p.270Ala>Ser OCT2 was significantly less variant. sensitive to inhibition by cimetidine, flurazepam, metformin, mexiletine, propranolol, and verapamil than wildtype OCT2 (e.g. for propranolol: IC50 wildtype vs whether 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 elimination. compounds and drugs. Moreover, for selected compounds the extent of OCT2-mediated drug interactions could depend on OCT2 c.808G>T genotype.

The only organic cation transporter 2 (OCT2) provides an important pathway for the uptake of cationic compounds in the kidney, which is Structural the essential step in their elimination from the organism. Although many drugs have been identified which interact with human OCT2,of structural elements required for an interaction with OCT2 are not well defined. To address this issue, HEK293 cells stably expressing To human OCT2 were generated. IC(50) values of commonly used drugs for inhibition of [(3)H]MPP(+) uptake were determined and correlated with interactions physicochemical descriptors. We found only a significant correlation between the topological polar surface area (TPSA) and IC(50) values (r =interact .71, p < .0001). Structural alignment of most potent inhibitor drugs of OCT2-mediated MPP(+) uptake was used to construct a OCT2. two-point pharmacophore consisting of an ion-pair interaction site and a hydrophobic aromatic site separated by 5. A. Taken together, our physicochemical data identify structural determinants for inhibitor interactions with OCT2.

Currently was the prognostic value of lymphovascular space involvement (LVSI) in patients with cervical cancer is unclear. We evaluated the prognostic impact While of different categories of LVSI on overall survival (OAS) and disease-free survival (DFS) in a Middle-European population of women with evaluated surgically staged, early cervical cancer. The records of 281 women with clinically and histologically diagnosed early cervical cancer undergoing primary Ulm surgical treatment at the University of Ulm School of Medicine between 1992 and 2006 were retrospectively reviewed. LVSI as determined needing by hematoxylin-eosin staining was topographically categorized as conjoined-LVSI and satellite-LVSI. The effect of LVSI, tumor stage, lymph node metastases, and records histology on OAS and DFS was assessed by Cox regression analyses. Tumor size and nodal status could be confirmed as adjuvant significant prognostic factors for OAS and DFS in early-stage cervical cancer. While no significant effect of LVSI in general (satellite-LVSI histology or conjoined-LVSI) on OAS and DFS was calculated, the presence of satellite-LVSI was associated with significant decreased rates of both,urgently OAS and DFS. We propose satellite-LVSI as new risk factor for patients with early-stage cervical cancer, in order to better were identify the patients urgently needing adjuvant therapy.