Epidermal growth factor receptor: a re-emerging target in glioblastoma.

PURPOSE OF REVIEW: Amplification and overexpression of the epidermal growth factor receptor (EGFR) gene are a hallmark of primary glioblastoma (45%), making it a prime target for therapy. In addition, these amplifications are frequently associated with oncogenic mutations in the extracellular domain. However, efforts at targeting the EGFR tyrosine kinase using small molecule inhibitors or antibodies have shown disappointing efficacy in clinical trials for newly diagnosed or recurrent glioblastoma. Here, we review recent insights into molecular mechanisms relevant for effective targeting of the EGFR pathway. RECENT FINDINGS: Molecular workup of glioblastoma tissue of patients under treatment with small molecule inhibitors has established drug concentrations in the tumor tissue, and has shed light on the effectiveness of target inhibition and respective effects on pathway signaling. Further, functional analyses of interaction of small molecule inhibitors with distinct properties to bind to the active or inactive form of EGFR have provided new insights that will impact the choice of drugs. Finally, vaccination approaches targeting the EGFRvIII mutant featuring a tumor-specific antigen have shown promising results that warrant larger controlled clinical trials. SUMMARY: A combination of preclinical and clinical studies at the molecular level has provided new insights that will allow refining strategies for targeting the EGFR pathway in glioblastoma.

Fluoroscopic-Guided Radial Endobronchial Ultrasound Without Guide Sheath For Peripheral Pulmonary Lesions: A Safe And Efficient Combination.

BACKGROUND: Several guidelines recommend computed tomography scans for populations with high-risk for lung cancer. The number of individuals evaluated for peripheral pulmonary lesions (PPL) will probably increase, and with it non-surgical biopsies. Associating a guidance method with a target confirmation technique has been shown to achieve the highest diagnostic yield, but the utility of bronchoscopy with radial probe endobronchial ultrasound using fluoroscopy as guidance without a guide sheath has not been reported. METHODS: We conducted a retrospective analysis of bronchoscopy with radial probe endobronchial ultrasound using fluoroscopy procedures for the investigation of PPL performed by experienced bronchoscopists with no specific previous training in this particular technique. Operator learning curves and radiological predictors were assessed for all consecutive patients examined during the first year of application of the technique. RESULTS: Fifty-one PPL were investigated. Diagnostic yield and visualization yield were 72.5 and 82.3% respectively. The diagnostic yield was 64.0% for PPL ≤20mm, and 80.8% for PPL>20mm. No false-positive results were recorded. The learning curve of all diagnostic tools showed a DY of 72.7% for the first sub-group of patients, 81.8% for the second, 72.7% for the third, and 81.8% for the last. CONCLUSION: Bronchoscopy with radial probe endobronchial ultrasound using fluoroscopy as guidance is safe and simple to perform, even without specific prior training, and diagnostic yield is high for PPL>and ≤20mm. Based on these findings, this method could be introduced as a first-line procedure for the investigation of PPL, particularly in centers with limited resources.

Acute flare induced by the calcific tendonitis of the rotator cuff: inhibition of IL-1 a potential therapeutic target?

Introduction: Calcific tendonitis of rotator cuff is observed on plainradiographs in 10% of adults, but remains asymptomatic in half thesecases. Sometimes, these calcifications induce acute flares withmassive inflammation similar to gout or CPPD crisis. Analgesics/anti-inflammatory medications are usually not sufficient to controlssymptoms in these situations. Local steroid infiltration with or withoutremoval of the calcific deposition with a needle aspiration may beuseful. A new approach could be IL-1 inhibitors. Indeed, basic calciumphosphate crystals are capable of stimulating the release of activeIL-1β in vitro. These crystals trigger IL-1β release, in an analogousmanner to MSU crystals in acute gout, suggesting that IL-1β blockademay be clinically useful.Case presentation: This report describes a 70-year old woman withacute rest pain of the right shoulder since 48 hours. On examination,we found massive limitations of active and passive movements. Thepatient evaluated, on the visual scale, her symptoms at 10/10 the nightand 5/10 the day. The radiography and showed a rounded, 8 mmcalcification in the subscapularis tendon. The ultrasound aspectrevealed a heterogeneous calcification partially non solid, surroundedby massive inflammation on Doppler. C-reactive protein anderythrocyte sedimentation rate were high (74 mg/ml, 54 mm/hour).The patient received subcutaneous injections of anakinra: 100 mgdaily for 3 days (D1-D3). We evaluated the patient in our consult at dayD1, D2, D3, D7, D16 and by phone at D70.This treatment rapidly relieved the inflammatory symptoms (within afew hours with no relapse). The mobility of the shoulder, the biologicsparameters improved and the size of the calcification as well thedegree of inflammation regressed on ultrasound after 3 days.Conclusion: This is the first report of a woman with an acute flareinduced by calcific tendonitis who received anakinra. IL-1 inhibitionmay be a therapeutic target in calcific tendonitis. To analyse thisresponse more precisely and elaborate definitive conclusions, aprospective pilot study is on-going in our ambulatory institute.

Effect of single nucleotide polymorphisms in cytochrome P450 isoenzyme and N-acetyltransferase 2 genes on the metabolism of artemisinin-based combination therapies in malaria patients from Cambodia and Tanzania.

The pharmacogenetics of antimalarial agents are poorly known, although the application of pharmacogenetics might be critical in optimizing treatment. This population pharmacokinetic-pharmacogenetic study aimed at assessing the effects of single nucleotide polymorphisms (SNPs) in cytochrome P450 isoenzyme genes (CYP, namely, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) and the N-acetyltransferase 2 gene (NAT2) on the pharmacokinetics of artemisinin-based combination therapies in 150 Tanzanian patients treated with artemether-lumefantrine, 64 Cambodian patients treated with artesunate-mefloquine, and 61 Cambodian patients treated with dihydroartemisinin-piperaquine. The frequency of SNPs varied with the enzyme and the population. Higher frequencies of mutant alleles were found in Cambodians than Tanzanians for CYP2C9*3, CYP2D6*10 (100C → T), CYP3A5*3, NAT2*6, and NAT2*7. In contrast, higher frequencies of mutant alleles were found in Tanzanians for CYP2D6*17 (1023C → T and 2850C → T), CYP3A4*1B, NAT2*5, and NAT2*14. For 8 SNPs, no significant differences in frequencies were observed. In the genetic-based population pharmacokinetic analyses, none of the SNPs improved model fit. This suggests that pharmacogenetic data need not be included in appropriate first-line treatments with the current artemisinin derivatives and quinolines for uncomplicated malaria in specific populations. However, it cannot be ruled out that our results represent isolated findings, and therefore more studies in different populations, ideally with the same artemisinin-based combination therapies, are needed to evaluate the influence of pharmacogenetic factors on the clearance of antimalarials.

Safety and immunogenicity of the M72/AS01 candidate tuberculosis vaccine in HIV-infected adults on combination antiretroviral therapy: a phase I/II, randomized trial.

OBJECTIVE: Tuberculosis (TB) is highly prevalent among HIV-infected people, including those receiving combination antiretroviral therapy (cART), necessitating a well tolerated and efficacious TB vaccine for these populations. We evaluated the safety and immunogenicity of the candidate TB vaccine M72/AS01 in adults with well controlled HIV infection on cART. DESIGN: A randomized, observer-blind, controlled trial (NCT00707967). METHODS: HIV-infected adults on cART in Switzerland were randomized 3 : 1 : 1 to receive two doses, 1 month apart, of M72/AS01, AS01 or 0.9% physiological saline (N = 22, N = 8 and N = 7, respectively) and were followed up to 6 months postdose 2 (D210). Individuals with CD4⁺ cell counts below 200 cells/μl were excluded. Adverse events (AEs) including HIV-specific and laboratory safety parameters were recorded. Cell-mediated (ICS) and humoral (ELISA) responses were evaluated before vaccination, 1 month after each dose (D30, D60) and D210. RESULTS: Thirty-seven individuals [interquartile range (IQR) CD4⁺ cell counts at screening: 438-872 cells/μl; undetectable HIV-1 viremia] were enrolled; 73% of individuals reported previous BCG vaccination, 97.3% tested negative for the QuantiFERON-TB assay. For M72/AS01 recipients, no vaccine-related serious AEs or cART-regimen adjustments were recorded, and there were no clinically relevant effects on laboratory safety parameters, HIV-1 viral loads or CD4⁺ cell counts. M72/AS01 was immunogenic, inducing persistent and polyfunctional M72-specific CD4⁺ T-cell responses [medians 0.70% (IQR 0.37-1.07) at D60] and 0.42% (0.24-0.61) at D210, predominantly CD40L⁺IL-2⁺TNF-α⁺, CD40L⁺IL-2⁺ and CD40L⁺IL-2⁺TNF-α⁺IFN-γ⁺]. All M72/AS01 vaccines were seropositive for anti-M72 IgG after second vaccination until study end. CONCLUSION: M72/AS01 was clinically well tolerated and immunogenic in this population, supporting further clinical evaluation in HIV-infected individuals in TB-endemic settings.

Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008.

OBJECTIVE: To provide an update to the original Surviving Sepsis Campaign clinical management guidelines, "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," published in 2004. DESIGN: Modified Delphi method with a consensus conference of 55 international experts, several subsequent meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. This process was conducted independently of any industry funding. METHODS: We used the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations. A strong recommendation (1) indicates that an intervention's desirable effects clearly outweigh its undesirable effects (risk, burden, cost) or clearly do not. Weak recommendations (2) indicate that the tradeoff between desirable and undesirable effects is less clear. The grade of strong or weak is considered of greater clinical importance than a difference in letter level of quality of evidence. In areas without complete agreement, a formal process of resolution was developed and applied. Recommendations are grouped into those directly targeting severe sepsis, recommendations targeting general care of the critically ill patient that are considered high priority in severe sepsis, and pediatric considerations. RESULTS: Key recommendations, listed by category, include early goal-directed resuscitation of the septic patient during the first 6 hrs after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm potential source of infection (1C); administration of broad-spectrum antibiotic therapy within 1 hr of diagnosis of septic shock (1B) and severe sepsis without septic shock (1D); reassessment of antibiotic therapy with microbiology and clinical data to narrow coverage, when appropriate (1C); a usual 7-10 days of antibiotic therapy guided by clinical response (1D); source control with attention to the balance of risks and benefits of the chosen method (1C); administration of either crystalloid or colloid fluid resuscitation (1B); fluid challenge to restore mean circulating filling pressure (1C); reduction in rate of fluid administration with rising filing pressures and no improvement in tissue perfusion (1D); vasopressor preference for norepinephrine or dopamine to maintain an initial target of mean arterial pressure > or = 65 mm Hg (1C); dobutamine inotropic therapy when cardiac output remains low despite fluid resuscitation and combined inotropic/vasopressor therapy (1C); stress-dose steroid therapy given only in septic shock after blood pressure is identified to be poorly responsive to fluid and vasopressor therapy (2C); recombinant activated protein C in patients with severe sepsis and clinical assessment of high risk for death (2B except 2C for postoperative patients). In the absence of tissue hypoperfusion, coronary artery disease, or acute hemorrhage, target a hemoglobin of 7-9 g/dL (1B); a low tidal volume (1B) and limitation of inspiratory plateau pressure strategy (1C) for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure in acute lung injury (1C); head of bed elevation in mechanically ventilated patients unless contraindicated (1B); avoiding routine use of pulmonary artery catheters in ALI/ARDS (1A); to decrease days of mechanical ventilation and ICU length of stay, a conservative fluid strategy for patients with established ALI/ARDS who are not in shock (1C); protocols for weaning and sedation/analgesia (1B); using either intermittent bolus sedation or continuous infusion sedation with daily interruptions or lightening (1B); avoidance of neuromuscular blockers, if at all possible (1B); institution of glycemic control (1B), targeting a blood glucose < 150 mg/dL after initial stabilization (2C); equivalency of continuous veno-veno hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1A); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding using H2 blockers (1A) or proton pump inhibitors (1B); and consideration of limitation of support where appropriate (1D). Recommendations specific to pediatric severe sepsis include greater use of physical examination therapeutic end points (2C); dopamine as the first drug of choice for hypotension (2C); steroids only in children with suspected or proven adrenal insufficiency (2C); and a recommendation against the use of recombinant activated protein C in children (1B). CONCLUSIONS: There was strong agreement among a large cohort of international experts regarding many level 1 recommendations for the best current care of patients with severe sepsis. Evidenced-based recommendations regarding the acute management of sepsis and septic shock are the first step toward improved outcomes for this important group of critically ill patients.

Membrane potential dynamics of neocortical projection neurons driving target-specific signals.

Primary sensory cortex discriminates incoming sensory information and generates multiple processing streams toward other cortical areas. However, the underlying cellular mechanisms remain unknown. Here, by making whole-cell recordings in primary somatosensory barrel cortex (S1) of behaving mice, we show that S1 neurons projecting to primary motor cortex (M1) and those projecting to secondary somatosensory cortex (S2) have distinct intrinsic membrane properties and exhibit markedly different membrane potential dynamics during behavior. Passive tactile stimulation evoked faster and larger postsynaptic potentials (PSPs) in M1-projecting neurons, rapidly driving phasic action potential firing, well-suited for stimulus detection. Repetitive active touch evoked strongly depressing PSPs and only transient firing in M1-projecting neurons. In contrast, PSP summation allowed S2-projecting neurons to robustly signal sensory information accumulated during repetitive touch, useful for encoding object features. Thus, target-specific transformation of sensory-evoked synaptic potentials by S1 projection neurons generates functionally distinct output signals for sensorimotor coordination and sensory perception.

AFT3 as a new therapeutic target for skin field cancerization in antagonism with compromised Notch/CSL signaling

Les interactions épithélio-mésenchymateuses jouent un rôle important dans le contrôle du développement normal de la peau, son homéostasie et sa tumorigenèse. Les fibroblastes dermiques (DFs) représentent la catégorie cellulaire la plus abondante dans le stroma et leur rôle est de plus en plus considéré. En ce qui concerne particulièrement la tumorigenèse, des facteurs diffusibles produits par les fibroblastes entourant les tumeurs épithéliales, appelés 'fibroblastes associés au cancer (CAF)', interagissent au niveau de l'inflammation impliquée directement ou indirectement dans la signalisation paracrine, entre le stroma et les cellules épiéliales cancéreuses. Le risque de cancer de la peau augmente de façon exponentielle avec l'âge. Comme un lien probable entre les deux, la sénescence des fibroblastes résulte de la production du sécrétome favorisant la sénescence (SMS), un groupe de facteurs diffusibles induisant une stimulation paracrine de la croissance, l'inflammation et le remodelage de la matrice. De façon fort intéressante, l'induction de ces gènes est aussi une caractéristique des CAFs. Cependant, le lien entre les deux événements cellulaires sénescence et activation des CAFs reste en grande partie inexploré. L'ATF3 (Activating Transcription Factor 3) est un facteur de transcription induit en réponse au stress, dont les fonctions sont hautement spécifiques du type cellulaire. Bien qu'il ait été découvert dans notre laboratoire en tant que promoteur de tumeurs dans les kératinocytes, ses fonctions biologique et biochimique dans le derme n'ont pas encore été étudiées. Récemment, nous avons constaté que, chez la souris, l'abrogation de la voie de signalisation de Notch/CSL dans les DFs, induisait la formation de tumeurs kératinocytaires multifocales. Ces dernières proviennent de la cancérisation en domaine, un phénomène associé à une atrophie du stroma, des altérations de la matrice et de l'inflammation. D'autres études ont montré que CSL agissait comme un régulateur négatif de gènes impliqués dans sénescence des DFs et dans l'activation des CAFs. Ici, nous montrons que la suppression ou l'atténuation de l'expression de ATF3 dans les DFs induit la sénescence et l'expression des gènes liés aux CAFs, de façon similaire à celle déclenchée par la perte de CSL, tandis que la surexpression de ATF3 supprime ces changements. Nous émettons l'hypothèse que ATF3 joue un rôle suppresseur dans l'activation des CAFs et dans la progression des tumeurs kératinocytaires, en surmontant les conséquences de l'abrogation de la voie de signalisation Notch/CSL. En concordance avec cette hypothèse, nous avons constaté que la perte de ATF3 dans les DFs favorisait la tumorigénicité des kératinocytes via le contrôle négatif de cytokines, des enzymes de la matrice de remodelage et de protéines associées au cancer, peut-être par liaison directe des effecteurs de la voie Notch/CSL : IL6 et les gènes Hes. Enfin, dans les échantillons cliniques humains, le stroma sous-jacent aux lésions précancéreuses de kératoses actiniques montre une diminution significative de l'expression de ATF3 par rapport au stroma jouxtant la peau normale. La restauration de l'expression de ATF3 pourrait être utilisée comme un outil thérapeutique en recherche translationnelle pour prévenir ou réprimer le processus de cancérisation en domaine. - Epithelial-mesenchymal interactions play an important role in control of normal skin development, homeostasis and tumorigenesis. The role of dermal fibroblasts (DFs) as the most abundant cell type in stroma is increasingly appreciated. Especially during tumorigenesis, fibroblasts surrounding epithelial tumors, called Cancer Associated Fibroblasts (CAFs), produce diffusible factors (growth factors, inflammatory cytokines, chemokines and enzymes, and matrix metalloproteinases) that mediate inflammation either directly or indirectly through paracrine signaling between stroma and epithelial cancer cells. The risk of skin cancer increases exponentially with age. As a likely link between the two, senescence of fibroblasts results in production of the senescence-messaging-secretome (SMS), a panel of diffusible factors inducing paracrine growth stimulation, inflammation, and matrix remodeling. Interestingly, induction of these genes is also a characteristic of Cancer Associated Fibroblasts (CAFs). However, the link between the two cellular events, senescence and CAF activation is largely unexplored. ATF3 is a key stress response transcription factor with highly cell type specific functions, which has been discovered as a tumor promoter in keratinocytes in our lab. However, the biological and biochemical function of ATF3 in the dermal compartment of the skin has not been studied yet. Recently, we found that compromised Notch/CSL signaling in dermal fibroblasts (DFs) in mice is a primary cause of multifocal keratinocyte tumors called field cancerization associated with stromal atrophy, matrix alterations and inflammation. Further studies showed that CSL functions as a negative regulator of genes involved in DFs senescence and CAF activation. Here, we show that deletion or silencing of the ATF3 gene in DFs activates senescence and CAF-related gene expression similar to that triggered by loss of CSL, while increased ATF3 suppresses these changes. We hypothesize that ATF3 plays a suppressing role in CAF activation and keratinocyte tumor progression, overcoming the consequences of compromised Notch/CSL signaling. In support of this hypothesis, we found that loss of ATF3 in DFs promotes tumorigenic behavior of keratinocytes via negative control of cytokines, matrix-remodeling enzymes and cancer-associated proteins, possibly through direct binding to Notch/CSL targets, IL6 and Hes genes. On the other hand, in human clinical samples, stromal fields underlying premalignant actinic keratosis lesions showed significantly decreased ATF3 expression relative to stroma of flanking normal skin. Restoration of ATF3, which is lost in cancer development, may be used as a therapeutic tool for translational research to prevent or suppress the field cancerization process.

MET: a promising anticancer therapeutic target.

The MET pathway is dysregulated in many human cancers and promotes tumour growth, invasion and dissemination. Abnormalities in MET signalling have been reported to correlate with poor clinical outcomes and drug resistance in patients with cancer. Thus, MET has emerged as an attractive target for cancer therapy. Several MET inhibitors have been introduced into the clinic, and are currently in all phases of clinical trials. In general, initial results from these studies indicate only a modest benefit in unselected populations. In this Review, we discuss current challenges in developing MET inhibitors--including identification of predictive biomarkers--as well as the most-efficient ways to combine these drugs with other targeted agents or with classic chemotherapy or radiotherapy.

Combination of transient lymphodepletion with busulfan and fludarabine and peptide vaccination in a phase I clinical trial for patients with advanced melanoma.

Taking advantage of homeostatic mechanisms to boost tumor-specific cellular immunity is raising increasing interest in the development of therapeutic strategies in the treatment of melanoma. Here, we have explored the potential of combining homeostatic proliferation, after transient immunosuppression, and antigenic stimulation of Melan-A/Mart-1 specific CD8 T-cells. In an effort to develop protocols that could be readily applicable to the clinic, we have designed a phase I clinical trial, involving lymphodepleting chemotherapy with Busulfan and Fludarabine, reinfusion of Melan-A specific CD8 T-cell containing peripheral blood mononuclear cells (exempt of growth factors), and Melan-A peptide vaccination. Six patients with advanced melanoma were enrolled in this outpatient regimen that demonstrated good feasibility combined with low toxicity. Consistent depletion of lymphocytes with persistent increased CD4/CD8 ratios was induced, although the proportion of circulating CD4 regulatory T-cells remained mostly unchanged. The study of the immune reconstitution period showed a steady recovery of whole T-cell numbers overtime. However, expansion of Melan-A specific CD8 T-cells, as measured in peripheral blood, was mostly inconsistent, accompanied with marginal phenotypic changes, despite vaccination with Melan-A/Mart-1 peptide. On the clinical level, 1 patient presented a partial but objective antitumor response following the beginning of the protocol, even though a direct effect of Busulfan/Fludarabine cannot be completely ruled out. Overall, these data provide further ground for the development of immunotherapeutic approaches to be both effective against melanoma and applicable in clinic.

Presence of alternative lengthening of telomeres mechanism in patients with glioblastoma identifies a less aggressive tumor type with longer survival.

Patients with glioblastoma (GBM) have variable clinical courses, but the factors that underlie this heterogeneity are not understood. To determine whether the presence of the telomerase-independent alternative lengthening of telomeres (ALTs) mechanism is a significant prognostic factor for survival, we performed a retrospective analysis of 573 GBM patients. The presence of ALT was identified in paraffin sections using a combination of immunofluorescence for promyelocytic leukemia body and telomere fluorescence in situ hybridization. Alternative lengthening of telomere was present in 15% of the GBM patients. Patients with ALT had longer survival that was independent of age, surgery, and other treatments. Mutations in isocitrate dehydrogenase (IDH1mut) 1 frequently accompanied ALT, and in the presence of both molecular events, there was significantly longer overall survival. These data suggest that most ALT+ tumors may be less aggressive proneural GBMs, and the better prognosis may relate to the set of genetic changes associated with this tumor subtype. Despite improved overall survival of patients treated with the addition of chemotherapy to radiotherapy and surgery, ALT and chemotherapy independently provided a survival advantage, but these factors were not found to be additive. These results suggest a critical need for developing new therapies to target these specific GBM subtypes.

TNF-alpha blockers in inflammatory bowel diseases: practical consensus recommendations and a user's guide.

More than seventy years after their initial characterisation, the aetiology of inflammatory bowel diseases remains elusive. A recent review evaluating the incidence trends of the last 25 years concluded that an increasing incidence has been observed almost worldwide. A north-south gradient is still found in Europe. Genetic associations are variably reproduced worldwide and indicate a strong impact of environmental factors. Tumour necrosis factor alpha (TNF-alpha) has been shown to play a critical role in the pathogenesis of inflammatory bowel disease (IBD). TNF-alpha blockers are biological agents that specifically target this key cytokine in the inflammatory process and have become a mainstay in the therapy of inflammatory bowel diseases. This paper reviews the necessary investigations before using such agents, the use of such agents in pregnancy and lactation, the role of co-immunosuppression, how to monitor efficacy and safety, dose-adaptation, and the decision as to when to switch to another TNF-alpha blocker. Finally it gives recommendations for special situations. Currently there are three TNF-alpha blockers available for clinical use in IBD in Switzerland: infliximab (Remicade), adalimumab (Humira) and certolizumab pegol (Cimzia). Infliximab is a chimeric monoclonal antibody composed of a human IgG1 constant region and a murine variable region and is administered intravenously. Adalimumab is a humanised monoclonal antibody, with both human IgG1 constant and variable regions. Certolizumab pegol is a pegylated, humanised monoclonal anti-TNF fragment antigen binding fragment. Both adalimumab and certolizumab pegol are administered by subcutaneous injection. The efficacy and safety of TNF-alpha blockers in Crohn's disease has been reviewed. The authors conclude that the three above-mentioned agents are effective in luminal Crohn's disease. In fistulizing Crohn's disease, TNF-alpha blockers other than infliximab require additional investigation.

β-Lactam Monotherapy vs β-Lactam-Macrolide Combination Treatment in Moderately Severe Community-Acquired Pneumonia: A Randomized Noninferiority Trial.

IMPORTANCE: The clinical benefit of adding a macrolide to a β-lactam for empirical treatment of moderately severe community-acquired pneumonia remains controversial. OBJECTIVE: To test noninferiority of a β-lactam alone compared with a β-lactam and macrolide combination in moderately severe community-acquired pneumonia. DESIGN, SETTING, AND PARTICIPANTS: Open-label, multicenter, noninferiority, randomized trial conducted from January 13, 2009, through January 31, 2013, in 580 immunocompetent adult patients hospitalized in 6 acute care hospitals in Switzerland for moderately severe community-acquired pneumonia. Follow-up extended to 90 days. Outcome assessors were masked to treatment allocation. INTERVENTIONS: Patients were treated with a β-lactam and a macrolide (combination arm) or with a β-lactam alone (monotherapy arm). Legionella pneumophila infection was systematically searched and treated by addition of a macrolide to the monotherapy arm. MAIN OUTCOMES AND MEASURES: Proportion of patients not reaching clinical stability (heart rate <100/min, systolic blood pressure >90 mm Hg, temperature <38.0°C, respiratory rate <24/min, and oxygen saturation >90% on room air) at day 7. RESULTS: After 7 days of treatment, 120 of 291 patients (41.2%) in the monotherapy arm vs 97 of 289 (33.6%) in the combination arm had not reached clinical stability (7.6% difference, P = .07). The upper limit of the 1-sided 90% CI was 13.0%, exceeding the predefined noninferiority boundary of 8%. Patients infected with atypical pathogens (hazard ratio [HR], 0.33; 95% CI, 0.13-0.85) or with Pneumonia Severity Index (PSI) category IV pneumonia (HR, 0.81; 95% CI, 0.59-1.10) were less likely to reach clinical stability with monotherapy, whereas patients not infected with atypical pathogens (HR, 0.99; 95% CI, 0.80-1.22) or with PSI category I to III pneumonia (HR, 1.06; 95% CI, 0.82-1.36) had equivalent outcomes in the 2 arms. There were more 30-day readmissions in the monotherapy arm (7.9% vs 3.1%, P = .01). Mortality, intensive care unit admission, complications, length of stay, and recurrence of pneumonia within 90 days did not differ between the 2 arms. CONCLUSIONS AND RELEVANCE: We did not find noninferiority of β-lactam monotherapy in patients hospitalized for moderately severe community-acquired pneumonia. Patients infected with atypical pathogens or with PSI category IV pneumonia had delayed clinical stability with monotherapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00818610.