Outcome of kidney transplantations from ≥65-year-old deceased donors with acute kidney injury.

Kidney transplantation (KT) from donors with acute kidney injury (AKI) has been associated with delayed graft function (DGF) but similar graft survival compared with KT from donors without AKI. Kidneys from ≥65-year-old donors with comorbidities are more susceptible to cold ischemia time (CIT) and DGF and it is unknown whether such elderly kidneys with AKI can also be transplanted with satisfactory outcomes. All KTs from ≥65-year-old donors performed at our center from 1999 to 2019 (n = 233) were retrospectively analyzed and short- as well as long-term outcomes were compared for KTs from donors with (n = 64) and without AKI (n = 169). There were no significant differences regarding the frequency of DGF as well as the estimated glomerular filtration rate (eGFR) 1 and 3 years post-transplant between the no-AKI and the AKI group (DGF: no-AKI 30.2% vs. AKI 40.6%, P = .17; eGFR at 1-year: 31.9 ml/min/1.73 m2 vs. 35.5 ml/min/1.73 m2 , P = .32; at 3-years: 33.8 ml/min/1.73 m2 vs. 40.9 ml/min/1.73 m2 , P = .18; respectively). Death-censored graft survival and patient survival were also not significantly different. Multivariable Cox regression analysis did not identify AKI as a significant risk factor for graft loss or death. Following careful donor and recipient selection, kidneys from ≥65-year-old AKI donors may potentially be transplanted with satisfactory outcomes.

Impact of the explanting surgeon's impression of donor arteriosclerosis on outcome of kidney transplantations from donors aged ≥65 years.

PURPOSE: Careful donor selection is important for kidney transplantations (KT) from suboptimal donors aged ≥65 years. Several tools such as histopathological assessment of preimplant biopsies have been shown to predict allograft survival and can be applied for selection. Whether the explanting surgeon's appraisal is associated with outcomes of KTs from suboptimal donors is unknown. METHODS: We compared outcomes of KTs from ≥65-year-old deceased donors performed at our centre between 1999 and 2018 for which grading of macroscopic 'donor arteriosclerosis' (n=104) and 'organ quality' (n=208) as judged by the explanting surgeon and documented on the Eurotransplant kidney organ report was available. RESULTS: No association was observed between degree of macroscopic donor arteriosclerosis and death-censored graft survival in univariable or multivariable regression analyses. Compared to KTs from donors with no/mild arteriosclerosis, KTs from donors with moderate/severe arteriosclerosis were associated with a significantly impaired allograft function 3 months, 1 year and 3 years after transplantation (e.g. at 3 years: 176.8 µmol/l vs 137.0 µmol/l, P=0.003). Following multivariable regression analysis, these differences remained significant at 3 months and 3 years after KT. No association was observed between degree of macroscopic arteriosclerosis and mortality or primary non-function as well as no consistent association with delayed graft function and histological arteriosclerosis. Assessment of 'organ quality' was not associated with outcomes. CONCLUSION: Our data suggest that the explanting surgeon's assessment of donor arteriosclerosis is associated with allograft function. Larger studies and better standardization of kidney inspection after explantation are required to further explore the impact of surgeon's appraisal in KT.

The Importance of Clinical Data for the Diagnosis of Breast Tumours in North Afghanistan.

BACKGROUND: This study was performed in knowledge of the increasing gap between breast disease treatment in countries with restricted resources and developed countries with increasingly sophisticated examination methods. METHODS: The authors present the analysis of a breast disease register consisting of diagnostic cases from Mazar e Sharif and Herat in 2018 and 2019. The study comprises a total of 567 cases, which were presented to experts via telemedicine for final diagnosis. 62 cases (10.9%) were excluded due to inacceptable data or insufficient image quality. These data provided by daily diagnostic classification were used for the built-up of a profile for each frequent breast disease and a breast cancer register. All images and cases were seen by at least 3 independent experts. The diagnoses were made in 60% of cases by cytology of fine needle aspiration and in 40% by histological images. RESULTS: For each entity of breast diseases (e.g., fibroadenoma), a profile of context variables was constructed allowing to assist medical decisions, as "wait and see," elective surgery or immediate surgical intervention with R0 (complete) resection. These "profiles" could be described for fibroadenoma, mastitis, galactocele, fibrous-cystic disease, and invasive breast cancer. CONCLUSIONS: The presented preliminary data set could serve as a cost-effective basis for a North Afghan breast cancer registry, with option to extent to a national model. These preliminary data are transformed in profiles of breast diseases, which are used by the local physicians in charge of breast disease patients. Each new case can be compared by the local treating physician with the profile of all preceded cases with the same diagnosis.

Impact of cardiopulmonary resuscitation on outcome of kidney transplantations from braindead donors aged ≥65 years.

INTRODUCTION: Patients with a history of cardiopulmonary resuscitation (CPR) and subsequent brain death are frequently evaluated for organ donation. Whether kidneys from ≥65-year-old braindead donors with a history of CPR can be transplanted with satisfactory outcomes is unknown. MATERIAL & METHODS: All kidney transplants (KTs) from ≥65-year-old donors performed at our center from 1999 to 2018 (n = 185) were retrospectively analyzed and outcome was compared for KTs from donors with and without a history of CPR (n = 27 and n = 158, respectively). RESULTS: No significant differences in the incidence of delayed graft function (DGF) as well as 1- and 3-year graft function were observed between the CPR and the no-CPR group (DGF: 26.0% vs. 31.0%, p = .76; 1-year serum creatinine: 150.4 µmol/L vs. 177.0 µmol/L, p = .11; 3-year serum creatinine: 150.4 µmol/L vs. 168.2 µmol/L, p = .52, respectively). Death-censored graft survival was comparable after 1 and 5 years (CPR group: 81.5% and 76.7% vs. no-CPR group: 86.6% and 75.7%, p = .70). Likewise, patient survival was not significantly different. Multivariable Cox regression analysis also did not identify CPR as a significant risk factor for graft loss or death. CONCLUSION: Our study suggests that, following stringent donor selection, the outcome of KTs from ≥65-year-old braindead donors with and without a history of CPR is comparable.

Refined risk stratification for thoracoscopic lobectomy or segmentectomy.

BACKGROUND: Given the wide adoption of thoracoscopic lobectomy and positive effect of the thoracoscopic approach for improving postoperative outcomes, questions have arisen regarding the validity of previously published risk assessment models. We sought to review the reliability of the established predictors for patients undergoing thoracoscopic lobectomy. METHODS: From January 2009 to May 2017, 606 patients (275 women, 331 men; median age 67 years) underwent thoracoscopic lobectomy or segmentectomy for confirmed or suspected early-stage lung cancer or metastasis at our institution. Logistic regression analyses were performed to determine the predictors of postoperative complications, followed by assessments of causal inference. RESULTS: The postoperative mortality, pulmonary complication, cardiovascular complication and overall morbidity rates were 1.0%, 8.9%, 5.8% and 18.0%, respectively. While the American Society of Anesthesiologists physical status (ASA-PS) emerged as an independent morbidity predictor, only a slightly significant association between lung function determinants and overall morbidity was found in the univariable regression analyses. Regarding causal inference, inverse probability of treatment weighting using propensity scores revealed 2- and 1.7-fold increases in the odds of cardiopulmonary complications and overall morbidity in patients with ASA-PS grade 3 or 4 compared with those with ASA-PS grade 1 or 2 (OR =2.116, 95% CI: 1.252-3.577, P=0.005; OR =1.740, 95% CI: 1.095-2.765, P=0.019, respectively). CONCLUSIONS: Our results suggested that the current physiologic evaluation algorithm is also applicable to major lung resection via thoracoscopic approach. ASA-PS is an easily assessable factor capable of predicting major complications following thoracoscopic lobectomy in patients properly selected in compliance with the current guideline. It is recommended to incorporate the ASA-PS into the existing algorithm for more accurate risk stratification in this patient population.

Preoperative serum lactate dehydrogenase level as a predictor of major complications following thoracoscopic lobectomy: a propensity-adjusted analysis.

OBJECTIVES: Despite the positive effects of a thoracoscopic approach on improving postoperative outcomes, the risk of major complications following thoracoscopic lobectomy is not negligible. We sought to assess the usefulness of the preoperative determination of serum biomarkers to refine risk stratification in this patient population. METHODS: From 2009 to 2017, 626 patients (285 women, 341 men; median age: 67 years) underwent thoracoscopic lobectomy or anatomical segmentectomy for confirmed or suspected early-stage lung cancer or metastasis at our institution. Preoperative serum biomarkers, including albumin, C-reactive protein, haemoglobin and lactate dehydrogenase (LDH), were examined as predictors of postoperative cardiopulmonary complications using logistic regression analyses followed by causal inference. RESULTS: The 90-day mortality, cardiopulmonary complication and overall morbidity rates were 1.0%, 13.1% and 18.1%, respectively. Although serum albumin, C-reactive protein and haemoglobin were not associated with cardiopulmonary complications in regression analyses, preoperative serum LDH level emerged as an independent morbidity predictor (odds ratio 1.008, 95% confidence interval 1.002-1.013; P = 0.006). The causal inference using the covariate balancing generalized propensity score methodology demonstrated similar results and an approximately positive linear relationship between the odds of cardiopulmonary complications and preoperative serum LDH level. For every 100 U/l increase in preoperative serum LDH, a 2-fold increase in the odds of cardiopulmonary complications was observed. CONCLUSIONS: Our results suggest that the preoperative serum LDH level is an independent predictor of 90-day cardiopulmonary complications following thoracoscopic lobectomy or segmentectomy, even in properly selected patients. Therefore, we recommend incorporating early serum LDH measurements as a readily available method into the risk assessment process prior to major lung resection.

Strong Associations Between Inflammation, Pruritus and Mental Health in Dialysis Patients.

Pruritus, impaired mental health and inflammation contribute to morbidity in end-stage renal disease. There are no studies on all 3 conditions. We therefore obtained inflammatory parameter data (C-reactive protein and interleukin-6), pruritus data and psychological test data (36-Item Short-Form Health Survey, "Allgemeine Depressionsskala" and Toronto Alexithymia Scale-20) for 19 dialysis patients with pruritus, 20 dialysis patients without pruritus and 15 healthy controls. Non-parametric hierarchical clustering revealed 3 clusters of parameters: one mainly driven by pruritus scores (chronic kidney disease-associated pruritus cluster), one by mental health scores (mental health cluster) and one by inflammatory parameters (inflammatory cluster). Factor analysis showed strong associations (mental health cluster/chronic kidney disease-associated pruritus cluster, r=-0.49; mental health cluster/inflammatory cluster, r=-0.52; inflammatory cluster/chronic kidney disease-associated pruritus cluster, r=0.48). For the first time, complete correlations between inflammation, mental health and pruritus in dialysis patients have been established. As all 3 conditions are associated with mortality, knowledge about their interdependence helps to understand end-stage renal disease pathophysiology.

Impact of comorbidity burden on morbidity following thoracoscopic lobectomy: a propensity-matched analysis.

BACKGROUND: Given the positive effect of a thoracoscopic approach on improving postoperative outcomes, it is reasonable to speculate whether an increased comorbidity burden is related to higher morbidity following thoracoscopic lobectomy. We sought to evaluate the impact of comorbidity burden on adverse postoperative outcomes in this patient population. METHODS: A retrospective review of our institutional database included 512 patients undergoing thoracoscopic lobectomy for early-stage non-small cell lung cancer (NSCLC) from 2009 through 2016. Comorbidity burden was assessed by the Charlson comorbidity index (CCI) and classified as high (CCI ≥3) or low (CCI <3) grade. Propensity score matching and random effects model were performed. RESULTS: Patients included 228 women and 284 men with a median age of 67 years. High and low comorbidity burdens were found in 193 and 319 patients, respectively. The postoperative mortality, pulmonary and cardiovascular complication rates and overall morbidity in patients with high comorbidity burden were comparable to those with low comorbidity burden (1.6% vs. 0.6%, 9.3% vs. 8.5%, 6.2% vs. 6.0%, 24.4% vs. 22.9%, respectively). Similar results were seen after propensity score matching, which balanced differences in demographics and preoperative characteristics between the comorbidity groups. On the analyses of propensity-matched data using generalized linear mixed model, a high comorbidity burden was not related to greater postoperative complication rates. CONCLUSIONS: Our results suggest that thoracoscopic lobectomy can be performed with low mortality and reasonable morbidity in lung cancer patients presenting with multiple comorbid diseases. The presence of a high comorbidity burden measured by CCI does not have a perceptible impact on adverse postoperative outcomes following thoracoscopic lobectomy.

Is Mistletoe Treatment Beneficial in Invasive Breast Cancer? A New Approach to an Unresolved Problem.

BACKGROUND/AIM: In this retrospective study, we compared breast cancer patients treated with and without mistletoe lectin I (ML-I) in addition to standard breast cancer treatment in order to determine a possible effect of this complementary treatment. PATIENTS AND METHODS: This study included 18,528 patients with invasive breast cancer. Data on additional ML-I treatments were reported for 164 patients. We developed a "similar case" method with a distance measure retrieved from the beta variable in Cox regression to compare these patients, after stage adjustment, with their non-ML-1 treated counterparts in order to answer three hypotheses concerning overall survival, recurrence free survival and life quality. RESULTS: Raw data analysis of an additional ML-I treatment yielded a worse outcome (p=0.02) for patients with ML treatment, possibly due to a bias inherent in the ML-I-treated patients. Using the "similar case" method (a case-based reasoning approach) we could not confirm this harm for patients using ML-I. Analysis of life quality data did not demonstrate reliable differences between patients treated with ML-I treatment and those without proven ML-I treatment. CONCLUSION: Based on a "similar case" model we did not observe any differences in the overall survival (OS), recurrence-free survival (RFS), and quality of life data between breast cancer patients with standard treatment and those who in addition to standard treatment received ML-I treatment.

American Society of Anesthesiologists physical status facilitates risk stratification of elderly patients undergoing thoracoscopic lobectomy.

OBJECTIVES: Accurate risk assessments are particularly important for elderly patients being considered for lobectomy. Considering the positive effects of the thoracoscopic approach on postoperative outcomes, we sought to review the reliability of the established risk factors for elderly patients undergoing thoracoscopic lobectomy. METHODS: From January 2009 to March 2016, 441 patients in our institution underwent thoracoscopic lobectomy for early-stage lung cancer. Clinical outcomes were compared between elderly (>70 years, n = 176) and younger patients (n = 265). RESULTS: There was no significant difference in postoperative mortality and morbidity between elderly and younger patients. In the regression analyses restricted to elderly patients, American Society of Anesthesiologists physical status (ASA-PS) was the single strong predictor of postoperative morbidity. The odds of pulmonary and cardiopulmonary complications increased nearly 6- and 3-fold, respectively, in those with ASA-PS Grade 3 compared with patients with ASA-PS Grade <3. Additionally, male gender was found to have a possible causal effect of pulmonary complication in elderly patients. After confounder adjustment using propensity score matching, the generalized linear mixed model revealed more than an 8-fold increase in the odds of pulmonary complications in elderly men compared with elderly women. To check the robustness of the above-mentioned finding, inverse probability of treatment weighting was used as an alternative analysis indicating a weaker but still substantively significant effect of male gender, with an odds ratio >3. CONCLUSIONS: Our results suggest that ASA-PS is a strong predictor of morbidity among elderly patients considered for thoracoscopic lobectomy. Compared with elderly women, elderly men are particularly prone to postoperative pulmonary complications.

The Influence of Thyroid Function, Inflammation, and Obesity on Risk Prediction of Acute Kidney Injury by Cystatin C in the Emergency Department.

BACKGROUND/AIMS: There is a growing role for emergency departments (ED) in assessing acute kidney injury (AKI) for hospital admissions but there are few studies addressing acute kidney injury biomarkers and confounding factors in the ED. Cystatin C (CysC), a newer renal biomarker, is influenced by thyroid function, inflammation and obesity. This study aims to be the first study to address the impact of these parameters in the ED. METHODS: Admitted patients (n=397) were enrolled in the ED at Robert-Bosch-Hospital, Stuttgart, Germany. Daily serum creatinine (sCr) was recorded for AKI classification by Kidney Diseases Improves Global Outcome (KDIGO) criteria. CysC, thyroid stimulating hormone (TSH), thyroxine (T4), C-reactive protein (CRP) and body mass index (BMI) were registered at enrollment in the ED. Serum samples were collected at enrollment, after 6 hours and in the following mornings (day 1 to day 3). The correlation of CysC and sCr was studied on a two variable logistic regression model. A linear predictor was computed to predict minimal AKI stage and area under the curve (AUC) was calculated. RESULTS: Of 397 patients enrolled for classification by KDIGO AKI criteria, n=152 (38%) developed AKI, n=69 (17.4%) reached AKI stage I, n=70 (17.6%) AKI stage II, and n=13 (3%) AKI stage III. Although a correlation between CRP and CysC levels was shown (rho=0.376), this didn't affect the predictive ability for AKI according to our data. We compared receiver operating characteristic (ROC) curves (DeLong test) of CysC to ROC curves of CysC with the additional variables TSH, BMI, and CRP respectively. Our data shows that addition of CRP, TSH, or BMI does not improve prediction of AKI stage beyond prediction based solely on CysC levels. CONCLUSIONS: CysC is known to be influenced by thyroid function, inflammation and obesity, but in our large ED population there was no significant impact of these factors on the diagnostic accuracy of CysC to detect AKI in ED patients.

Postoperative survival of lung cancer patients: are there predictors beyond TNM?

BACKGROUND/AIM: We report on survival data of 595 patients with stage I-III lung cancer with respect to TNM classification. MATERIALS AND METHODS: We constructed a basic model consisting of stage and grade, and assessed the improvement of survival prediction after adding comorbidity data, spirometric data, clinical and laboratory parameters. RESULTS: Body mass index (BMI) and presence of a cardiac disease reached statistical significance for prediction of overall survival in a Cox regression model. In addition to BMI (<25 kg/m(2)) and the presence of cardiovascular disease, the spirometric variable (FEV1) predicted early death (less than five months postoperatively). When the survival random forest method was employed to predict disease outcome, creatinine levels and VO2 max became additional variables of interest for predicting survival. CONCLUSION: We propose that our lung cancer database may help to identify variables (aside from histomorphological variables) that are suitable for identifying patients at risk of death after surgical treatment of lung cancer.

Catheter-based delivery of fluid paclitaxel for prevention of restenosis in native coronary artery lesions after stent implantation.

BACKGROUND: Stents eluting antiproliferative drugs reduce the incidence of restenosis but delay healing of the vascular wall. We assessed the safety and efficacy of catheter-based local delivery of fluid paclitaxel in patients with coronary de novo stenoses after implantation of a bare metal stent. METHODS AND RESULTS: We conducted a prospective, randomized trial comparing the local delivery of fluid paclitaxel after bare metal stent implantation (group I) with the implantation of a bare metal stent (group II) and the implantation of a paclitaxel-eluting stent (group III) in 204 patients. The primary end point was in-stent late lumen loss. Secondary end points included binary restenosis rate >50%, minimal lumen diameter, diameter stenosis, and a composite clinical end point (major adverse cardiac events and revascularization of the target lesion) 6 months after intervention. At 6 months, angiography showed an in-stent late lumen loss of 0.61+/-0.44 mm in group I versus 0.99+/-0.72 mm in group II (I versus II, P=0.0006) and 0.44+/-0.48 mm in group III (noninferiority of I versus III, P=0.023). The 1-sided 95% CI for the true difference of the means of in-stent late lumen loss in groups I and III was -infinity to 0.3174188. The cumulative overall rate of major cardiac events was 13.4% in group I, 26.8% in group II, and 14.9% in group III. Target lesion revascularization rate was 13.4% (group I), 22.1% (group II), and 13.4% (group III). CONCLUSIONS: Additional antiproliferative treatment of de novo lesions in native coronary arteries with catheter-based delivery of fluid paclitaxel after bare metal stenting was safe and significantly reduced neointimal proliferation, restenosis, and clinical events compared with bare metal stent implantation alone.

Trimodal therapy for histologically proven N2/3 non-small cell lung cancer: mid-term results and indicators for survival.

BACKGROUND: Surgery alone for stage III non-small cell lung cancer provides a 5-year survival of 20% and competes with multimodal treatments. In 1999, a trimodal protocol was implemented at the Schillerhöhe Clinic. The aim of this study was to verify the feasibility and outcome of this trimodal protocol including survival, risk factors for survival, and comorbidity in a single institution. METHODS: Included were all patients with potentially resectable, previously untreated stage III non-small cell lung cancer operated on between February 1999 and May 2006 in the General Thoracic Surgery Unit of the Schillerhöhe Clinic following the same neoadjuvant protocol. Treatment-related morbidity, recurrence, survival after R0 resection, and risk factors for survival (pN0 after trimodal therapy, downstaging of International Union Against Cancer stage, T downstaging, N downstaging, regression rate, and histologic type of tumor) were analyzed. RESULTS: From 107 patients with stage III non-small cell lung cancer, 55 patients with mediastinoscopy-positive N2 or N3 were eligible for this study. Forty patients (72%) had the effect of International Union Against Cancer downstaging. Treatment-related comorbidity was 54% with hospital and 120-day mortality of 3.6% and 5.4%, respectively. Overall mean survival (Kaplan-Meier) was 43 months (95% confidence interval, 35 to 52) with an estimated 5-year survival rate of 49%. In multivariate testing, International Union Against Cancer downstaging after trimodal therapy achieved a level of significance (p = 0.031), and patients with UICC-downstaging after trimodal therapy had a mean survival of 53 months (95% confidence interval, 44 to 63) with an estimated 5-year survival rate of 60%. CONCLUSIONS: Neoadjuvant trimodal treatment for histologically proven N2 or N3 stage III non-small cell lung cancer is promising and can, like no other approach at present time, considerably improve 5-year survival rates up to 63% in selected patients.

Polymorphic loci of E2F2, CCND1 and CCND3 are associated with HER2 status of breast tumors.

Overexpression of the human epidermal growth factor receptor 2 (HER2) in breast tumors is associated with bad prognosis. Therefore, it is highly relevant to further improve understanding of the regulatory mechanisms of HER2 expression. In addition to gene amplification, transcriptional regulation plays a crucial role in HER2 overexpression. In this study, we analyzed 3 polymorphisms E2F2_-5368_A>G, CCND1_870_A>G and CCND3_-677_C>T located in genes involved in cell cycle regulation in the GENICA population-based and age-matched breast cancer case-control study from Germany. We genotyped 1,021 cases and 1,015 controls by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Statistical analyses were performed by conditional logistic regression. We observed no differences in genotype frequencies between breast cancer cases and controls. Subgroup analysis showed associations between carriers of the E2F2_-5368_G allele (OR: 0.60, 95% CI: 0.42-0.85), carriers of the CCND1_870_G allele (OR: 0.66, 95% CI: 0.45-0.96) and carriers of the CCND3_-677_T allele (OR: 1.72, 95% CI: 1.20-2.49) and HER2 expression in breast tumors. This finding points to an association of an increased expression of these cell cycle regulators with lower expression of HER2. An explanation for this observation might be that low expression of E2F2, CCND1 and CCND3 decrease levels of factors down-regulating HER2. We conclude that the analyzed polymorphisms located in E2F2, CCND1 and CCND3 are potential markers for HER2 status of breast tumors.

Statins do not adversely affect post-interventional residual platelet aggregation and outcomes in patients undergoing coronary stenting treated by dual antiplatelet therapy.

AIMS: There are growing data suggesting a clinical relevance of residual platelet aggregation (RPA) in patients undergoing PCI. Drug-drug interaction of statins and clopidogrel has been controversially discussed in ex vivo studies and clinical trials. The aim of the present study was to investigate the effects of peri-procedural statin medication on the metabolization of aspirin and clopidogrel with regard to platelet aggregation and clinical outcome in patients undergoing coronary intervention. METHODS AND RESULTS: Patients with coronary stenting for symptomatic coronary artery disease are routinely evaluated by platelet function analysis in a monocentre registry, and for the present study, a consecutive cohort of 1155 patients were analysed. About 87.7% of the patients were treated with statins at the time of platelet function analysis. Residual platelet activity assessed by adenosine diphosphate (20 micromol/L)-induced platelet aggregation was not significantly influenced by statin treatment. Nor the significant effects of CYP3A4-metabolization pathway on post-treatment aggregation were recorded, although there was even a trend to lower RPA values in patients treated with CYP3A4-metabolized statins. Further, in an inter-individual analysis comparing patients treated with CYP3A4- and non-CYP3A4-metabolized statins, no time-dependent difference of clopidogrels anti-aggregatory effects was observed. Clinical follow-up of major adverse events (myocardial infarction, ischaemic stroke, death) in 991 patients within 3 months revealed no significant adverse effects of statin treatment on clinical outcome. Instead, statin treatment was independently associated with lower incidence of composite events (HR 0.44, 95% confidence interval 0.23-0.83, P = 0.01). CONCLUSION: Peri-procedural co-administration of statins does not increase the post-interventional RPA in cardiovascular patients treated with dual antiplatelet therapy and does not worsen the clinical prognosis of these patients.

Full-thickness resection with myocutaneous flap reconstruction for locally recurrent breast cancer.

BACKGROUND: Despite available recommendations, therapeutic procedures of locally recurrent breast cancer are very different. This retrospective study presents the possibilities and results of complete, full-thickness chest wall resection. METHODS: Between 1985 and 2006, 63 women (mean age, 58 years) with local recurrence of breast cancer invading the chest wall underwent chest wall resection with myocutaneous flap coverage and are included in this study. Adequate lung, cardiovascular, renal, and hepatic functions were additional eligibility requirements for inclusion. Preoperative known extrapulmonary metastases, pleural dissemination, and Eastern Cooperative Oncology Group (ECOG) status 3 or 4 were exclusion criteria. Survival rates were calculated by the Kaplan-Meier method. Univariable and multivariable Cox regression analysis was used for relative risk factors. RESULTS: The median interval between operation for the primary tumor and of the local recurrence was 89 months, with median follow-up at 28 months. In the total collective, cumulative 5-, 10- and 15-year survival rates were 46%, 29%, and 22%, respectively, with a median survival of 56 months. R0 resection was associated with a 5-year survival of 50.4%. Prognostic factors were patient age at the time of the primary operation and tumor invasion of bony structures. Mortality was 1.6% and morbidity was 25%. CONCLUSIONS: Full-thickness chest wall resection of locally recurrent breast cancer performed by a team of thoracic and plastic surgeons provides the best survival rates, with low mortality and morbidity. An earlier application of this method may lead to further improvement of these results.

Analysis of the distribution of functionally relevant rare codons.

BACKGROUND: The substitution of rare codons with more frequent codons is a commonly applied method in heterologous gene expression to increase protein yields. However, in some cases these substitutions lead to a decrease of protein solubility or activity. To predict these functionally relevant rare codons, a method was developed which is based on an analysis of multisequence alignments of homologous protein families. RESULTS: The method successfully predicts functionally relevant codons in fatty acid binding protein and chloramphenicol acetyltransferase which had been experimentally determined. However, the analysis of 16 homologous protein families belonging to the alpha/beta hydrolase fold showed that functionally rare codons share no common location in respect to the tertiary and secondary structure. CONCLUSION: A systematic analysis of multisequence alignments of homologous protein families can be used to predict rare codons with a potential impact on protein expression. Our analysis showed that most genes contain at least one putative rare codon rich region. Rare codons located near to those regions should be excluded in an approach of improving protein expression by an exchange of rare codons by more frequent codons.

Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group.

PURPOSE: To assess the predictive value of polymorphisms in dihydropyrimidine dehydrogenase (DPYD ), thymidylate synthase (TYMS ), and methylene tetrahydrofolate reductase (MTHFR ) and of nongenetic factors for severe leukopenia, diarrhea, and mucositis related to fluorouracil (FU) treatment. PATIENTS AND METHODS: A multicenter prospective clinical trial included 683 patients with cancer treated with FU monotherapy. Toxicity was documented according to World Health Organization grades. DPYD, TYMS, and MTHFR genotypes were determined, and DPYD was resequenced in patients with severe toxicity. RESULTS: Grade 3 to 4 toxicity occurred in 16.1% of patients. The sensitivity of DPYD*2A genotyping for overall toxicity was 5.5% (95%CI, 0.02 to 0.11), with a positive predictive value of 0.46 (95% CI, 0.19 to 0.75; P = .01). Inclusion of additional DPYD variants improved prediction only marginally. Analysis according to toxicity type revealed significant association of DPYD with mucositis and leukopenia, whereas TYMS was associated with diarrhea. Genotype, female sex, mode of FU administration, and modulation by folinic acid were identified as independent risk factors by multivariable analysis. A previously unrecognized significant interaction was found between sex and DPYD, which resulted in an odds ratio for toxicity of 41.8 for male patients (95% CI, 9.2 to 190; P < .0001) but only 1.33 (95% CI, 0.34 to 5.2) in female patients. Homozygosity for the TYMS enhancer region double repeat allele increased risk for toxicity 1.6-fold (95% CI, 1.08 to 2.22; P = .02). CONCLUSION: DPYD, TYMS, and MTHFR play a limited role for FU related toxicity but a pronounced DPYD gene/sex-interaction increases prediction rate for male patients. Toxicity risk assessment should include sex, mode of administration, and folinic acid as additional predictive factors.

The CYP1B1_1358_GG genotype is associated with estrogen receptor-negative breast cancer.

Cytochrome P450 1B1 (CYP1B1) is a major enzyme in the initial catabolic step of estradiol (E2) metabolism and belongs to the multitude of genes regulated by the estrogen receptor alpha (ERalpha). The common non-synonymous polymorphisms CYP1B1_1358_A>G and CYP1B1_1294_C>G increase CYP1B1 enzymatic activity. Given a relationship between CYP1B1 and breast tumor E2 level as well as E2 level and breast tumor ERalpha expression it is of interest to know whether CYP1B1 polymorphisms have an impact on the ERalpha status of breast cancer. We genotyped the GENICA population-based breast cancer case-control collection (1,021 cases, 1,015 controls) by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and investigated in cases the association between genotypes and tumor ERalpha status (739 ERalpha positive cases; 212 ERalpha negative cases) by logistic regression. We observed a significant association between the homozygous variant CYP1B1_1358_GG genotype and negative ERalpha status (P = 0.005; OR 2.82, 95% CI: 1.37-5.82) with a highly significant Ptrend for CYP1B1_1358_A>G and negative ERalpha status (P = 0.003). We also observed an association of CYP1B1_1358_GG and negative PR status (P = 0.015; OR 2.36, 95% CI: 1.18-4.70) and a Ptrend of 0.111 for CYP1B1_1358_A>G and negative progesterone receptor (PR) status. We conclude that the CYP1B1_1358_A>G polymorphism has an impact on ERalpha status in breast cancer in that the CYP1B1_1358_GG genotype known to encode higher CYP1B1 activity is associated with ERalpha negativity.