Marshall W. Pitz

Inhaled Corticosteroids in Patients With Stable Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-analysis

CONTEXT Recent studies of inhaled corticosteroid (ICS) therapy for managing stable chronic obstructive pulmonary disease (COPD) have yielded conflicting results regarding survival and risk of adverse events. OBJECTIVE To systematically review and quantitatively synthesize the effects of ICS therapy on mortality and adverse events in patients with stable COPD. DATA SOURCES Search of MEDLINE, CENTRAL, EMBASE, CINAHL, Web of Science, and PsychInfo through February 9, 2008. STUDY SELECTION Eligible studies were double-blind, randomized controlled trials comparing ICS therapy for 6 or more months with nonsteroid inhaled therapy in patients with COPD. DATA EXTRACTION Two authors independently abstracted data including study characteristics, all-cause mortality, pneumonia, and bone fractures. The I(2) statistic was used to assess heterogeneity. Study-level data were pooled using a random-effects model (when I(2) > or = 50%) or a fixed-effects model (when I(2) < 50%). For the primary outcome of all-cause mortality at 1 year, our meta-analysis was powered to detect a 1.0% absolute difference in mortality, assuming a 2-sided alpha of .05 and power of 0.80. RESULTS Eleven eligible randomized controlled trials (14,426 participants) were included. In trials with mortality data, no difference was observed in 1-year all-cause mortality (128 deaths among 4636 patients in the treatment group and 148 deaths among 4597 patients in the control group; relative risk [RR], 0.86; 95% confidence interval [CI], 0.68-1.09; P = .20; I(2) = 0%). In the trials with data on pneumonia, ICS therapy was associated with a significantly higher incidence of pneumonia (777 cases among 5405 patients in the treatment group and 561 cases among 5371 patients in the control group; RR, 1.34; 95% CI, 1.03-1.75; P = .03; I(2) = 72%). Subgroup analyses indicated an increased risk of pneumonia in the following subgroups: highest ICS dose (RR, 1.46; 95% CI, 1.10-1.92; P = .008; I(2) = 78%), shorter duration of ICS use (RR, 2.12; 95% CI, 1.47-3.05; P < .001; I(2) = 0%), lowest baseline forced expiratory volume in the first second of expiration (RR, 1.90; 95% CI, 1.26-2.85; P = .002; I(2) = 0%), and combined ICS and bronchodilator therapy (RR, 1.57; 95% CI, 1.35-1.82; P < .001; I(2) = 24%). CONCLUSIONS Among patients with COPD, ICS therapy does not affect 1-year all-cause mortality. ICS therapy is associated with a higher risk of pneumonia. Future studies should determine whether specific subsets of patients with COPD benefit from ICS therapy.

Targeting the EGFR pathway for cancer therapy

Clinical studies have shown that HER-2/Neu is over-expressed in up to one-third of patients with a variety of cancers, including B-cell acute lymphoblastic leukemia (B-ALL), breast cancer and lung cancer, and that these patients are frequently resistant to conventional chemo-therapies. Additionally, in most patients with multiple myeloma, the malignant cells over-express a number of epidermal growth factor receptors (EGFR)s and their ligands, HB-EGF and amphiregulin, thus this growth-factor family may be an important aspect in the patho-biology of this disease. These and other, related findings have provided the rationale for the targeting of the components of the EGFR signaling pathways for cancer therapy. Below we discuss various aspects of EGFR-targeted therapies mainly in hematologic malignancies, lung cancer and breast cancer. Beside novel therapeutic approaches, we also discuss specific side effects associated with the therapeutic inhibition of components of the EGFR-pathways. Alongside small inhibitors, such as Lapatinib (Tykerb, GW572016), Gefitinib (Iressa, ZD1839), and Erlotinib (Tarceva, OSI-774), a significant part of the review is also dedicated to therapeutic antibodies (e.g.: Trastuzumab/Herceptin, Pertuzumab/Omnitarg/rhuMab-2C4, Cetuximab/Erbitux/IMC-C225, Panitumumab/Abenix/ABX-EGF, and also ZD6474). In addition, we summarize, both current therapy development driven by antibody-based targeting of the EGFR-dependent signaling pathways, and furthermore, we provide a background on the history and the development of therapeutic antibodies.

Defining the predictors of the placebo response in irritable bowel syndrome

BACKGROUND AND AIMS We sought to determine the components of irritable bowel syndrome (IBS) clinical trials that correlate with higher levels of placebo response. METHODS We performed a systematic review of placebo-controlled trials in patients with IBS to assess which variables correlate with a higher placebo response. Placebo responses for global symptom improvement and for decreased abdominal pain were assessed. Univariate and multiple linear regression analyses were conducted. RESULTS Higher rates of global improvement correlated with frequency of administration of study intervention ( r = .31, P = .03), duration of the study ( r = .28, P = .04), and overall treatment effect of the active agent being studied ( r = .33, P = .02). Higher rates of decreased abdominal pain correlated with the frequency of intervention ( r = .39, P = .02) and overall treatment effect ( r = .40, P = .01), whereas lower placebo response rates correlated with year of the study ( r = -.36, P = .03), median age ( r = -.38, P = .04), and duration of study run-in period ( r = -.33, P = .04). On multivariate analysis, global improvement in the placebo group was associated significantly with intervention frequency ( P = .0079), overall treatment response ( P = .0031), and parallel study design ( P = .0044). Decreased abdominal pain was associated significantly with frequency of intervention ( P = .0061) and overall treatment response ( P = .0128). CONCLUSIONS In IBS studies, higher placebo response rates correlated with frequency of the intervention and with overall treatment effect of the active agent being studied. In designing IBS trials, it may be possible to minimize placebo response by less frequent dosing. In treating patients with IBS, it may be possible to harness the placebo response and maximize therapeutic response rates by more frequent dosing.

Cortical mapping of visceral pain in patients with GI disorders using functional magnetic resonance imaging

OBJECTIVE:We sought to identify central loci that activate in response to visceral stimuli (stool and pain). We had a particular interest in observing the anterior cingulate gyrus and frontal cortex in normals and in patients with intestinal disease, including inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS).METHODS:Subjects underwent rectal balloon distention to a sensation of stool and to a sensation of pain while undergoing blood oxygenation level-dependent functional magnetic resonance imaging. Experiments were conducted in a Magnex 3.0-T whole body magnet with a Bruker Biospec console and a quadrature head coil. Four contiguous 5.0-mm oblique axial slices designed to optimize coverage of areas believed to be responsive to noxious stimulation were acquired. Activations were detected by using cross-correlation maps (p < 0.001) for individual subjects. The experimental groups were compared using both an analysis of variance and profile analysis.RESULTS:A significantly higher percentage of pixels activated in the anterior cingulate gyrus over both pain and stool conditions for the control group than for the IBS group and for the IBS group than for the IBD group (p < 0.035). Deactivation of left somatosensory cortex was greater for the IBS group than for the IBD group and greater for the IBD group than for the controls (p < 0.0065) in the boxcar condition. Frontal deactivation in controls compared with disease groups bordered on statistical significance. Profile analysis of the three groups across six regions of interest revealed that the control and IBD groups were distinguished by different profiles of response (p < 0.005). Nonparametric evaluation of the data suggests that, among the pixels in the anterior cingulate activating to pain, there are two patterns of response to pain—on/off and graded. This was true for both controls and disease groups.CONCLUSIONS:Normal controls and subjects with IBD and IBS share similar loci of activations to visceral sensations of stool and pain. Both activation and deactivation of particular regions of interest differentiate the three groups, as do profiles of patterned response across six of the regions of interest for the control and IBD groups.

Tissue concentration of systemically administered antineoplastic agents in human brain tumors

The blood–brain-barrier (BBB) limits the penetration of many systemic antineoplastic therapies. Consequently, many agents may be used in clinical studies and clinical practice though they may not achieve therapeutic levels within the tumor. We sought to compile the currently available human data on antineoplastic drug concentrations in brain and tumor tissue according to BBB status. A review of the literature was conducted for human studies providing concentrations of antineoplastic agents in blood and metastatic brain tumors or high-grade gliomas. Studies were considered optimal if they reported simultaneous tissue and blood concentration, multiple sampling times and locations, MRI localization, BBB status at sampling site, tumor histology, and individual subject data. Twenty-Four studies of 19 compounds were included. These examined 18 agents in contrast-enhancing regions of high-grade gliomas, with optimal data for 2. For metastatic brain tumors, adequate data was found for 9 agents. Considerable heterogeneity was found in the measurement value, tumor type, measurement timing, and sampling location within and among studies, limiting the applicability of the results. Tissue to blood ratios ranged from 0.054 for carboplatin to 34 for mitoxantrone in high-grade gliomas, and were lowest for temozolomide (0.118) and etoposide (0.116), and highest for mitoxantrone (32.02) in metastatic tumors. The available data examining the concentration of antineoplastic agents in brain and tumor tissue is sparse and limited by considerable heterogeneity. More studies with careful quantification of antineoplastic agents in brain and tumor tissue is required for the rational development of therapeutic regimens.

Phase II study of PX-866 in recurrent glioblastoma

BACKGROUND Glioblastoma (GBM) is the most aggressive malignancy of the central nervous system in adults. Increased activity of the phosphatidylinositol-3-OH kinase (PI3K) signal transduction pathway is common. We performed a phase II study using PX-866, an oral PI3K inhibitor, in participants with recurrent GBM. METHODS Patients with histologically confirmed GBM at first recurrence were given oral PX-866 at a dose of 8 mg daily. An MRI and clinical exam were done every 8 weeks. Tissue was analyzed for potential predictive markers. RESULTS Thirty-three participants (12 female) were enrolled. Median age was 56 years (range 35-78y). Eastern Cooperative Oncology Group performance status was 0-1 in 29 participants and 2 in the remainder. Median number of cycles was 1 (range 1-8). All participants have discontinued therapy: 27 for disease progression and 6 for toxicity (5 liver enzymes and 1 allergic reaction). Four participants had treatment-related serious adverse events (1 liver enzyme, 1 diarrhea, 2 venous thromboembolism). Other adverse effects included fatigue, diarrhea, nausea, vomiting, and lymphopenia. Twenty-four participants had a response of progression (73%), 1 had partial response (3%, and 8 (24%) had stable disease (median, 6.3 months; range, 3.1-16.8 months). Median 6-month progression-free survival was 17%. None of the associations between stable disease and PTEN, PIK3CA, PIK3R1, or EGFRvIII status were statistically significant. CONCLUSIONS PX-866 was relatively well tolerated. Overall response rate was low, and the study did not meet its primary endpoint; however, 21% of participants obtained durable stable disease. This study also failed to identify a statistically significant association between clinical outcome and relevant biomarkers in patients with available tissue.

High incidence of chronic lymphocytic leukemia (CLL) diagnosed by immunophenotyping: A population-based Canadian cohort

Incidence and outcomes of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) are not well established at the population level, especially since the widespread use of immunophenotyping. We studied the epidemiology of CLL in Manitoba (Canada) by combining data from a centralized flow cytometry facility and the provincial cancer registry for the period 1998-2003. Of 616 cases identified, 27% of patients identified by flow cytometry were not on the cancer registry. The age-adjusted incidence of 7.99/100,000 is substantially higher than the reported incidence in registry reports. We also noted differences in relative survival based on age and gender.

The utility of cardiac biomarkers and echocardiography for the early detection of bevacizumab- and sunitinib-mediated cardiotoxicity

The recent introduction of novel anticancer therapies, including bevacizumab (BVZ) and sunitinib (SNT), is associated with an increased risk of cardiotoxicity. However, early identification of left ventricular (LV) systolic dysfunction may facilitate dose modification and avoid the development of advanced heart failure. Using a murine model of BVZ- and SNT-mediated cardiotoxicity, we investigated whether cardiac biomarkers and/or tissue velocity imaging (TVI) using echocardiography can detect early changes in cardiac function, before a decrease in LV ejection fraction is identified. A total of 75 wild-type C57Bl/6 male mice were treated with either 0.9% saline, BVZ, or SNT. Serial monitoring of blood pressure, high-sensitivity troponin I, and echocardiographic indexes were performed over a 14-day study period, after which the mice were euthanized for histological and biochemical analyses. Mice treated with either BVZ or SNT developed systemic hypertension as early as day 7, which increased by day 14. Cardiac biomarkers, specifically high-sensitivity troponin I, were not predictive of early LV systolic dysfunction. Although conventional LV ejection fraction values decreased at day 13 in mice treated with either BVZ or SNT, TVI confirmed early LV systolic dysfunction at day 8. Histological and biochemical analysis demonstrated loss of cellular integrity, increased oxidative stress, and increased cardiac apoptosis in mice treated with BVZ or SNT therapy at day 14. In a murine model of BVZ- or SNT-mediated cardiomyopathy, noninvasive assessment by TVI detected early LV systolic dysfunction before alterations in conventional echocardiographic indexes.

Antiestrogen Use and Survival of Women with Non-small Cell Lung Cancer in Manitoba, Canada

Lung cancer is the leading cause of cancer death worldwide. Sex differences in lung cancer incidence and survival are known. Female sex is an independent good prognostic factor. Estrogens appear to play a key role in lung cancer outcomes. Accordingly, antiestrogen use may also influence survival in female non-small cell lung cancer (NSCLC) patients. In this study, we compared survival among antiestrogen users and nonusers. We performed a retrospective population-based study. Using the Manitoba Cancer Registry (MCR), we identified all women diagnosed with NSCLC from 2000 to 2007. The population-based Drug Program Information Network was accessed to establish which patients received antiestrogens. Demographic data (e.g., smoking patterns, stage, histology) were gathered from the MCR and by chart review. Survival differences between antiestrogen-exposed and not exposed groups were compared using multivariable Cox regression. Two thousand three hundred twenty women fit our patient criteria, of which 156 had received antiestrogens. Exposure to antiestrogens was associated with a significantly decreased mortality in those exposed both before and after the diagnosis of NSCLC (adjusted hazard ratio, 0.42, p = 0.0006). This association remained consistent across age and stage groups. Antiestrogen use before and after the diagnosis of NSCLC is associated with decreased mortality. This supports previous evidence that estrogens may play a key role in the biology and outcomes of NSCLC and suggests a potential therapeutic use for these agents in this disease.

Increased risk of second malignancies in chronic lymphocytic leukaemia patients as compared with follicular lymphoma patients: a Canadian population-based study

Background:Chronic lymphocytic leukaemia (CLL) patients have an increased risk of other malignancies. This may be due to surveillance bias, treatment or immunosuppression.Methods:Cohort study of 612 consecutively diagnosed CLL patients in a Canadian province, with comparisons to follicular lymphoma (FL) patients.Results:Treated CLL patients had a 1.7-fold increased risk of second cancers compared with untreated CLL patients. As compared with untreated FL patients, untreated CLL patients had a two-fold increased incidence of second malignancies.Conclusion:Chronic lymphocytic leukaemia patients have an inherent predisposition to second cancers and the incidence is further increased by treatment.