Acute megakaryoblastic leukaemia shows high frequency of chromosome 1q aberrations and dismal outcome.

Acute megakaryoblastic leukaemia (AMKL) is associated with poor prognosis. Limited information is available on its cytogenetics, molecular genetics and clinical outcome. We performed genetic analyses, evaluated prognostic factors and the value of allogeneic haematopoietic stem cell transplantation (allo-HSCT) in a homogenous adult AMKL patient cohort. We retrospectively analysed 38 adult patients with AMKL (median age: 58 years, range: 21-80). Most received intensive treatment in AML Cooperative Group (AMLCG) trials between 2001 and 2016. Cytogenetic data showed an accumulation of adverse risk markers according to ELN 2017 and an unexpected high frequency of structural aberrations on chromosome arm 1q (33%). Most frequently, mutations occurred in TET2 (23%), TP53 (23%), JAK2 (19%), PTPN11 (19%) and RUNX1 (15%). Complete remission rate in 33 patients receiving intensive chemotherapy was 33% and median overall survival (OS) was 33 weeks (95% CI: 21-45). Patients undergoing allo-HSCT (n = 14) had a superior median OS (68 weeks; 95% CI: 11-126) and relapse-free survival (RFS) of 27 weeks (95% CI: 4-50), although cumulative incidence of relapse after allo-HSCT was high (62%). The prognosis of AMKL is determined by adverse genetic risk factors and therapy resistance. So far allo-HSCT is the only potentially curative treatment option in this dismal AML subgroup.

Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia.

The clinical and prognostic relevance of many recently identified driver gene mutations in adult acute myeloid leukemia (AML) is poorly defined. We sequenced the coding regions or hotspot areas of 68 recurrently mutated genes in a cohort of 664 patients aged 18 to 86 years treated on 2 phase 3 trials of the German AML Cooperative Group (AMLCG). The median number of 4 mutations per patient varied according to cytogenetic subgroup, age, and history of previous hematologic disorder or antineoplastic therapy. We found patterns of significantly comutated driver genes suggesting functional synergism. Conversely, we identified 8 virtually nonoverlapping patient subgroups, jointly comprising 78% of AML patients, that are defined by mutually exclusive genetic alterations. These subgroups, likely representing distinct underlying pathways of leukemogenesis, show widely divergent outcomes. Furthermore, we provide detailed information on associations between gene mutations, clinical patient characteristics, and therapeutic outcomes in this large cohort of uniformly treated AML patients. In multivariate analyses including a comprehensive set of molecular and clinical variables, we identified DNMT3A and RUNX1 mutations as important predictors of shorter overall survival (OS) in AML patients <60 years, and particularly in those with intermediate-risk cytogenetics. NPM1 mutations in the absence of FLT3-ITD, mutated TP53, and biallelic CEBPA mutations were identified as important molecular prognosticators of OS irrespective of patient age. In summary, our study provides a comprehensive overview of the spectrum, clinical associations, and prognostic relevance of recurrent driver gene mutations in a large cohort representing a broad spectrum and age range of intensively treated AML patients.

A 29-gene and cytogenetic score for the prediction of resistance to induction treatment in acute myeloid leukemia.

Primary therapy resistance is a major problem in acute myeloid leukemia treatment. We set out to develop a powerful and robust predictor for therapy resistance for intensively treated adult patients. We used two large gene expression data sets (n=856) to develop a predictor of therapy resistance, which was validated in an independent cohort analyzed by RNA sequencing (n=250). In addition to gene expression markers, standard clinical and laboratory variables as well as the mutation status of 68 genes were considered during construction of the model. The final predictor (PS29MRC) consisted of 29 gene expression markers and a cytogenetic risk classification. A continuous predictor is calculated as a weighted linear sum of the individual variables. In addition, a cut off was defined to divide patients into a high-risk and a low-risk group for resistant disease. PS29MRC was highly significant in the validation set, both as a continuous score (OR=2.39, P=8.63·10-9, AUC=0.76) and as a dichotomous classifier (OR=8.03, P=4.29·10-9); accuracy was 77%. In multivariable models, only TP53 mutation, age and PS29MRC (continuous: OR=1.75, P=0.0011; dichotomous: OR=4.44, P=0.00021) were left as significant variables. PS29MRC dominated all models when compared with currently used predictors, and also predicted overall survival independently of established markers. When integrated into the European LeukemiaNet (ELN) 2017 genetic risk stratification, four groups (median survival of 8, 18, 41 months, and not reached) could be defined (P=4.01·10-10). PS29MRC will make it possible to design trials which stratify induction treatment according to the probability of response, and refines the ELN 2017 classification.

The Visual Analog Scale as a Comprehensible Patient-Reported Outcome Measure (PROM) in Septorhinoplasty.

The patient's satisfaction with the esthetic result is a major criterion of success in septorhinoplasty. However, the idea of esthetic perfection varies greatly and primarily depends on subjective perception. Hence, patient-reported instruments are important and necessary to assess the outcome in septorhinoplasty. To analyze the potential of the visual analog scale (VAS) as a patient-reported outcome measure in septorhinoplasty, the perception of the nasal appearance was assessed by a VAS pre- and postoperatively in 213 patients undergoing septorhinoplasty. Furthermore, in this prospective study, the patients' satisfaction concerning the procedure's result was analyzed using a five-point Likert scale. Females had lower preoperative VAS scores but a higher increase compared to males. Patients with lower initial VAS scores showed a higher improvement in the VAS score postoperatively compared to patients with higher initial VAS scores. Satisfaction with the result depends on the increase in the VAS score value. The VAS scale is a short and comprehensible tool to assess patients' perception of nasal appearance preoperatively and represents an appropriate instrument to assess the esthetic patient-reported outcome in septorhinoplasty.Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Assessment of first-trimester thymus size and correlation with maternal diseases and fetal outcome.

INTRODUCTION: We investigated the reliability of fetal thymus measurement during first-trimester screening, and associated fetal thymus size with crown-rump length, maternal diseases and fetal outcome. MATERIAL AND METHODS: In a retrospective cohort of 971 normal singleton first-trimester fetuses, we measured the anterior-posterior diameter of the thymus in a midsagittal plane in 767 fetuses. The intra-observer and inter-observer reliabilities were tested by intra-class correlation coefficient. We correlated thymus size with fetal crown-rump length, and investigated its association with maternal diseases (diabetes mellitus, rheumatic disorders, hypertension and coagulation disorders) and fetal outcome (small for gestational age, preterm birth and umbilical artery pH) using regression analyses. RESULTS: The intra-observer and inter-observer reliabilities of fetal thymus measurement were excellent (intra-class correlation coefficient 0.926, 95% CI 0.745-0.981 and 0.945, 95% CI 0.886-0.993, respectively). A linear relationship was found between crown-rump length and thymus size (ß = 0.023, p = 0.001). Pregnancies affected by maternal diabetes had a decreased fetal thymus size (ß = -0.209, p = 0.001), whereas in pregnancies affected by maternal rheumatic disease the thymus size was increased (ß = 0.285, p < 0.001). Fetal thymus size was not associated with maternal hypertension or maternal coagulation disorders. There was a positive association between preterm birth and fetal thymus size (p < 0.001). CONCLUSION: Measurement of first-trimester thymus size is reliable. Fetal thymus size has a linear correlation with crown-rump length. Maternal diabetes, rheumatic disease and preterm birth appear to have an association with fetal thymus size.

Factors influencing life satisfaction in acute myeloid leukemia survivors following allogeneic stem cell transplantation: a cross-sectional study.

BACKGROUND: Allogeneic stem cell transplantation (alloSCT) is the preferred option of postremission therapy for high-risk patients suffering from acute myeloid leukemia (AML). Therefore, monitoring life satisfaction (LS) of long-term survivors following alloSCT is becoming increasingly important for oncologists. The aim of the study was to evaluate individual survivor priority of various general and health-related domains of life and their satisfaction with these domains. Furthermore, we investigated the impact of general and health-related LS on resilience, anxiety, depression and quality of life in AML survivors following alloSCT. METHODS: Forty-one AML survivors (median age at time of assessment = 49.0 years) who had undergone alloSCT (median time since transplantation = 3.1 years) were enrolled in the study. Psychosocial parameters were assessed using the following instruments: FLZ(M) (Questions on Life Satisfaction), EORTC QLQ-C30, HADS (Hospital Anxiety and Depression Scale) and the RS-25 (Resilience Scale-25 items). Correlation analyses were computed to reveal the associations between the different questionnaires. RESULTS: Independence from help or care, well-regulated living conditions and financial security contributed positively to LS, whereas being off work due to health-reasons and dissatisfaction with physical aspects were negatively associated to the subjective feelings of overall satisfaction. Moreover, a high quality of life was strongly positively correlated with LS (Spearman's rho general LS: 0.643 and health-related LS: 0.726, both p < 0.001). A high degree of resilience was also strongly positively correlated with better LS (general LS: 0.700, health-related LS: 0.675, both p < 0.001). Symptoms of anxiety and depression were associated with an impaired general LS (anxiety: -0.674, depression: -0.698, both p < 0.001). CONCLUSIONS: Our results indicate that LS should be considered an important key contributor to the survivors' well-being following alloSCT. Thus, identifying protective psychological and physical factors that relieve stressors is of high importance in order to support long-term AML survivors with their special needs.

Renal oligo- and anhydramnios: cause, course and outcome--a single-center study.

PURPOSE: To evaluate the outcome of patients with renal oligohydramnios and explore the impact of patient variables on outcome and prognosis. METHODS: A retrospective single-center study was conducted analyzing 104 pregnancies complicated by oligohydramnios of renal origin from 2001 to 2011. Statistical analysis was performed to assess the influence of pre- and postnatal data on pregnancy outcome, morbidity and mortality. RESULTS: Prenatal renal diagnoses were as follows: hydronephrosis/megaureter: n = 21 (20.2 %), aberrance in renal form or location: n = 7 (6.7 %), cystic renal disease: n = 28 (26.9 %), renal dysplasia: n = 24 (23.1 %), renal agenesis: n = 42 (30.4 %), posterior urethral valves: n = 11 (10.6 %). Hydronephrosis/megaureter and late onset of oligohydramnios were prognostic factors for fetal survival, whereas renal agenesis and associated anomalies had a negative impact on pregnancy outcome. Prenatal interventions did not improve prognosis. CONCLUSIONS: Pregnancies complicated by renal oligohydramnios still have a poor outcome. Careful weighing of prognostic factors is necessary to decide about further therapeutic measures.

The value of high-dose chemotherapy in patients with first relapsed Ewing sarcoma.

BACKGROUND: Prognosis of patients with relapsed Ewing sarcoma (ES) is poor. The 5-year overall survival (OS) is 13%. We analyzed high-dose chemotherapy (HDtx) versus conventional chemotherapy (CHtx) in patients with relapsed ES. PROCEDURE: Data from 239 patients with first relapse, registered during 2000-2011 in the ES relapse registry of the Cooperative Ewing Sarcoma Study Group (CESS) were analyzed. RESULTS: Of 239 patients, 200 received various non-HDtx second-line CHtx regimens. Seventy-three patients had additional HDtx followed by autologous stem cell rescue. The 2-year event-free survival (EFS) was 10% (SE = 0.02) in patients treated without HDtx and 45% (SE = 0.09) in patients treated with HDtx. In a second step, we focused on those patients who achieved complete remission (CR) or partial remission (PR) after four to six cycles of conventional second-line CHtx. Here, the 2-year EFS was 31% (SE = 0.08) without additional HDtx and 44% (SE = 0.09) with additional HDtx. In addition, multivariate regression analysis indicates absence of HDtx treatment, with a Hazard ratio (HR) of 2.90 (95% CI 1.41-6.0), and early relapse, with a HR of 4.76 (95% CI 2.31-9.78), as independent prognostic factors for EFS. CONCLUSION: Additional HDtx may contribute to further reduce the risk of further events in patients who respond to conventional second-line CHtx.

Imaging of fetal thymus in pregnant women with rheumatic diseases.

OBJECTIVE: To determine whether certain rheumatic diseases will affect the fetal thymus diameter when compared to uncomplicated singleton pregnancies. Additionally, we created a reference chart for fetal thymus size in healthy singleton pregnancies from 19 to 37 weeks of gestation. METHODS: Sonographic fetal thymus size was retrospectively evaluated in 190 healthy pregnant women, and 84 pregnancies of mothers suffering from systemic lupus erythematosus, antiphospholipid syndrome (APS), or Sjögren's syndrome between 19 and 37 weeks of gestation. These fetuses were matched one-to-one for gestational age with control fetuses. The thymic-thoracic ratio (TT-ratio) was defined as the quotient of the anteroposterior thymic and the intrathoracic mediastinal diameter. RESULTS: Rheumatic diseases often affect pregnancy outcome, especially in case of primary APS. The TT ratio of fetuses of mothers suffering from rheumatic disease was equal to controls (P=0.807). CONCLUSIONS: Ours is the first study to assess the correlation of fetal thymus size in high-risk pregnancies with rheumatic diseases in comparison to controls. Women with rheumatic diseases deal with pregnancy complications more frequently than controls. Our data suggest that maternal rheumatic diseases do not affect the fetal thymus size.

High phosphate directly affects endothelial function by downregulating annexin II.

Hyperphosphatemia is associated with increased cardiovascular risk in patients with renal disease and in healthy individuals. Here we tested whether high phosphate has a role in the pathophysiology of cardiovascular events by interfering with endothelial function, thereby impairing microvascular function and angiogenesis. Protein expression analysis found downregulation of annexin II in human coronary artery endothelial cells, an effect associated with exacerbated shedding of annexin II-positive microparticles by the cells exposed to high phosphate media. EAhy926 endothelial cells exposed to sera from hyperphosphatemic patients also display decreased annexin II, suggesting a negative correlation between serum phosphate and annexin II expression. By using endothelial cell-based assays in vitro and the chicken chorioallantoic membrane assay in vivo, we found that angiogenesis, vessel wall morphology, endothelial cell migration, capillary tube formation, and endothelial survival were impaired in a hyperphosphatemic milieu. Blockade of membrane-bound extracellular annexin II with a specific antibody mimicked the effects of high phosphate. In addition, high phosphate stiffened endothelial cells in vitro and in rats in vivo. Thus, our results link phosphate and adverse clinical outcomes involving the endothelium in both healthy individuals and patients with renal disease.

Immunocompetent hamsters as a model for orthobunyavirus-induced neuroinvasion and neuropathology.

BACKGROUND: Bunyavirus infections, including those caused by Bunyamwera serogroup orthobunyaviruses, represent a significant and yet likely still vastly underappreciated cause of mild to moderate human febrile infections. In severe cases, these infections can also cause neurological disease, particularly meningitis and encephalitis, and infection can even be fatal. However, with a few exceptions, information regarding the mechanisms underlying the neuroinvasion and neuropathogenesis of such infections is limited. This is due in part to a lack of animal models to facilitate such studies. METHODOLOGY/PRINCIPAL FINDINGS: In an effort to develop an immunocompetent model of infection with Bunyamwera serogroup orthobunyaviruses, we infected 4-6-week-old female hamsters via either the intraperitoneal or subcutaneous route with 106 pfu/animal of Bunyamwera virus (BUNV), Batai virus or Ngari virus. Only BUNV infection resulted in clinical disease, which was characterized by weight loss, lethargy and neurological signs (i.e. tremor of the head or limbs, loss of righting reflex, "waltzing"). While symptoms were of similar severity for both routes, they occurred more frequently following subcutaneous inoculation. Consistent with these clinical signs, both antigen staining and histopathological abnormalities were found extensively throughout the brain. CONCLUSIONS/SIGNIFICANCE: The reported hamster model of BUNV infection provides a new tool for studying orthobunyavirus infection, and particularly neuroinvasion and the development of neuropathology. This model is particularly significant because it makes use of immunologically competent animals and relies on a subcutaneous inoculation route that more closely mimics the natural infection route for arboviruses, thereby providing a more authentic cellular and immunological context at the initial site of infection.

Effect of Bone Morphogenetic Protein-2 in the Treatment of Long Bone Non-Unions.

BACKGROUND: Delayed fracture healing continues to cause significant patient morbidity and an economic burden to society. Biological stimulation of non-unions includes application of recombinant bone morphogenetic protein-2 (rhBMP-2). However, rhBMP-2 use continues to be a matter of controversy as literature shows scarce evidence for treatment effectiveness. QUESTIONS: The objective of this study was to evaluate the effectiveness of rhBMP-2 treatment on long bone non-unions measuring union rate and time to union. Furthermore, we assess risk factors for treatment failure. METHODS AND PATIENTS: A total of 91 patients with non-unions of long bones were treated with rhBMP-2 (n = 72) or standard care without BMP (n = 19) at our institution. Patient characteristics, comorbidities, nicotine consumption, and complications were recorded. Bone healing was assessed by plane X-rays and clinical examination. Patients were followed up with for 24 months. RESULTS: Overall, there was significantly faster bone healing after rhBMP-2 application compared to the no-BMP group (p < 0.001; HR = 2.78; 95% CI 1.4-5.6). Union rates differed significantly between rhBMP-2 compared to the no-BMP group (89% vs. 47%; p < 0.001). At the humerus, there was neither a significantly higher union rate in the rhBMP-2 (83%) compared to the no-BMP group (50%) (p = 0.26; n = 12) nor a faster bone healing with a median time of 9 months in both groups (HR = 2.01; 95% CI 0.49-8.61; p = 0.315). The 33 femora treated using rhBMP-2 healed significantly faster than 9 femora in the no-BMP group (HR = 2.93; 95% CI 1.00-8.4; p = 0.023) with significant differences in union rate with 85% and 44%, respectively (p = 0.022). Regarding tibia non-unions, 25 out of 27 (93%) healed with a median of 9 months after rhBMP-2 application with no significant difference in the no-BMP group (33%) in time to union (p = 0.097) but a significantly higher union rate (p = 0.039). There was no effect of comorbidities, age, sex, soft tissue damage, or nicotine use on time to union, union rate, or secondary interventions. CONCLUSION: Consistent with the literature, overall, significantly higher union rates with reduced time to union were achieved after rhBMP-2 application. Femoral and tibial non-unions in particular seem to profit from rhBMP-2 application.

Assessing the occurrence of the novel zoonotic variegated squirrel bornavirus 1 in captive squirrels in Germany -A prevalence study.

The newly described zoonotic variegated squirrel bornavirus 1 (VSBV-1) in German squirrel holdings has been associated with the death of three private owners and one zoo animal caretaker (confirmed cases). Epidemiological investigations were severely impeded by the general lack of data on holdings of the putative reservoir hosts, the family Sciuridae. To fill this lack of data for detailed epidemiological investigations of the captive squirrel population, a register of private and zoological squirrel holdings was established. The findings show a broad variety of kept species and their frequency distribution. By contacting the different stakeholders via Web-based social groups and societies, information passed in both directions so that disease awareness could be raised and participants could be recruited for further studies. Cross-sectional studies revealed a prevalence of VSBV-1-positive subpopulations of 0% (95% CI 0%-6.2%) among private squirrel collections and 1.9% (95% CI: 0%-9.9%) among zoos in Germany. The approach presented here can be transferred to other populations of non-traditional pets, which may be equally difficult to monitor, in the case of an emerging zoonotic infectious disease.

Success rates of retinal buckling surgery: relationship to refractive error and lens status: results from a large German case series.

OBJECTIVE: First, to evaluate the anatomic success rates of scleral buckling surgery in the treatment of rhegmatogenous retinal detachment and possible differences in outcome depending on patients' refractive error and lens status. Second, to evaluate demographic characteristics of patients with retinal detachment to contribute to our knowledge of the epidemiology of this important and sight-threatening disease. DESIGN: Retrospective interventional case series. PARTICIPANTS: The Munster Study on Therapy Achievements in Retinal Detachment (MUSTARD) is one of the largest case series of patients with retinal detachment and their outcome after buckling surgery ever established, with 4325 subjects who underwent surgery between 1980 and 2001. METHODS: All 4325 patients with retinal detachment underwent scleral buckling surgery. MAIN OUTCOME MEASURES: Complete anatomic attachment of the retina. RESULTS: The overall success rate in all 4325 MUSTARD cases was 83.98%. The highest success rate was achieved in patients aged 51 to 60 years, with 86.72%. With regard to refractive error, success rates were highest in moderate myopes, that is, in 707 patients with a refractive error between -2.75 and -8.0 diopters (86.70%) and in 573 patients with mild myopia between -0.5 and -2.0 diopters (86.21%). The lens status did not play a significant role in outcome. In patients with nontrauma-related retinal detachment, success rates were 84.45% for phakic patients, 82.88% for pseudophakic patients, and 81.88% for aphakic patients. An epidemiologically surprising result was the lower than expected number of myopic individuals among patients with retinal detachment: Only approximately one quarter had myopia of -2.75 diopters or more. In phakic patients aged 51 to 80 years, only 16% were myopic. CONCLUSIONS: Scleral buckling is an established and generally successful method for the treatment of retinal detachment. As our case series has demonstrated, myopia, aphakia, and pseudophakia do not constitute factors that might diminish the chances of success. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

The soluble VEGF receptor sFlt1 contributes to endothelial dysfunction in CKD.

Endothelial dysfunction contributes to the increased cardiovascular risk that accompanies CKD. We hypothesized that the soluble VEGF receptor 1 (sFlt-1), a VEGF antagonist, plays a role in endothelial dysfunction and decreased angiogenesis in CKD. We enrolled 130 patients with CKD stages 3 to 5 and 56 age- and gender-matched control patients. Plasma sFlt-1 levels were higher in patients with CKD and, after multivariate regression analyses, exclusively associated with renal function and levels of vWF, a marker of endothelial dysfunction. Compared with serum from control patients, both recombinant sFlt-1 and serum from patients with CKD had antiangiogenic activity in the chick chorioallantoic membrane (CAM) assay, induced endothelial cell apoptosis in vitro, and decreased nitric oxide generation in two different endothelial cell lines. Pretreating the sera with an antibody against sFlt-1 abrogated all of these effects. Furthermore, we observed increased sFlt1 levels in 5/6-nephrectomized rats compared with sham-operated animals. Finally, using real-time PCR and ELISA, we identified monocytes as a possible source of increased sFlt-1 in patients with CKD. Our findings show that excess sFlt-1 associates with endothelial dysfunction in CKD and suggest that increased sFlt-1 may predict cardiovascular risk in CKD.

Author Correction: The potential role of scavengers in spreading African swine fever among wild boar.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Modulation of lethal HPAIV H5N8 clade 2.3.4.4B infection in AIV pre-exposed mallards.

In 2016/2017, a severe epidemic of HPAIV H5N8 clade 2.3.4.4 group B (H5N8B) affected Europe. To analyse the role of mallards in the spatiotemporal dynamics of global HPAIV H5N8B dispersal, mallards (Anas platyrhynchos), naturally exposed to various AIV and therefore seropositive, were challenged with H5N8B. All experiments were controlled by infection and co-housing of seronegative juvenile Pekin ducklings. All ducks that survived the first infection were re-challenged 21 dpi with the homologous H5N8B strain. After the first H5N8B infection, seropositive mallards showed only mild clinical symptoms. Moderate to low viral shedding, occurring particularly from the oropharynx and lasting for 7 days maximum, led to severe clinical disease of all contact ducklings. All challenged seronegative Pekin ducks and contact ducklings died or had to be euthanized. H5-specific antibodies were detected in surviving birds within 2 weeks. Virus and viral RNA could be isolated from several water samples until 6 and 9 dpi, respectively. Conversely, upon re-infection with homologous H5N8B neither inoculated nor contact ducklings showed any clinical symptoms, nor was an antibody titer increase of seropositive mallards or any seroconversion of contact ducklings observed. Mallard ducks naturally pre-exposed to LPAIV can play a role as a clinically unsuspicious virus reservoir for H5N8B effective in virus transmission. Mallards with homologous immunity did not contribute to virus transmission.

Multicentric investigation of ionising radiation-induced cell death as a predictive parameter of individual radiosensitivity.

In the present study, the predictive value of ionising radiation (IR)-induced cell death was tested in peripheral blood lymphocytes (PBLs) and their corresponding Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) in an interlaboratory comparison. PBLs and their corresponding LCLs were derived from 15 tumour patients, that were considered clinically radiosensitive based on acute side-effects, and matched controls. Upon coding of the samples, radiosensitivity of the matched pairs was analysed in parallel in three different laboratories by assessing radiation-induced apoptotic and necrotic cell death using annexin V. All participating laboratories detected a dose-dependent increase of apoptosis and necrosis in the individual samples, to a very similar extent. However, comparing the mean values of apoptotic and necrotic levels derived from PBLs of the radiosensitive cohort with the mean values of the control cohort did not reveal a significant difference. Furthermore, within 15 matched pairs, no sample was unambiguously and independently identified by all three participating laboratories to demonstrate in vitro hypersensitivity that matched the clinical hypersensitivity. As has been reported previously, apoptotic and necrotic cell death is barely detectable in immortalised LCL derivatives using low doses of IR. Concomitantly, the differences in apoptosis or necrosis levels found in primary cells of different individuals were not observed in the corresponding LCL derivatives. All participating laboratories concordantly reasoned that, with the methods applied here, IR-induced cell death in PBLs is unsuitable to unequivocally predict the individual clinical radiosensitivity of cancer patients. Furthermore, LCLs do not reflect the physiological properties of the corresponding primary blood lymphocytes with regard to IR-induced cell death. Their value to predict clinical radiosensitivity is thus highly questionable.

Blood pressure, antihypertensive treatment, and graft survival in kidney transplant patients.

Whether the use of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker inhibitor (ACEI/ARB) is beneficial in renal transplant recipients remains controversial. In this retrospective study on 505 renal transplant recipients, we analyzed blood pressure and graft survival according to antihypertensive treatment with ACE-I/ARB and/or calcium channel blockers (CCB) over a period of 10 years. Patients were stratified according to their blood pressure 1 year after transplantation [controlled (130/80 mmHg; non-CTR, 324 patients)] and according to antihypertensive treatment (ACE-I/ARB and/or CCB taken for at least 2 years). One year after transplantation, 88.4% of CTR and 96.6% of non-CTR received antihypertensive treatment (P < 0.05). Graft survival was longer in CTR than in non-CTR (P < 0.05). Importantly, graft survival was longer in patients who received long-term treatment with ACEI/ARB, CCB, or a combination of ACEI/ARB and CCB (P < 0.001). The beneficial effect of ACEI/ARB therapy was more pronounced in non-CTR compared with that of CTR. We conclude that blood pressure control is a key target for long-term graft survival in renal transplant patients. Long-term ACEI/ARB and CCB therapy is beneficial for graft survival, especially in patients with diabetes and/or albuminuria.

Estimation of patient accrual rates in clinical trials based on routine data from hospital information systems.

BACKGROUND: Delayed patient recruitment is a common problem in clinical trials. According to the literature, only about a third of medical research studies recruit their planned number of patients within the time originally specified. OBJECTIVES: To provide a method to estimate patient accrual rates in clinical trials based on routine data from hospital information systems (HIS). METHODS: Based on inclusion and exclusion criteria for each trial, a specific HIS report is generated to list potential trial subjects. Because not all information relevant for assessment of patient eligibility is available as coded HIS items, a sample of this patient list is reviewed manually by study physicians. Proportions of matching and non-matching patients are analyzed with a Chi-squared test. An estimation formula for patient accrual rate is derived from this data. RESULTS: The method is demonstrated with two datasets from cardiology and oncology. HIS reports should account for previous disease episodes and eliminate duplicate persons. CONCLUSION: HIS data in combination with manual chart review can be applied to estimate patient recruitment for clinical trials.