Assessment of panobacumab as adjunctive immunotherapy for the treatment of nosocomial Pseudomonas aeruginosa pneumonia.

The fully human anti-lipopolysaccharide (LPS) immunoglobulin M (IgM) monoclonal antibody panobacumab was developed as an adjunctive immunotherapy for the treatment of O11 serotype Pseudomonas aeruginosa infections. We evaluated the potential clinical efficacy of panobacumab in the treatment of nosocomial pneumonia. We performed a post-hoc analysis of a multicenter phase IIa trial (NCT00851435) designed to prospectively evaluate the safety and pharmacokinetics of panobacumab. Patients treated with panobacumab (n = 17), including 13 patients receiving the full treatment (three doses of 1.2 mg/kg), were compared to 14 patients who did not receive the antibody. Overall, the 17 patients receiving panobacumab were more ill. They were an average of 72 years old [interquartile range (IQR): 64-79] versus an average of 50 years old (IQR: 30-73) (p = 0.024) and had Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of 17 (IQR: 16-22) versus 15 (IQR: 10-19) (p = 0.043). Adjunctive immunotherapy resulted in an improved clinical outcome in the group receiving the full three-course panobacumab treatment, with a resolution rate of 85 % (11/13) versus 64 % (9/14) (p = 0.048). The Kaplan-Meier survival curve showed a statistically significantly shorter time to clinical resolution in this group of patients (8.0 [IQR: 7.0-11.5] versus 18.5 [IQR: 8-30] days in those who did not receive the antibody; p = 0.004). Panobacumab adjunctive immunotherapy may improve clinical outcome in a shorter time if patients receive the full treatment (three doses). These preliminary results suggest that passive immunotherapy targeting LPS may be a complementary strategy for the treatment of nosocomial O11 P. aeruginosa pneumonia.

Difficult-to-engage patients: a specific target for time-limited assertive outreach in a Swiss setting.

OBJECTIVE: Assertive community treatment (ACT) failed to develop in Europe, and its efficacy is debated. In Lausanne, Switzerland, ACT focuses on difficult-to-engage patients and aims to facilitate linkage with outpatient care through time-limited interventions. This study aimed to evaluate the applicability and efficiency of time-limited ACT. METHODS: We retrospectively assessed social, clinical, and functional outcomes and motivation for treatment in 75 consecutively seen subjects treated between 2000 and 2002. RESULTS: With 70% of the interventions lasting less than 6 months, we observed significant improvement in most clinical and social problems, in collaboration, in motivation for treatment, and in social network support, despite high baseline levels of clinical and social problems. The number of hospitalizations decreased significantly. CONCLUSIONS: Time-limited ACT is a useful treatment for difficult-to-engage patients with severe clinical and social problems, and it facilitates linkage to care. This narrower target for ACT may facilitate its implementation in Europe.

Surgical treatment of perforated peptic ulcer. Is there a need for a change?

The aim of this study is to evaluate the risk and the results of surgical treatment for perforated peptic ulcer (PPU), to compare them through time, and to determine the current optimal surgical treatment. In a retrospective study, the charts of all the patients admitted for PPU between January 1976 and October 1991 were reviewed. The features believed to be of importance in the outcome were assessed for statistical analysis. A comparison was made between three periods of the study (1976-1980, 1981-1985, 1986-1991). 247 patients were included. Mortality was 11.7% (29/247). Factors associated with an increased mortality were: shock on admission (p = 0.01), age (p < 0.001), severe associated medical illnesses (p < 0.001) and the form of treatment (p < 0.01). After multivariate analysis, only shock on admission and associated disease remained significant. Chronic peptic ulcer disease occurred in 76% of the patients. Comparing the periods showed that age, associated illnesses, percentage of acute or subacute ulcers, mortality, as well as the number of patients, are increasing. The main determinant of surgical treatment for PPU is the patient and his/her general state. Because of the high frequency of chronic peptic ulcer disease, we believe that the gold standard in the treatment for PPU remains definitive surgery. However, in the presence of more than one risk factor, suture and patch are probably safer.

Long-term antiretroviral treatment initiated at primary HIV-1 infection affects the size, composition, and decay kinetics of the reservoir of HIV-1-infected CD4 T cells.

Initiation of antiretroviral therapy during the earliest stages of HIV-1 infection may limit the seeding of a long-lasting viral reservoir, but long-term effects of early antiretroviral treatment initiation remain unknown. Here, we analyzed immunological and virological characteristics of nine patients who started antiretroviral therapy at primary HIV-1 infection and remained on suppressive treatment for >10 years; patients with similar treatment duration but initiation of suppressive therapy during chronic HIV-1 infection served as controls. We observed that independently of the timing of treatment initiation, HIV-1 DNA in CD4 T cells decayed primarily during the initial 3 to 4 years of treatment. However, in patients who started antiretroviral therapy in early infection, this decay occurred faster and was more pronounced, leading to substantially lower levels of cell-associated HIV-1 DNA after long-term treatment. Despite this smaller size, the viral CD4 T cell reservoir in persons with early treatment initiation consisted more dominantly of the long-lasting central-memory and T memory stem cells. HIV-1-specific T cell responses remained continuously detectable during antiretroviral therapy, independently of the timing of treatment initiation. Together, these data suggest that early HIV-1 treatment initiation, even when continued for >10 years, is unlikely to lead to viral eradication, but the presence of low viral reservoirs and durable HIV-1 T cell responses may make such patients good candidates for future interventional studies aiming at HIV-1 eradication and cure. IMPORTANCE: Antiretroviral therapy can effectively suppress HIV-1 replication to undetectable levels; however, HIV-1 can persist despite treatment, and viral replication rapidly rebounds when treatment is discontinued. This is mainly due to the presence of latently infected CD4 T cells, which are not susceptible to antiretroviral drugs. Starting treatment in the earliest stages of HIV-1 infection can limit the number of these latently infected cells, raising the possibility that these viral reservoirs are naturally eliminated if suppressive antiretroviral treatment is continued for extremely long periods of time. Here, we analyzed nine patients who started on antiretroviral therapy within the earliest weeks of the disease and continued treatment for more than 10 years. Our data show that early treatment accelerated the decay of infected CD4 T cells and led to very low residual levels of detectable HIV-1 after long-term therapy, levels that were otherwise detectable in patients who are able to maintain a spontaneous, drug-free control of HIV-1 replication. Thus, long-term antiretroviral treatment started during early infection cannot eliminate HIV-1, but the reduced reservoirs of HIV-1 infected cells in such patients may increase their chances to respond to clinical interventions aiming at inducing a drug-free remission of HIV-1 infection.

Longer term clinical and virological outcome of sub-Saharan African participants on antiretroviral treatment in the Swiss HIV Cohort Study.

OBJECTIVES: Persons from sub-Saharan Africa (SSA) are increasingly enrolled in the Swiss HIV Cohort Study (SHCS). Cohorts from other European countries showed higher rates of viral failure among their SSA participants. We analyzed long-term outcomes of SSA versus North Western European participants. DESIGN: We analyzed data of the SHCS, a nation-wide prospective cohort study of HIV-infected adults at 7 sites in Switzerland. METHODS: SSA and North Western European participants were included if their first treatment combination consisted of at least 3 antiretroviral drugs (cART), if they had at least 1 follow-up visit, did not report active injecting drug use, and did not start cART with CD4 counts >200 cells per microliter during pregnancy. Early viral response, CD4 cell recovery, viral failure, adherence, discontinuation from SHCS, new AIDS-defining events, and survival were analyzed using linear regression and Cox proportional hazard models. RESULTS: The proportion of participants from SSA within the SHCS increased from 2.6% (<1995) to 20.8% (2005-2009). Of 4656 included participants, 808 (17.4%) were from SSA. Early viral response (6 months) and rate of viral failure in an intent-to-stay-on-cART approach were similar. However, SSA participants had a higher risk of viral failure on cART (adjusted hazard ratio: 2.03, 95% confidence interval: 1.50 to 2.75). Self-reported adherence was inferior for SSA. There was no increase of AIDS-defining events or mortality in SSA participants. CONCLUSIONS: Increased attention must be given to factors negatively influencing adherence to cART in participants from SSA to guarantee equal longer-term results on cART.

Computational analysis of the genetic and environmental contributions to disease-related human phenotypes: From predicting adverse lipid response of HIV patients receiving antiretroviral therapy to genome-wide association studies of cardiovascular and lipid related disorders

Genetic variants influence the risk to develop certain diseases or give rise to differences in drug response. Recent progresses in cost-effective, high-throughput genome-wide techniques, such as microarrays measuring Single Nucleotide Polymorphisms (SNPs), have facilitated genotyping of large clinical and population cohorts. Combining the massive genotypic data with measurements of phenotypic traits allows for the determination of genetic differences that explain, at least in part, the phenotypic variations within a population. So far, models combining the most significant variants can only explain a small fraction of the variance, indicating the limitations of current models. In particular, researchers have only begun to address the possibility of interactions between genotypes and the environment. Elucidating the contributions of such interactions is a difficult task because of the large number of genetic as well as possible environmental factors.In this thesis, I worked on several projects within this context. My first and main project was the identification of possible SNP-environment interactions, where the phenotypes were serum lipid levels of patients from the Swiss HIV Cohort Study (SHCS) treated with antiretroviral therapy. Here the genotypes consisted of a limited set of SNPs in candidate genes relevant for lipid transport and metabolism. The environmental variables were the specific combinations of drugs given to each patient over the treatment period. My work explored bioinformatic and statistical approaches to relate patients' lipid responses to these SNPs, drugs and, importantly, their interactions. The goal of this project was to improve our understanding and to explore the possibility of predicting dyslipidemia, a well-known adverse drug reaction of antiretroviral therapy. Specifically, I quantified how much of the variance in lipid profiles could be explained by the host genetic variants, the administered drugs and SNP-drug interactions and assessed the predictive power of these features on lipid responses. Using cross-validation stratified by patients, we could not validate our hypothesis that models that select a subset of SNP-drug interactions in a principled way have better predictive power than the control models using "random" subsets. Nevertheless, all models tested containing SNP and/or drug terms, exhibited significant predictive power (as compared to a random predictor) and explained a sizable proportion of variance, in the patient stratified cross-validation context. Importantly, the model containing stepwise selected SNP terms showed higher capacity to predict triglyceride levels than a model containing randomly selected SNPs. Dyslipidemia is a complex trait for which many factors remain to be discovered, thus missing from the data, and possibly explaining the limitations of our analysis. In particular, the interactions of drugs with SNPs selected from the set of candidate genes likely have small effect sizes which we were unable to detect in a sample of the present size (<800 patients).In the second part of my thesis, I performed genome-wide association studies within the Cohorte Lausannoise (CoLaus). I have been involved in several international projects to identify SNPs that are associated with various traits, such as serum calcium, body mass index, two-hour glucose levels, as well as metabolic syndrome and its components. These phenotypes are all related to major human health issues, such as cardiovascular disease. I applied statistical methods to detect new variants associated with these phenotypes, contributing to the identification of new genetic loci that may lead to new insights into the genetic basis of these traits. This kind of research will lead to a better understanding of the mechanisms underlying these pathologies, a better evaluation of disease risk, the identification of new therapeutic leads and may ultimately lead to the realization of "personalized" medicine.

Involuntary treatment of alcohol-dependent patients: a study of 17 consecutive cases of civil commitment.

AIM: To investigate the baseline and follow-up characteristics of a group of alcohol-dependent patients being treated under civil commitment. METHODS: This study involved a cross-sectional comparative analysis of baseline characteristics and a follow-up survey of a group of committed alcoholic patients. The study was undertaken in the Alcohol Unit of a 1,000-bed general and university hospital. The study included 17 consecutive cases of civil commitment (representing 15 patients, of whom 2 were committed twice) and a comparative group of 34 randomly selected age- and sex-matched patients. Baseline characteristics of the cases (at the time of commitment) and of patients from the comparative group were collected from medical records, including sociodemographic data, medical condition, patterns of drinking and number and dates of previous treatments for alcohol-related problems. A structured follow-up interview of the cases provided information on their medical condition, social status, patterns of alcohol use, type and duration of residential treatment as well as their perceptions of commitment. RESULTS: During a 4-year period, our Unit referred 23 cases of alcohol-dependent patients (out of 367) to the Guardianship Authority, requesting civil commitment. On 17 occasions, patients were committed to residential treatment, including 2 patients who underwent commitment on two separate occasions, thus representing a total of 15 different patients. In comparison with age- and sex-matched patients seen at the Unit, the cases were characterized by multiple medical, social and psychological alcohol-related impairments. At the time of follow-up, 14 out of 15 patients were alive, among whom 10 agreed to be interviewed. Eight of these reported complete abstinence, whereas 9 considered their alcohol problem as less severe than before. The average duration of commitment was 29 weeks. The majority of patients retrospectively considered the measure as having been justified and useful. The patients' satisfaction with the decision to commit was higher among women than among men. Health-related quality of life at the time of follow-up, as assessed by the MOS 36-Item Short Form Health Survey questionnaire, was good on average and better than that usually reported by other cohorts of alcoholics undergoing treatment. CONCLUSIONS: The usefulness of residential civil commitment of certain severely impaired alcohol-dependent patients is underscored. This study suggests that civil commitment not only may save the lives of endangered patients but could also be a health-promoting measure that may sometimes allow for recovery from dependence. Unexpectedly, this measure was retrospectively well accepted by many patients, who considered the commitment decision as having been justified and useful.

Traitement des plagiocéphalies postérieures d'origine positionnelle [Treatment of posterior positional plagiocephaly]

In 1992, the American academy of paediatrics has recommended that infants be placed on their backs to sleep, because prone sleeping has been correlated with sudden infant death syndrome. Following this article, medical paediatric community has documented an exponential increase in the diagnosis of posterior cranial deformities, which were considered as the consequence of unrelieved pressure onto the occiput during infant sleep. These last 15 years, management of posterior positional plagiocephaly has evolved but is still not standardized; it varies according to local specificities, and medical or parental preferences. Treatment of deformational plagiocephaly includes preventive counseling, repositioning adjustments and exercises, physiotherapy, osteopathy, treatment by dynamic cranial orthosis. On extremely rare occasions, corrective surgery is proposed. This article aims at reviewing the epidemiologic, diagnostic, and various therapeutic options of posterior positional plagiocephaly.

Treatment of brain metastases from non-small cell lung cancer with whole-brain radiotherapy (wbrt) in combination with gefitinib (gft) or temozolomide (tmz): a randomized multicenter phase ii trial of the swiss group of clinical cancer research (sakk #70/03)

BACKGROUND: Patients with BM rarely survive .6 months and are commonly excluded from clinical trials. We aimed at improving outcome by exploring 2 combined modality regimens with at the time novel agents for which single-agent activity had been shown. METHODS: NSCLC patients with multiple BM were randomized to WBRT (10 × 3 Gy) and either GFT 250 mg p.o. daily or TMZ 75 mg/m2 p.o. daily ×21/28 days, starting on Day 1 of RT and to be continued until PD. Primary endpoint was overall survival, a Simon's optimal 2-stage design was based on assumptions for the 3-month survival rate. Cognitive functioning and quality of life were also evaluated. RESULTS: Fifty-nine patients (36 M, 23 F; 9 after prior chemo) were included. Median age was 61 years (range 46-82), WHO PS was 0 in 18 patients, 1 in 31 patients, and 2 in 10 patients. All but 1 patients had extracranial disease; 33 of 43 (TMZ) and 15 of 16 (GFT) had adenocarcinoma histology. GFT arm was closed early after stage 1 analysis when the prespecified 3-mo survival rate threshold (66%) was not reached, causes of death were not GFT related. Main causes of death were PD in the CNS 24%, systemic 41%, both 8%, and toxicity 10% [intestinal perforation (2 patients), pneumonia (2), pulmonary emboli (1), pneumonitis NOS (1), seizure (1)]. We summarize here other patients' characteristics for the 2 trial arms: TMZ (n ¼ 43)/GFT (n ¼ 16); median treatment duration: 1.6 /1.8 mo; Grade 3-4 toxicity: lymphopenia 5 patients (12%)/0; fatigue 8 patients (19%)/2 patients (13%). Survival data for TMZ/GFT arms: 3-month survival rate: 58.1% (95% CI 42.1-73)/62.5% (95% CI 35- 85); median OS: 4.9 months (95% CI 2.5-5.6)/6.3 months (95% CI 2.2- 14.6); median PFS: 1.8 months (95% CI 1.5-1.8)/1.8 (95% CI 1.1-3.9); median time to neurol. progr.: 8.0 months (95% CI 2.2-X)/4.8 (95% CI 3.9-10.5). In a model to predict survival time including the variables' age, PS, number of BM, global QL, total MMSE score, and subjective cognitive function, none of the variables accounted for a significant improvement in survival time. CONCLUSIONS: The combinations of WBRT with GFT or TMZ were feasible. However, in this unselected patient population, survival remains poor and a high rate of complication was observed. Four patients died as a result of high-dose corticosteroids. Preliminary evaluation of cognitive function andQL failed to show significant improvement. Indications and patient selection for palliative treatment should be revisited and careful monitoring and supportive care is required. Research and progress for this frequent clinical situation is urgently needed. Trial partly supported by AstraZeneca (Switzerland), Essex Chemie (Switzerland) and Swiss Federal Government.

The INTERMED questionnaire for predicting return to work after a multidisciplinary rehabilitation program for chronic low back pain.

OBJECTIVES: To evaluate the performance of the INTERMED questionnaire score, alone or combined with other criteria, in predicting return to work after a multidisciplinary rehabilitation program in patients with non-specific chronic low back pain. METHODS: The INTERMED questionnaire is a biopsychosocial assessment and clinical classification tool that separates heterogeneous populations into subgroups according to case complexity. We studied 88 patients with chronic low back pain who followed an intensive multidisciplinary rehabilitation program on an outpatient basis. Before the program, we recorded the INTERMED score, radiological abnormalities, subjective pain severity, and sick leave duration. Associations between these variables and return to full-time work within 3 months after the end of the program were evaluated using one-sided Fisher tests and univariate logistic regression followed by multivariate logistic regression. RESULTS: The univariate analysis showed a significant association between the INTERMED score and return to work (P<0.001; odds ratio, 0.90; 95% confidence interval, 0.86-0.96). In the multivariate analysis, prediction was best when the INTERMED score and sick leave duration were used in combination (P=0.03; odds ratio, 0.48; 95% confidence interval, 0.25-0.93). CONCLUSION: The INTERMED questionnaire is useful for evaluating patients with chronic low back pain. It could be used to improve the selection of patients for intensive multidisciplinary programs, thereby improving the quality of care, while reducing healthcare costs.

Predictors of the Indefinite-Duration Anticoagulation Treatment Strategy In Patients with Cancer Associated Thrombosis

Background: In patients with cancer and acute venous thromboembolism (VTE), current consensus guidelines recommend anticoagulation therapy for an indefinite duration or until the cancer is resolved. Methods and results: Among 1'247 patients with acute VTE enrolled in the Swiss Venous Thromboembolism Registry (SWIVTER) from 18 hospitals, 315 (25%) had cancer of whom 179 (57%) had metastatic disease, 159 (50%) ongoing or recent chemotherapy, and 83 (26%) tumor surgery within 6 months. Patients with cancer were older (66±14 vs. 60±19 years, p<0.001), more often hospitalized at the time of VTE diagnosis (46% vs. 36%, p=0.001), immobile for >3 days (25% vs. 16%, p<0.001), and more often had thrombocytopenia (6% vs. 1%, p<0.001) than patients without cancer. The 30-day rate of VTE-related death or recurrent VTE was 9% in cancer patients vs. 4% in patients without cancer (p<0.001), and the rates of bleeding requiring medical attention were 5% in both groups (p=0.57). Cancer patients received indefinite-duration anticoagulation treatment more often than patients without cancer (47% vs. 19%, p<0.001), and LMWH mono-therapy during the initial 3 months was prescribed to 45% vs. 8%, p<0.001, respectively. Among patients with cancer, prior VTE (OR 4.0, 95%CI 2.0-8.0), metastatic disease (OR 3.0, 95%CI 1.7-5.2), outpatient status at the time of VTE diagnosis (OR 3.8, 95%CI 1.9-7.6), and inpatient treatment (OR 4.4, 95%CI 2.1-9.2) were independently associated with the prescription of indefinite-duration anticoagulation treatment. Conclusions: Less than half of the cancer patients with acute VTE received a prescription for indefinite-duration anticoagulation treatment. Recurrent VTE, metastatic cancer, outpatient VTE diagnosis, and VTE requiring hospitalization were associated with an increased use of this strategy.

An international validation study of the EORTC brain cancer module (EORTC QLQ-BN20) for assessing health-related quality of life and symptoms in brain cancer patients.

Aims: The psychometric properties of the EORTC QLQ-BN20, a brain cancer-specific HRQOL questionnaire, have been previously determined in an English-speaking sample of patients. This study examined the validity and reliability of the questionnaire in a multi-national, multi-lingual study. Methods: QLQ-BN20 data were selected from two completed phase III EORTC/NCIC clinical trials in brain cancer (N=891), including 12 languages. Experimental treatments were surgery followed by radiotherapy (RT) and adjuvant PCV chemotherapy or surgery followed by concomitant RT plus temozolomide (TMZ) chemotherapy and adjuvant TMZ chemotherapy. Standard treatment consisted of surgery and postoperative RT alone. The psychometrics of the QLQ-BN20 were examined by means of multi-trait scaling analyses, reliability estimation, known groups validity testing, and responsiveness analysis. Results: All QLQ-BN20 items correlated more strongly with their own scale (r>0.70) than with other QLQ-BN20 scales. Internal consistency reliability coefficients were high (all alpha0.70). Known-groups comparisons yielded positive results, with the QLQ-BN20 distinguishing between patients with differing levels of performance status and mental functioning. Responsiveness of the questionnaire to changes over time was acceptable. Conclusion: The QLQ-BN20 demonstrates adequate psychometric properties and can be recommended for use in conjunction with the QLQ-C30 in assessing the HRQOL of brain cancer patients in international studies.

Telementoring during endovascular treatment of abdominal aortic aneurysms: a prospective study.

PURPOSE: To explore the use of telementoring for distant teaching and training in endovascular aortic aneurysm repair (EVAR). METHODS: According to a prospectively designed study protocol, 48 patients underwent EVAR: the first 12 patients (group A) were treated at a secondary care center by an experienced interventionist, who was training the local team; a further 12 patients (group B) were operated by the local team at their secondary center with telementoring by the experienced operator from an adjacent suite; and the last 24 patients (group C) were operated by the local team with remote telementoring support from the experienced interventionist at a tertiary care center. Telementoring was performed using 3 video sources; images were transmitted using 4 ISDN lines. EVAR was performed using intravascular ultrasound and simultaneous fluoroscopy to obtain road mapping of the abdominal aorta and its branches, as well as for identifying the origins of the renal arteries, assessing the aortic neck, and monitoring the attachment of the stent-graft proximally and distally. RESULTS: Average duration of telementoring was 2.1 hours during the first 12 patients (group B) and 1.2 hours for the remaining 24 patients (group C). There was no difference in procedural duration (127+/-59 minutes in group A, 120+/-4 minutes in group B, and 119+/-39 minutes in group C; p=0.94) or the mean time spent in the ICU (26+/-15 hours in group A, 22+/-2 hours in group B, and 22+/-11 hours for group C; p=0.95). The length of hospital stay (11+/-4 days in group A, 9+/-4 days in group B, and 7+/-1 days in group C; p=0.002) was significantly different only for group C versus A (p=0.002). Only 1 (8.3%) patient (in group A: EVAR performed by the experienced operator) required conversion to open surgery because of iliac artery rupture. This was the only conversion (and the only death) in the entire study group (1/12 in group A versus 0/36 in groups B + C, p=0.31). CONCLUSIONS: Telementoring for EVAR is feasible and shows promising results. It may serve as a model for development of similar projects for teaching other invasive procedures in cardiovascular medicine.

Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen.

Background: Estrogen receptor positive (ER+) breast cancers (BC) are heterogeneous with regard to their clinical behavior and response to therapies. The ER is currently the best predictor of response to the anti-estrogen agent tamoxifen, yet up to 30-40% of ER+ BC will relapse despite tamoxifen treatment. New prognostic biomarkers and further biological understanding of tamoxifen resistance are required. We used gene expression profiling to develop an outcome-based predictor using a training set of 255 ER+ BC samples from women treated with adjuvant tamoxifen monotherapy. We used clusters of highly correlated genes to develop our predictor to facilitate both signature stability and biological interpretation. Independent validation was performed using 362 tamoxifen-treated ER+ BC samples obtained from multiple institutions and treated with tamoxifen only in the adjuvant and metastatic settings.Results: We developed a gene classifier consisting of 181 genes belonging to 13 biological clusters. In the independent set of adjuvantly-treated samples, it was able to define two distinct prognostic groups (HR 2.01 95% CI: 1.29-3.13; p = 0.002). Six of the 13 gene clusters represented pathways involved in cell cycle and proliferation. In 112 metastatic breast cancer patients treated with tamoxifen, one of the classifier components suggesting a cellular inflammatory mechanism was significantly predictive of response.Conclusion: We have developed a gene classifier that can predict clinical outcome in tamoxifen-treated ER+ BC patients. Whilst our study emphasizes the important role of proliferation genes in prognosis, our approach proposes other genes and pathways that may elucidate further mechanisms that influence clinical outcome and prediction of response to tamoxifen.

Transcranial Doppler for predicting delayed cerebral ischemia after subarachnoid hemorrhage.

OBJECTIVE: Transcranial Doppler (TCD) is widely used to monitor the temporal course of vasospasm after subarachnoid hemorrhage (SAH), but its ability to predict clinical deterioration or infarction from delayed cerebral ischemia (DCI) remains controversial. We sought to determine the prognostic utility of serial TCD examination after SAH. METHODS: We analyzed 1877 TCD examinations in 441 aneurysmal SAH patients within 14 days of onset. The highest mean blood flow velocity (mBFV) value in any vessel before DCI onset was recorded. DCI was defined as clinical deterioration or computed tomographic evidence of infarction caused by vasospasm, with adjudication by consensus of the study team. Logistic regression was used to calculate adjusted odds ratios for DCI risk after controlling for other risk factors. RESULTS: DCI occurred in 21% of patients (n = 92). Multivariate predictors of DCI included modified Fisher computed tomographic score (P = 0.001), poor clinical grade (P = 0.04), and female sex (P = 0.008). After controlling for these variables, all TCD mBFV thresholds between 120 and 180 cm/s added a modest degree of incremental predictive value for DCI at nearly all time points, with maximal sensitivity by SAH day 8. However, the sensitivity of any mBFV more than 120 cm/s for subsequent DCI was only 63%, with a positive predictive value of 22% among patients with Hunt and Hess grades I to III and 36% in patients with Hunt and Hess grades IV and V. Positive predictive value was only slightly higher if mBFV exceeded 180 cm/s. CONCLUSION: Increased TCD flow velocities imply only a mild incremental risk of DCI after SAH, with maximal sensitivity by day 8. Nearly 40% of patients with DCI never attained an mBFV more than 120 cm/s during the course of monitoring. Given the poor overall sensitivity of TCD, improved methods for identifying patients at high risk for DCI after SAH are needed.