CD34-related coexpression of MDR1 and BCRP indicates a clinically resistant phenotype in patients with acute myeloid leukemia (AML) of older age

Clinical resistance to chemotherapy in acute myeloid leukemia (AML) is associated with the expression of the multidrug resistance (MDR) proteins P-glycoprotein, encoded by the MDR1/ABCB1 gene, multidrug resistant-related protein (MRP/ABCC1), the lung resistance-related protein (LRP), or major vault protein (MVP), and the breast cancer resistance protein (BCRP/ABCG2). The clinical value of MDR1, MRP1, LRP/MVP, and BCRP messenger RNA (mRNA) expression was prospectively studied in 154 newly diagnosed AML patients >or=60 years who were treated in a multicenter, randomized phase 3 trial. Expression of MDR1 and BCRP showed a negative whereas MRP1 and LRP showed a positive correlation with high white blood cell count (respectively, p < 0.05, p < 0.001, p < 0.001 and p < 0.001). Higher BCRP mRNA was associated with secondary AML (p < 0.05). MDR1 and BCRP mRNA were highly significantly associated (p < 0.001), as were MRP1 and LRP mRNA (p < 0.001) expression. Univariate regression analyses revealed that CD34 expression, increasing MDR1 mRNA as well as MDR1/BCRP coexpression, were associated with a lower complete response (CR) rate and with worse event-free survival and overall survival. When adjusted for other prognostic actors, only CD34-related MDR1/BCRP coexpression remained significantly associated with a lower CR rate (p = 0.03), thereby identifying a clinically resistant subgroup of elderly AML patients.

Hepatoblastoma with a low serum alpha-fetoprotein level at diagnosis: The SIOPEL group experience

AIM OF THE STUDY: To investigate the characteristics of patients with hepatoblastoma and low serum alpha-fetoprotein (AFP) at diagnosis. PATIENTS AND METHODS: Inclusion of all 21 patients accrued onto SIOPEL trials, whose serum AFP was <100ng/ml at diagnosis. Slides of all 15 patients with available histological material were centrally reviewed. RESULTS: Median age: 10 months. Disease extension at diagnosis: PRETEXT group: II (3 patients), III (10 patients) and IV (8 patients). Extra-hepatic extension: 8 patients. Multifocal tumour: 8 patients. Histology at review: wholly epithelial subtype: 11/15 patients including nine with a small-cell undifferentiated histology. Outcome: only 9 patients achieved a partial response and 16 died. Median survival: 4.4 months. Two-year overall survival: 24% (confidence interval 10-45%). CONCLUSION: This study clearly identifies patients with hepatoblastoma and low serum AFP at diagnosis as a high-risk subgroup with extensive disease at diagnosis, poor response to chemotherapy and a poor outcome.

Genetic polymorphisms of manganese-superoxide dismutase and glutathione-S-transferase in chronic alcoholic pancreatitis

Chronic alcohol consumption is a major risk factor for the development of chronic pancreatitis. However, chronic pancreatitis occurs only in a minority of heavy drinkers. This variability may be due to yet unidentified genetic factors. Several enzymes involved in the degradation of reactive oxidants and xenobiotics, such as glutathione-S-transferase P1 (GSTP1) and manganese-superoxide dismutase (MnSOD) reveal functional polymorphisms that affect the antioxidative capacity and may therefore modulate the development of chronic pancreatitis and long-term complications like endocrine and exocrine pancreatic insufficiency. Two functional polymorphisms of the MnSOD and the GSTP1 gene were assessed by polymerase chain reaction and restriction fragment length polymorphism in 165 patients with chronic alcoholic pancreatitis, 140 alcoholics without evidence of pancreatic disease and 160 healthy control subjects. The distribution of GSTP1 and MnSOD genotypes were in Hardy-Weinberg equilibrium in the total cohort. Genotype and allele frequencies for both genes were not statistically different between the three groups. Although genotype MnSOD Ala/Val was seemingly associated with the presence of exocrine pancreatic insufficiency, this subgroup was too small and the association statistically underpowered. None of the tested genotypes affected the development of endocrine pancreatic insufficiency. Polymorphisms of MnSOD and GSTP1 are not associated with chronic alcoholic pancreatitis. The present data emphasize the need for stringently designed candidate gene association studies with well-characterized cases and controls and sufficient statistical power to exclude chance observations.

Psychophysiological ambulatory assessment of affective dysregulation in borderline personality disorder

Many experts now believe that pervasive problems in affect regulation constitute the central area of dysfunction in borderline personality disorder (BPD). However, data is sparse and inconclusive. We hypothesized that patients with BPD, in contrast to healthy gender and nationality-matched controls, show a higher frequency and intensity of self-reported emotions, altered physiological indices of emotions, more complex emotions and greater problems in identifying specific emotions. We took a 24-hour psychophysiological ambulatory monitoring approach to investigate affect regulation during everyday life in 50 patients with BPD and in 50 healthy controls. To provide a typical and unmanipulated sample, we included only patients who were currently in treatment and did not alter their medication schedule. BPD patients reported more negative emotions, fewer positive emotions, and a greater intensity of negative emotions. A subgroup of non-medicated BPD patients manifested higher values of additional heart rate. Additional heart rate is that part of a heart rate increase that does not directly result from metabolic activity, and is used as an indicator of emotional reactivity. Borderline participants were more likely to report the concurrent presence of more than one emotion, and those patients who just started treatment in particular had greater problems in identifying specific emotions. Our findings during naturalistic ambulatory assessment support emotional dysregulation in BPD as defined by the biosocial theory of [Linehan, M.M., 1993. Cognitive-Behavioral Treatment of Borderline Personality Disorder. The Guildford Press, New York.] and suggest the potential utility for evaluating treatment outcome.

Is pseudophakia a risk factor for neovascular age-related macular degeneration?

PURPOSE: To examine the possible association between pseudophakia and neovascular age-related macular degeneration (AMD). METHODS: Reports of all patients undergoing fluorescein angiography in the authors' department over a 6-year period were retrospectively reviewed. Four hundred ninety-nine patients with recent onset of neovascular AMD in one eye and early age-related maculopathy (ARM) in the fellow eye were included in the study. Lens status (phakic or pseudophakic) in both eyes at the time of onset of neovascular AMD and the time between cataract surgeries (if performed) and onset of neovascular AMD were determined. RESULTS: There was no significant difference in lens status between eyes with neovascular AMD and fellow eyes with early ARM (115/499 [23.0%] vs. 112/499 [22.4%] pseudophakic; P = 0.88, odds ratio 1.035, 95% CI 0.770-1.391). Subgroup analysis revealed no difference between the groups with large drusen, small drusen, or pigmentary changes only (respectively, 20.3% vs. 19.6% pseudophakic, P = 0.92; 20.5% vs. 23.3% pseudophakic, P = 0.84; 33.3% vs. 31.7% pseudophakic, P = 1.0). Pseudophakic eyes with neovascular AMD had not been pseudophakic for a significantly longer period at the time of onset of neovascular AMD than their pseudophakic fellow eyes at the same time point (225.9 +/- 170.4 vs. 209.9 +/- 158.2 weeks, P = 0.27). CONCLUSIONS: The results do not support the hypothesis that pseudophakia is a major risk factor for the development of neovascular AMD.

Long-term outcome of trans-scleral diode laser cyclophotocoagulation in refractory glaucoma

BACKGROUND: Long-term outcome and complications of diode laser cyclophotocoagulation (DCPC) may be important, since eyes, once treated with DCPC, are less likely to be subjected to other types of interventions in the further follow-up. METHODS: Retrospective review of 131 eyes of 127 patients treated from 2000 through 2004. Success was defined as intraocular pressure (IOP) at last visit 6-21 mm Hg; hypotony: IOP subgroup (61%). IOP decreased from 36.9 (10.7) mm Hg pretreatment to 15.3 (10.4) mm Hg at the end of FU. Success was noted in 69.5% (91 eyes), failure (non-response) in 13%. Hypotony occurred in 17.6% eyes, of which 74% had NVG. Hypotony developed after mean 19.3 (11.0) months, range 6 to 36; with 96% of these eyes having received only 1 or 2 treatments; delivered energy did not differ from that in the successful eyes. CONCLUSIONS: DCPC is an efficient treatment for refractory glaucoma. Hypotony, the most common complication, may develop as late as 36 months post-treatment. Diagnostic category and age seem to influence the outcome stronger than laser protocol and delivered energy.

[Retinal abnormalities in adult acute myeloid leukemia: semeiological features and prognostic correlations. Analysis of 178 cases]

INTRODUCTION: Adult patients with acute myeloid leukemia (AML) frequently present retinal abnormalities. We tried to find a relationship between fundus lesions and treatment responsiveness, prognosis, and several hematologic parameters. PATIENTS AND METHODS: We examined 178 adult patients with newly diagnosed AML. All patients were assigned to two groups regarding retinal parameters (1 or 2) and age (A or B). Group 1 included cases with retinal dysfunction classified as retinal abnormalities with impaired visual acuity; group 2 included cases with no or only minor retinal changes. Subgroup A included patients younger than 60 years (n=97), subgroup B patients older than 60 years (n=81). RESULTS: In this study, higher age and a lower Hb value were associated with retinal findings (group 1). Among the younger patients (subgroup A), 78% of those with complete remission had no retinal findings (group 2) compared to 18% of the nonresponders. In the elderly population (subgroup B), this ratio was 58% versus 19%. In the younger patients (subgroup A), the mean overall survival was 50 months if they had no retinal abnormalities (group 2) and 7 months in the case of retinal changes (group 1). In the older population (subgroup B), the ratio was 15 months versus 3 months, respectively. CONCLUSION: Retinal abnormalities in AML are generally associated with higher age, although they correlate with a shorter survival in both age groups. This association is stronger in younger patients.

Minimal extracorporeal circulation is a promising technique for coronary artery bypass grafting

BACKGROUND: Minimal extracorporeal circulation (MECC) is a promising perfusion technology, taking the advantage of an ECC while having a significantly reduced priming volume. We analyzed the actual possible benefits of using MECC in patients undergoing CABG procedures and compared the results with conventional extracorporeal circulation (CECC). METHODS: One thousand fifty-three consecutive patients underwent CABG surgery using the MECC perfusion technique. Subgroup analyses focused on perioperative myocardial markers (cardiac troponin I [cTnI]), incidence of atrial fibrillation (AF), and perioperative evaluation of inflammatory markers and data were compared with those of patients who underwent CABG using CECC. A propensity score analysis was performed. RESULTS: Patient characteristics and distribution of EuroSCORE risk were similar in both groups. Severity of coronary artery disease and extent of revascularization were also comparable in both groups (number of distal anastomoses: 3.2 +/- 1.1 in CECC vs 3.2 +/- 0.9 in MECC; p = not significant [ns]). The cTnI was significantly lower in the MECC group (11.0 +/- 10.8 microg/L in MECC vs 24.7 +/- 25.3 microg/L in CECC; p < 0.05). Incidence of AF was 11.1% in MECC and 39.0% in CECC (p < 0.05). Inflammatory markers (interleukin-6, SC5b-9) were lower in MECC patients (p < 0.05). Propensity score analysis confirmed faster recovery in MECC patients and lower incidence of AF. CONCLUSIONS: Minimal extracorporeal circulation is a safe perfusion technique for CABG and may therefore concurrence OPCAB and traditional CABG under CECC.

Elective implantation of sirolimus-eluting stents for bifurcated and non-bifurcated unprotected left main coronary artery lesions: clinical outcomes at one year

AIMS: Recent studies of drug-eluting stents for unprotected left main coronary artery (LMCA) disease have been encouraging. We examined the performance of sirolimus-eluting stents (SES) for this indication. METHODS AND RESULTS: This retrospective study included 228 consecutive patients (mean age = 68 +/- 11 years, 80.6% men, 26.3% diabetics) who underwent implantation of SES for de novo LMCA stenoses. The mean additive and logistic EuroSCOREs were 5.2 +/- 3.9 and 8.2 +/- 13.2, respectively. The main objective of this study was to measure the rate of major adverse cardiac events (MACE), including death, myocardial infarction and target lesion revascularisation (TLR) at 12 months. Other objectives were to measure the rates of in-hospital MACE and 12-month TLR. Outcomes in 143 patients with (BIF+ group), versus 84 patients without (BIF-group) involvement of the bifurcation were compared. The pre-procedural percent diameter stenosis (%DS) was 60.1 +/- 11.2 in the BIF+ versus 54.7 +/- 12.2% in the BIF- group (p=0.008), and decreased to 18.0 +/- 9.7 and 13.9 +/- 11.3%, respectively (ns), after SES implant. The overall in-hospital MACE rate was 3.5%, and similar in both subgroups. The 1-year MACE rate was 14.5% overall, 16.8% in the BIF+ and 10.7% in the BIF- subgroup (ns). CONCLUSIONS: SES implants in high-risk patients with LMCA stenoses were associated with a low 1-year MACE rate. Stenting of the bifurcation was associated with significant increases in neither mortality nor 1-year MACE rate.

Drug-eluting or bare-metal stents for large coronary vessel stenting? The BASKET-PROVE (PROspective Validation Examination) trial: study protocol and design

BACKGROUND: Based on a subgroup analysis of 18-month BAsel Stent Kosten Effektivitäts Trial (BASKET) outcome data, we hypothesized that very late (> 12 months) stent thrombosis occurs predominantly after drug-eluting stent implantation in large native coronary vessel stenting. METHODS: To prove or refute this hypothesis, we set up an 11-center 4-country prospective trial of 2260 consecutive patients treated with > or = 3.0-mm stents only, randomized to receive Cypher (Johnson ; Johnson, Miami Lakes, FL), Vision (Abbott Vascular, Abbott Laboratories, IL), or Xience stents (Abbott Vascular). Only patients with left main or bypass graft disease, in-stent restenosis or stent thrombosis, in need of nonheart surgery, at increased bleeding risk, without compliance/consent are excluded. All patients are treated with dual antiplatelet therapy for 12 months. The primary end point will be cardiac death/nonfatal myocardial infarction after 24 months with further follow-up up to 5 years. RESULTS: By June 12, 229 patients (10% of the planned total) were included with a baseline risk similar to that of the same subgroup of BASKET (n = 588). CONCLUSIONS: This study will answer several important questions of contemporary stent use in patients with large native vessel stenting. The 2-year death/myocardial infarction-as well as target vessel revascularization-and bleeding rates in these patients with a first- versus second-generation drug-eluting stent should demonstrate the benefit or harm of these stents compared to cobalt-chromium bare-metal stents in this relevant, low-risk group of everyday patients. In addition, a comparison with similar BASKET patients will allow to estimate the impact of 12- versus 6-month dual antiplatelet therapy on these outcomes.

Non-invasive gene-expression-based detection of well-developed collateral function in individuals with and without coronary artery disease

BACKGROUND: In patients with coronary artery disease (CAD), a well grown collateral circulation has been shown to be important. The aim of this prospective study using peripheral blood monocytes was to identify marker genes for an extensively grown coronary collateral circulation. METHODS: Collateral flow index (CFI) was obtained invasively by angioplasty pressure sensor guidewire in 160 individuals (110 patients with CAD, and 50 individuals without CAD). RNA was extracted from monocytes followed by microarray-based gene-expression analysis. 76 selected genes were analysed by real-time polymerase chain reaction (PCR). A receiver operating characteristics analysis based on differential gene expression was then performed to separate individuals with poor (CFI<0.21) and well-developed collaterals (CFI>or=0.21) Thereafter, the influence of the chemokine MCP-1 on the expression of six selected genes was tested by PCR. RESULTS: The expression of 203 genes significantly correlated with CFI (p = 0.000002-0.00267) in patients with CAD and 56 genes in individuals without CAD (p = 00079-0.0430). Biological pathway analysis revealed 76 of those genes belonging to four different pathways: angiogenesis, integrin-, platelet-derived growth factor-, and transforming growth factor beta-signalling. Three genes in each subgroup differentiated with high specificity among individuals with low and high CFI (>or=0.21). Two out of these genes showed pronounced differential expression between the two groups after cell stimulation with MCP-1. CONCLUSIONS: Genetic factors play a role in the formation and the preformation of the coronary collateral circulation. Gene expression analysis in peripheral blood monocytes can be used for non-invasive differentiation between individuals with poorly and with well grown collaterals. MCP-1 can influence the arteriogenic potential of monocytes.

Prognostic factors in lymph node metastases of prostatic cancer patients: the size of the metastases but not extranodal extension independently predicts survival

AIMS: To analyse tumour characteristics and the prognostic significance of prostatic cancers with extranodal extension of lymph node metastases (ENE) in 102 node-positive, hormone treatment-naive patients undergoing radical prostatectomy and extended lymphadenectomy. METHODS AND RESULTS: The median number of nodes examined per patient was 21 (range 9-68), and the median follow-up time was 92 months (range 12-191). ENE was observed in 71 patients (70%). They had significantly more, larger and less differentiated nodal metastases, paralleled by significantly larger primary tumours at more advanced stages and with higher Gleason scores than patients without ENE. ENE defined a subgroup with significantly decreased biochemical recurrence-free (P = 0.038) and overall survival (P = 0.037). In multivariate analyses the diameter of the largest metastasis and Gleason score of the primary tumour were independent predictors of survival. CONCLUSIONS: ENE in prostatic cancer is an indicator lesion for advanced/aggressive tumours with poor outcome. However, the strong correlation with larger metastases suggests that ENE may result from their size, which was the only independent risk factor in the metastasizing component. Consequently, histopathological reports should specify the true indicator of poor survival in the lymphadenectomy specimens, which is the size of the largest metastasis in each patient.

Transfusion efficacy of ABO major-mismatched platelets (PLTs) in children is inferior to that of ABO-identical PLTs

BACKGROUND: ABO major compatibility is essential in transfusions of red blood cells but is not requisite in PLT transfusions. In adults there is some evidence that transfusion efficacy of ABO blood group-identical platelets (PLTs) is superior to major-mismatched PLTs. However, in children this question has not been investigated for more than 30 years. STUDY DESIGN AND METHODS: In a prospective study, the efficacy (based on the 1-hour percentage of PLT recovery [PPR(1hr)]) of 400 eligible ABO blood group-identical or out-of-group apheresis PLT concentrates (APCs), transfused mainly prophylactically to 50 children with hematologic malignancies, solid tumors, or aplastic anemia was investigated. The primary objective was to compare PPR(1hr) between ABO-identical and major-mismatched transfusions. RESULTS: After ABO major-mismatched transfusions, PPR(1hr) was significantly lower than after ABO blood group-identical transfusions (median 21% vs. 32%; p = 0.034). Multivariate analysis showed major-mismatched transfusions to be significantly more often unsuccessful than identical transfusions (odds ratio [OR], 3.97; 95% confidence interval [CI], 1.52-10.39; p = 0.005). Using flow cytometry and fluorescent microscopy, it could be demonstrated that PLTs of subgroup A(1), significantly expressing A antigen on their surface, were rapidly cleared from the circulation of group O or B recipients. In contrast, major-mismatched transfusions of A(2) PLTs, expressing no detectable A antigen, were as successful as identical transfusions (OR, 1.13; 95% CI, 0.16-7.88; p = 0.90). CONCLUSION: These data clearly indicate that in children ABO major-mismatched PLT transfusions result in inferior transfusion efficacy, with the only exception of group A(2) PLTs. ABO minor-mismatched PLTs showed comparable efficacy to identical transfusions.

Karyotypic characterization of infant embryonal rhabdomyosarcoma

Despite embryonal rhabdomyosarcoma (eRMS) representing the most frequent form of RMS, the karyotypic characterization of this tumor subtype is still incomplete. We report the karyotypic analysis of two new cases of infant-onset eRMS. Both cases had a hyperdiploid karyotype, including gain of chromosomes 2 and 8. Only one of the cases showed a structural aberration, an unbalanced rearrangement involving 4p. These cases, together with a review of the literature, suggest that a karyotypic subgroup exists in infant eRMS that is defined by hyperdiploidy (<53 chromosomes) and includes gain of chromosomes 2, 8, 11, and 17, with few or no structural aberrations. Hence, this report illustrates that distinct karyotypic subgroups may be found in eRMS, which ultimately may be shown to have prognostic relevance.

Non-classical karyotypic features in relapsed childhood B-cell precursor acute lymphoblastic leukemia

Karyotype analysis of acute lymphoblastic leukemia (ALL) at diagnosis has provided valuable prognostic markers for treatment stratification. However, reports of cytogenetic studies of relapsed ALL samples are limited. We compared the karyotypes from 436 nonselected B-cell precursor ALL patients at initial diagnosis and of 76 patients at first relapse. We noticed a relative increase of karyotypes that did not fall into the classic ALL cytogenetic subgroups (high hyperdiploidy, t(12;21), t(9;22), 11q23, t(1;19), <45 chromosomes) in a group of 29 patients at relapse (38%) compared to 130 patients at presentation (30%). Non-classical cytogenetic aberrations in these 29 patients were mostly found on chromosomes 1, 2, 7, 9, 13, 14, and 17. We also describe six rare reciprocal translocations, three of which involved 14q32. The most frequent abnormalities were found in 9p (12/29 cases) and were associated with a marked decrease in the duration of the second remission, but not of the probability of 10-year event-free survival after relapse treatment. From 29 patients with non-classical cytogenetic aberrations, only 8 (28%) had been stratified to a high risk-arm on the first treatment protocol, suggesting that this subgroup might benefit from the identification of new prognostic markers in future studies.