Individual Clinical Outcome Research Articles

M71 - HIGH-THROUGHPUT ANTIBODY-BASED PROFILING OF SERUM IN SCHIZOPHRENIA AND BIPOLAR DISORDER PATIENTS: AN INTEGRATIVE GENOMICS-PROTEOMICS PILOT STUDY

Background The identification of biological markers in the peripheral blood for the prediction of the individual clinical outcome has an enormous potential in the frame of personalized medicine. Previous studies have already tried to create predictive models for major psychiatric disorders based on serum protein profiles though with inconclusive results. This study leverages the rich repertoire of biosamples available in the KFO241/PsyCourse cohort to perform a high-throughput antibody-based serum protein profiling. The aim of this pilot study is to establish the feasibility of such an analysis in the serum of these patients. This study also capitalizes on the availability of genomic data to carry out an integrative (genomics/proteomics) profiling. Methods Serum samples of 113 Schizophrenia (SCZ) and 125 Bipolar Disorder (BD) patients belonging to the German KFO241/PsyCourse cohort (www.kfo241.de; www.PsyCourse.de) were included in this study. All biomaterials in this cohort (blood, serum, plasma, DNA, RNA), available at different time points given its longitudinal design, are part of a high-end biobank. The expression of a selected panel of ~100 serum proteins was determined using a set of 155 antibodies in a high-throughput antibody-based assay. This suspension bead array technology enables a multiplexed protein profiling and it leverages the information generated by the Human Protein Atlas (www.proteinatlas.org). Median fluorescent intensities were log-transformed / standardized for downstream analyses. DNA samples were genotyped (Infinium PsychArray) and underwent genotype imputation (1000 Genomes Phase 3 ref. panel). Polygenic Risk Scores (PRS) were calculated by summing up the weighted effect of each SNP contributing to the PRS to obtain an individual estimate of SCZ genetic risk burden. Age, sex and ancestry principal components were used as covariates. Results Multivariate profiles based on the whole panel of quantified proteins did not significantly discriminate between both diagnoses (SCZ and BD). Single-protein ANCOVA analyses revealed, after Bonferroni correction, significant differences in C4B, CFB, VWF, NRG1, BACE1 and other proteins between SCZ and BD samples. High-risk versus Low-risk patients (according to PRS thresholds 5E-8, 5E-2 and 1) did not show a differential level of expression of these proteins. Likewise, polygenic risk did not correlate with the serum level of any of the proteins. Suggestive serum pQTL loci were identified. Discussion Our results confirm the feasibility and potential of this approach using serum samples of psychiatric patients. The observed differences in protein levels between diagnoses warrant replication in independent samples controlling the effect of medication. These results lay the groundwork for large-scale analyses for the discovery of predictive biomarkers of course, outcome and treatment response in SCZ and BD. Such an approach, joining the longitudinal phenotyping and biosample availability at four different time points in the KFO241/PsyCourse cohort with state-of-the-art biomarker quantification methodologies, holds promise for the generation of clinically-relevant predictive models in complex psychiatric disorders.

Monitoring CD49d Receptor Occupancy: A Method to Optimize and Personalize Natalizumab Therapy in Multiple Sclerosis Patients.

In natalizumab-treated relapsing-remitting MS (RRMS) patients, various extended interval dosing strategies are under evaluation to minimize severe treatment-associated side effects, mainly progressive multifocal leukoencephalopathy development. Up to now, it has not been presented any approach, even in form of assay design, to determine the optimal percentage of CD49d receptor occupancy (RO) associated with a favorable clinical, radiological, and immunological response. A multiparametric quantitative flow cytometry method was settled to measure CD49d RO on peripheral blood lymphocytes. The analytical protocol was tested in a 6-month follow-up from 19 RRMS patients treated with the natalizumab standard dosing of every 4 weeks or an extended-interval dosing of every 6 weeks. Extended natalizumab dose schedule promoted an increase of CD49d molecules per cell surface and a reduction of CD49d RO levels. The reduction observed on CD49d RO was not only depending on dose schedule but also on individual parameters such as body mass. Interestingly, individual clinical outcome was apparently the same between the different dose schedules or even better with the extended interval dosing. Following up CD49d RO levels with a well-regulated monitoring work scheme is crucial to further identify over-/under-treated patients and to define a safe, personalized natalizumab regimen. © 2017 International Clinical Cytometry Society.

Diagnostic and Prognostic Relevance of Magnetic Resonance Imaging and Electrophysiological Findings in Acute Spinal Ischemia

Our purpose was to classify the rare entity of spontaneous spinal ischemia with clinical, magnetic resonance-tomographic, and electrophysiological parameters to determine criteria for outcome prediction. We analyzed the stroke registry database of the University Hospital Mannheim, Germany, from 2004 to 2010 for patients with a diagnosis of vascular spinal cord ischemia. Ten patients were identified (mean age 65 years [range 50-83], 5 women). In 5 patients an etiology was found. Spinal diffusion-weighted magnetic resonance imaging revealed acute ischemia in 7 patients at initial imaging and this diagnosis was confirmed during the first week in the remaining 3 patients. Electrophysiological studies showed abnormal motor evoked potentials (MEPs) in 8 patients and abnormal somatosensory evoked potentials (SSEPs) in 7 patients. After rehabilitation, 5 patients had regained walking ability, whereas 5 patients stayed wheelchair bound. All patients with unfavorable outcome (American Spinal Injury Association (ASIA) Impairment score [AIS] score of ≤C) showed severe pyramidal tract lesions in MEPs during the first week. All patients with normal MEPs had an excellent outcome (AIS of E, P < .05). Diffusion-weighted imaging (DWI) is a useful tool to confirm acute spinal ischemia suspected in patients within the first days after symptom onset. Poor outcome was associated with severe electrophysiological abnormalities in MEPs and SSEPs. Normal MEPs were significantly predictive of an excellent prognosis. A multimodal diagnostic approach combining DWI and electrophysiological evaluation facilitates the prediction of the individual clinical outcome.

Measuring long radiographs affects the positioning of femoral components in total knee arthroplasty: a randomized controlled trial.

The aim of this study was to investigate if preoperative measurements of the femoral valgus angle (FVA) affected the mechanical alignment, individual component positions and clinical outcome in total knee arthroplasty (TKA). 120 patients were randomized into two groups. In one group (control), a fixed FVA for the intramedullary femoral guide was set at 7°, whereas in the other group (measured) FVA was measured preoperatively on long hip-knee-ankle radiographs, and the angle for the distal femoral cut was set accordingly. Preoperatively and 1year after TKA, range of motion (ROM) and Knee Society Score (KSS) were assessed. Postoperatively, the coronal alignments of the components and the mechanical alignment were measured comparing the rate of outliers which deviated more than 3° from the neutral mechanical axis. 104 patients remained for the radiological analysis (52 in each group). There were no significant differences either in the mean preoperative or postoperative mechanical alignment, or femoral or tibial component alignment; also, there were no differences in the number of postoperative mechanical axis or tibial component alignment outliers. However, the number of femoral component alignment outliers was significantly higher in the control group. 97 patients were available for clinical outcome analysis. Preoperatively, the groups did not differ significantly with respect to KSS or ROM. The postoperative ROM and KSS functional subscale scores were similar between the groups. However, there was slightly but significantly better postoperative KSS objective subscale score in the measured group. Preoperative FVA measurement and following femoral distal cut adjustments did not affect overall leg alignment postoperatively, while positioning of femoral component was improved together with minor improvements in objective KSS subscale scores.

EVOLUŢIA PARTICULARĂ A SINDROAMELOR LIMFOPROLIFERATIVE CRONICE ASOCIATE CU INFECŢIA CU VIRUS HEPATITIC B ŞI REACTIVAREA VIRALĂ – O PROBLEMĂ IMPORTANTĂ CU ABORDARE MULTIDISCIPLINARĂ

Background. The association of hepatitis B virus (HBV) infection with chronic lymphoproliferative disorders becomes a matter of debate, with multidisciplinary approach due to possible viral reactivation after immuno-chemotherapy. Material and methods. We studied two patient groups with chronic lymphoproliferative disorders, one with HBV infection (HbsAg+ and HbsAg- HbcAb+ HBs+/-) – 43 patients and one without viral infection (104 patients). Clinical and paraclinical parameters, therapy, survival of both groups were compared; the occurrence of viral reactivation was followed. Data were statistically analyzed. Results and discussion. The HBV infection group included HbsAg+-ve patients (72%) and occult HBV infection patients. The median onset age for lymphoproliferative disorders HBV+-ve was significantly younger (55 vs. 61 years, p&lt;0.05). Hepatomegaly and abdominal adenopathies were more frequent in HBV patients (p=0.003, respectively p=0.027). Hepatic function was altered in HBV patients both at disease onset (AST p=0.0213, GGT p=0.0002) and after first line therapy (AST p=0.0003, ALT p=0.019, FA p=0.008, GGT p=0.000, total bilirubine p=0.043, INR p=0.0003 and albumine p=0.05). The risk of hepatic dysfunction after first line therapy is increased 6 times by HBV infection (p=0.0009, OR=6.000, 95%CI: 1.9121-18.8272), which could negatively impact the hematological disease evolution by lowering therapeutic dose, leading to an inferior treatment result. Viral reactivation occurred both in HbsAg+-ve (21.42%) and HbsAg- HbcAb+-ve patients (60%). None of the occult carriers received antiviral prophylaxis. Whithin our occult carrier group, the viral reactivation percentage is high, therefore we would reccomand antiviral prophylaxis. The overall survival was similar in both group of patients. Conclusions. HBV-positive chronic lymphoproliferative disorders could become a new pathological entity, with individual clinical features and outcome and possibly with negative impact on long term survival. Antiviral prophylaxis for occult carriers could significantly reduce the viral reactivation rate and therefore the therapeutic guidelines should be revised.

Predictability of the individual clinical outcome of extracorporeal shock wave therapy for cellulite.

BackgroundExtracorporeal shock wave therapy has been successfully introduced for the treatment of cellulite in recent years. However, it is still unknown whether the individual clinical outcome of cellulite treatment with extracorporeal shock wave therapy can be predicted by the patient’s individual cellulite grade at baseline, individual patient age, body mass index (BMI), weight, and/or height.MethodsFourteen Caucasian females with cellulite were enrolled in a prospective, single-center, randomized, open-label Phase II study. The mean (± standard error of the mean) cellulite grade at baseline was 2.5±0.09 and mean BMI was 22.8±1.17. All patients were treated with radial extracorporeal shock waves using the Swiss DolorClast® device (Electro Medical Systems, S.A., Nyon, Switzerland). Patients were treated unilaterally with 2 weekly treatments for 4 weeks on a randomly selected side (left or right), totaling eight treatments on the selected side. Treatment was performed at 3.5–4.0 bar, with 15,000 impulses per session applied at 15 Hz. Impulses were homogeneously distributed over the posterior thigh and buttock area (resulting in 7,500 impulses per area). Treatment success was evaluated after the last treatment and 4 weeks later by clinical examination, photographic documentation, contact thermography, and patient satisfaction questionnaires.ResultsThe mean cellulite grade improved from 2.5±0.09 at baseline to 1.57±0.18 after the last treatment (ie, mean δ-1 was 0.93 cellulite grades) and 1.68±0.16 at follow-up (ie, mean δ-2 was 0.82 cellulite grades). Compared with baseline, no patient’s condition worsened, the treatment was well tolerated, and no unwanted side effects were observed. No statistically significant (ie, P<0.05) correlation was found between individual values for δ-1 and δ-2 and cellulite grade at baseline, BMI, weight, height, or age.ConclusionRadial shock wave therapy is a safe and effective treatment option for cellulite. The individual clinical outcome cannot be predicted by the patient’s individual cellulite grade at baseline, BMI, weight, height, or age.

Analysis of regional compliance in a porcine model of acute lung injury

Lung protective ventilation in Acute Lung Injury (ALI) focuses on using low tidal volumes and adequate levels of positive end-expiratory pressure (PEEP). Identifying optimal pressure is difficult because pressure–volume (PV) relations differ regionally. Precise analysis demands local measurements of pressures and related alveolar morphologies. In a porcine model of surfactant depletion (n=24), we combined measuring static pressures with endoscopic microscopy and electrical impedance tomography (EIT) to examine regional PV loops and morphologic heterogeneities between healthy (control group; CON) and ALI lungs ventilated with low (LVT) or high tidal volumes (HVT). Quantification included indices for microscopy (Volume Air Index (VAI), Heterogeneity and Circularity Index), EIT analysis and calculation of regional compliances due to generated PV loops.We found that: (1) VAI decreased in lower lobe after ALI, (2) electrical impedance decreased in dorsal regions and (3) PV loops differed regionally.Further studies should prove the potentials of these techniques on individual respiratory settings and clinical outcome.

Abstract 3658: The association of mitochondrial DNA content with bladder cancer risk and outcome

Abstract Mitochondrion plays essential role in energy production and apoptosis process from the initiation to regulation of apoptosis. Many studies have showed the association of dys-regulated mitochondrial DNA (mtDNA) with the development and progression of cancer, aging and longevity, and neurodegenerative diseases. In this study, we will test the hypothesis that variation in mtDNA content (also called mtDNA copy number) may be associated with individual's bladder cancer risk and clinical outcome in a case-control study of 1026 bladder cancer patients and 980 healthy-controls. We will also assess the association of mtDNA content with progression/recurrence in non-muscle invasive bladder cancer (NMIBC) patients and overall survival in muscle invasive and metastatic bladder cancer (MIMBC) patients. Quantitative real-time polymerase chain reaction in peripheral blood lymphocytes was used to measure mtDNA content. We observed significantly lower mtDNA content in bladder cancer patients (mean = 1.05, SD = 0.36) than controls (mean = 1.11, SD = 0.39) with P value &amp;lt; 0.001. When we categorized the mtDNA content using the quartile distribution in controls, Lower mtDNA content (less than 1st quantile) was associated with 1.69-fold increased risk of bladder cancer (95% confidence interval [CI] = 1.17 to 1.68), compared to those who have higher mtDNA content (greater than 4th quartile). In patients with MIMBC, we also observed the significant association of lower mtDNA content with poor survival. After categorizing the mtDNA content using quartile distribution in patients who were alive, there is a significantly increased risk of death for patients with lower mtDNA content (hazard ratio = 1.75, 95% CI = 1.11 to 2.77). There is also a significantly reduced median survival time (44.5 months vs 25.4 months, log-rank P = 0.004). However, there is no significant association of mtDNA content with progression/recurrence in NMIBC patients. In conclusion, low mtDNA content is associated with significantly increased risk of bladder cancer risk and poor survival. The resulted from our study will contribute to personalized risk prediction and may also become potential molecular targets for prevention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3658. doi:1538-7445.AM2012-3658

Axonal pathways linked to therapeutic and nontherapeutic outcomes during psychiatric deep brain stimulation

The underlying hypothesis of our work is that specific clinical neuropsychiatric benefits can be achieved by selective activation of specific axonal pathways during deep brain stimulation (DBS). As such, the goal of this study was to develop a method for identifying axonal pathways whose activation is most likely necessary for achieving therapeutic benefits during DBS. Our approach combined clinical data, diffusion tensor tractography, and computer models of patient-specific neurostimulation to identify particular axonal pathways activated by DBS and determine their correlations with individual clinical outcome measures. We used this method to evaluate a cohort of seven treatment-resistant depression patients treated with DBS of the ventral anterior internal capsule and ventral striatum (VC/VS). Clinical responders exhibited five axonal pathways that were consistently activated by DBS. All five pathways coursed lateral and medial to the VS or dorsal and lateral to the nucleus accumbens; however, details of their specific trajectories differed. Similarly, one common pathway was identified across nonresponders. Our method and preliminary results provide important background for studies aiming to expand scientific characterization of neural circuitry associated with specific psychiatric outcomes from DBS. Furthermore, identification of pathways linked to therapeutic benefit provides opportunities to improve clinical selection of surgical targets and stimulation settings for DBS devices.

Drug-induced Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS-TEN overlap: A multicentric retrospective study

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare immune-mediated severe cutaneous adverse reactions with incidence rate of 0.05 to 2 persons per million populations per year. Drugs are the most commonly implicated in 95% of cases. To audit the causative drugs, clinical outcome, and cost of management in SJS, TEN, and SJS-TEN overlap. Tertiary care hospitals-based multicentric retrospective study (case series). Indoor case papers of SJS, TEN, and SJS-TEN overlap admitted between January 2006 and December 2009 in four tertiary care hospitals of Gujarat were scrutinized. Data were collected for demographic information, causative drugs, investigations, treatment given, duration of hospital stay, time interval between onset of symptoms and drug intake, clinical outcome, and complications. Data were analyzed to find out proportion of individual drugs responsible, major complications, and clinical outcome in SJS, TEN, and SJS-TEN overlap. Total cost of management was calculated by using cost of drugs, investigations, and consumables used during entire hospital stay. One-way Analysis of Variance followed by Tukey-Kramer multiple comparison test was used for comparison of incubation period, duration of hospital stay, and cost of management. Antimicrobials (50%), nonsteroidal anti-inflammatory drugs (22.41%), and antiseizure drugs (18.96%) were the most commonly associated groups. Nevirapine (28.12%) was the most common drug. Antiseizure drugs were more often associated with serious form of adverse reaction (TEN: 81.8%) than other drugs. Duration of hospital stay (20.6 vs 9.7 days) and cost of management (7,910/- vs 2,460/-) were significantly higher in TEN than SJS (P=0.020 and P<0.001, respectively). Time duration between drug intake and onset of symptoms (17.7 vs 27.5 days) was nonsignificantly lower in TEN as compared with SJS. Secondary infection (28.12%) was the most common complication noted. Mortality rate was 15.6% among all cases; 9% in SJS and 26.7% in TEN. Antimicrobial drugs are the most commonly implicated drugs and cost of managing these adverse drug reactions is higher than other serious ADRs.

Preoperative neutrophil response as a predictive marker of clinical outcome following open heart surgery and the impact of leukocyte filtration☆,☆☆,☆☆☆

Open heart surgery is associated with a massive systemic inflammatory response. Neutrophils, are the main mediator of this response. We hypothesised that the degree of neutrophil activation and inflammatory response to open heart surgery varies individually and correlates with clinical outcome. The aim of this study was to determine if individual clinical outcome can be predicted preoperatively through assessment of in-vitro stimulated neutrophil responses. Following that, the effects of neutrophil depletion through leukocyte filters are examined. Neutrophil responses were assessed preoperatively (n=40) through change in neutrophil adhesion molecule [CD11b, CD62L and P Selectin Glycoprotein-1 (PSGL-1)] expression before and after in-vitro stimulation with Phorbol 12-myristate 13-acetate, PMA (1ng/ml), lipopolysaccharide, LPS (1μg/ml) and N-Formyl-Met-Leu-Phe, fMLP (1ng/ml). Stimulated neutrophil responses were then correlated with postoperative clinical outcome. Patients were then randomised to leukocyte filtration (n=20) and a control group (n=20) and the effect of leukocyte filtration on neutrophil response and clinical outcome were investigated. An individual variation in in-vitro stimulated neutrophil responses was demonstrated. Significant correlations were shown between neutrophil responses and maximum serum creatinine change, CKMB-fraction, adrenaline requirement, noradrenaline requirement, duration of adrenaline required and time to extubation. White cell count and percentage neutrophils were lower in the LD group (P=0.05). CD11b expression (P=0.005) and PSGL-1 expression (P=0.043) across leukocyte filters were also increased. However, no significant difference was detected in clinical outcome between the LD and control groups. Preoperative neutrophil responses to in-vitro stimuli can predict clinical outcome following open heart surgery. However, leukocyte filtration did not offer significant benefit in clinical outcome in our study.

First annual report of the Austrian CML registry

The Austrian chronic myeloid leukemia (CML) registry monitors individual disease courses, treatments applied, clinical outcome, and side effects of CML patients on a nationwide basis to provide data on the "real-life" situation and to complement the information and interpretation gained from the selected patient population observed in clinical trials. This report summarizes the Austrian CML registry data as of March 2009. A total of 179 patients have been registered with a median number of 1012 follow-up visits and median observation duration of 20 months. At diagnosis most patients (n = 163) were in chronic phase (early, late, and secondary), whereas only 4 were in advanced phase. A total of 137 patients were treated with tyrosine kinase inhibitors (TKIs), of which 14 received first and second generation TKIs sequentially. Other treatment modalities included chemotherapy or interferon and stem cell transplantation (SCT). Cumulative incidence rates for complete hematological responses (CHR) were 91.6% and 94.4% at 12 and 24 months, respectively, compared to cumulative incidence rates of complete cytogenetical response rates of 64% and 80% at these timepoints. A total of 5 patients progressed from chronic phase to accelerated (n = 3) and blastic phase (n = 2) while receiving imatinib standard dose. Estimated overall survival (OS) rate at 60 months was 90% and progression free survival (PFS) according to European Leukemia Net (ELN) failure definition was 58%.

Prognostic Ability of Practitioners of Traditional Arabic Medicine: Comparison with Western Methods through a Relative Patient Progress Scale

The ancient Greek medical theory based on balance or imbalance of humors disappeared in the western world, but does survive elsewhere. Is this survival related to a certain degree of health care efficiency? We explored this hypothesis through a study of classical Greco-Arab medicine in Mauritania. Modern general practitioners evaluated the safety and effectiveness of classical Arabic medicine in a Mauritanian traditional clinic, with a prognosis/follow-up method allowing the following comparisons: (i) actual patient progress (clinical outcome) compared with what the traditional ‘tabib’ had anticipated (= prognostic ability) and (ii) patient progress compared with what could be hoped for if the patient were treated by a modern physician in the same neighborhood. The practice appeared fairly safe and, on average, clinical outcome was similar to what could be expected with modern medicine. In some cases, patient progress was better than expected. The ability to correctly predict an individual's clinical outcome did not seem to be better along modern or Greco-Arab theories. Weekly joint meetings (modern and traditional practitioners) were spontaneously organized with a modern health centre in the neighborhood. Practitioners of a different medical system can predict patient progress. For the patient, avoiding false expectations with health care and ensuring appropriate referral may be the most important. Prognosis and outcome studies such as the one presented here may help to develop institutions where patients find support in making their choices, not only among several treatment options, but also among several medical systems.

Impact of evidence‐based interdisciplinary guidelines on testis cancer management

In 1999, interdisciplinary evidence-based guidelines were elaborated for treatment of germ cell tumors in Germany. The aims of the current study were to analyze failures in diagnosis and therapy and to demonstrate the influence of guidelines on individual therapeutic approaches and clinical outcome. Therefore, patient collectives treated before the introduction of guidelines (Group A, 1990-1999, n = 234) and those thereafter (Group B, 2000-2002, n = 84) were compared for recurrence and survival. In both groups, medical and/or surgical treatment and clinical outcome were evaluated for therapeutic mistakes and violations of guidelines. These were analyzed for their clinical consequences. There was no significant difference between groups concerning median age of patients or clinical stage before therapy. Altogether, 27.8% and 8.3% of all patients in Group A and B, respectively, displayed therapeutic mistakes (P < 0.005); 63% of these patients in Group A and 100% of these patients in Group B received an overtreatment. In Group A, 19/234 (8.1%) patients relapsed and 53% of these patients had been treated insufficiently (P < 0.005). Advanced disease caused the death of 3/234 patients in this study. As of this writing, only 3 of 84 (3.6%) patients in Group B have relapsed, and no patient has died because of tumor or consecutive treatment. The integration of interdisciplinary evidence-based guidelines for treatment of testicular germ cell tumors has led to significant reduction of both overtreatment and treatment failure and/or relapse that were due to inappropriate primary therapy. Evidence-based guidelines should serve as internal quality controls in all institutions treating patients with testicular germ cell tumors.

Bilateral near-infrared monitoring of the cerebral concentration and oxygen-saturation of hemoglobin during right unilateral electro-convulsive therapy

Reductions in right prefrontal cerebral blood flow have been correlated with symptomatic improvement in depressed individuals receiving electroconvulsive therapy (ECT). Non-invasive near infrared spectroscopy has previously been shown to reliably measure changes in cerebral hemoglobin concentrations and oxygen saturation. In this study, we measured the concentration and oxygen saturation of hemoglobin on the right and left frontal brain regions of nine patients during right unilateral ECT. In all patients, we have found that the electrically induced seizure causes a stronger cerebral deoxygenation on the side ipsilateral to the electrical current (−21±5%) with respect to the contralateral side (−6±4%). On the brain side ipsilateral to the ECT electrical discharge, we have consistently observed a discharge-induced decrease in the total hemoglobin concentration, i.e. in the cerebral blood volume, by −7±3 μM, as opposed to an average increase by 6±3 μM on the contralateral side. The ipsilateral decrease in blood volume is assigned to a vascular constriction associated with the electrical discharge, as indicated by the observed decrease in cerebral oxy-hemoglobin concentration and minimal change in deoxy-hemoglobin concentration during the electrical discharge on the side of the discharge. These findings provide indications about the cerebral hemodynamic/metabolic mechanisms associated with ECT, and may lead to useful parameters to predict the individual clinical outcome of ECT.

Novel concepts in the staging of renal cell carcinoma.

The incidence of renal cell carcinoma (RCC) continues to rise steadily; unfortunately, our ability to cure patients with metastatic RCC remains limited. When developing and evaluating new treatment protocols, it is important to consider the role of prognostic factors, often defined as pretreatment features, that are predictive of outcome. The complexity and variability of patients' individual clinical outcome and the recently recognized limitation of conventional staging systems have lead to the formulation of integrated prognostic staging systems. In this review, we discuss the evolution of various clinically relevant integrated staging systems for RCC.

Staging small cell lung cancer: Veterans Administration Lung Study Group versus International Association for the Study of Lung Cancer—what limits limited disease?

Small cell lung cancer (SCLC) is usually classified into a two-stage system, limited (LD) and extensive disease (ED). However, the criteria for these two categories remain controversial. The widely used Veterans Administration Lung Study Group (VALG) definition of LD includes patients with primary tumor and nodal involvement limited to one hemithorax. In contrast, the International Association for the Study of Lung Cancer (IASLC) recommends that LD should additionally include all patients without distant metastasis. As a consequence, since treatment modalities for LD and ED could be different, individual clinical outcome of SCLC patients may be influenced by the staging system chosen. Among 109 consecutive SCLC patients treated in our clinic between 1989 and 1999 (mean age 68±9.1 years, 81% male) 23 patients (21%) could be either classified as LD or ED (LD-ED), depending on the staging system used. The prognosis of this overlapping group (LD-ED: median survival 291 days) was not statistically different from patients with limited disease defined by VALG criteria (LD-VALG: 385 days, log–rank test P=0.42). On the other hand the survival difference between LD-ED patients and the ED-IASLC population was relevant (ED-IASLC: 208 days, P=0.05), indicating that LD-ED patients should rather be included in the LD category. This is further supported by the results of a multivariate Cox regression analysis with all clinically relevant data. Only stage as defined by IASLC criteria was an independent prognostic factor in the likelihood-ratio-forward (hazard ratio=1.94, CI=1.26–2.99; P=0.005) and backward model (hazard ratio=1.76, CI: 1.12–2.76; P=0.012), confirming the higher discriminatory power of the IASLC definition. In conclusion, the IASLC staging criteria for SCLC patients have a higher prognostic impact and are therefore preferable in clinical practice and future therapeutic trials.

Individual blood-brain barrier phenylalanine transport determines clinical outcome in phenylketonuria.

Different clinical outcomes in spite of comparable dietary controls are well known in patients with phenylketonuria. Currently, reasons for this phenomenon are unknown. Kinetic investigations in 15 patients with classic phenylketonuria were performed using in vivo nuclear magnetic resonance spectroscopy before and after an oral phenylalanine load (100 mg/kg body weight). Patients' brain phenylalanine concentrations were quite different in spite of similar blood phenylalanine levels. Interindividual variations of the apparent transport Michaelis constant, K(t,app), covered a range from 0.10 to 1.03 mmol/L. The ratio of the maximal transport velocity, Tmax, over the intracerebral consumption rate, Vmet, varied between 2.61 and 14.0. Both parameters as well as the preload brain phenylalanine levels correlated significantly with the degree of cerebral white matter abnormalities on magnetic resonance images. Correlations of K(t,app), Tmax/Vmet, and the preload brain phenylalanine levels with patients' intelligence scores approached significance. In conclusion, blood-brain barrier phenylalanine transport characteristics and the resultant brain phenylalanine levels seem to be causative factors for the individual clinical outcome in phenylketonuria. This observation may lead to individual dietary recommendations in the future.

Prediction of survival in extrahepatic biliary atresia by hepatic duplex sonography.

The clinical course of biliary atresia patients is extremely variable. To optimize conservative treatment and correctly schedule liver transplantation, noninvasive investigations that are predictive of individual survival and that can be performed regularly are needed. In this study, the prognostic value of Doppler sonography was investigated in these patients. Thirty biliary atresia patients (age range, 1 month to 15.2 years; mean, 4.0 years) and 38 control subjects underwent standardized Doppler sonography of liver and spleen. Biochemical tests of liver function and of fibrogenesis were performed in parallel. Individual clinical outcome was registered 1 and 2 years later. In control subjects, maximum portal flow velocity (Vmax) was more than 16 cm/sec, and the hepatic vein flow pattern was triphasic. Among children with biliary atresia, those with diminished portal Vmax, a flattened hepatic vein flow curve, or a hepatic artery resistance index of 0.8 or more had significantly lower indices of hepatic protein synthesis (albumin, cholinesterase), higher bilirubin levels, and higher concentrations of markers of connective tissue turnover (procollagen peptides, laminin P1) than did those with normal Doppler sonography measurements. The rate of survival without transplantation during the following 2 years was significantly lower in children with abnormal Doppler findings. From portal and hepatic vein flow measurements, patient survival 2 years later could be predicted with an accuracy of 93%. In children with extrahepatic biliary atresia, Doppler sonography of the hepatic blood flow is a noninvasive indicator of disease severity. Moreover, it allows a highly accurate prediction of patient survival for the following 2 years.

Blood-brain barrier phenylalanine transport and individual vulnerability in phenylketonuria.

In vivo nuclear magnetic resonance spectroscopy can be used to measure intracerebral phenylalanine (Phe) concentrations in patients with phenylketonuria (PKU). Stationary levels, obtained under free nutrition, as well as time courses after an oral Phe load (100 mg/kg) were investigated in 11 PKU patients and were correlated with the individual clinical outcome. At blood levels around 1.2 mmol/L, brain Phe was 0.41 to 0.73 mmol/L in clinically "typical" patients, but less than 0.15 mmol/L in three untreated, normally intelligent, adult women. Kinetic investigations revealed higher transport Michaelis constants and lower ratios of the brain influx and consumption rates in these women than in the "typical" control patients (Kt,app = 0.45 to 1.10 mmol/L versus 0.10 mmol/L; T(max)/v(met) = 2.55 to 3.19 versus 7.8 to 14.0). Such variations seem to be major causative factors for the individual vulnerability to PKU.