Androgen Receptor and Ki67 Expression and Survival Outcomes in Non-small Cell Lung Cancer.

Lung cancer is the most common cause of cancer-related deaths worldwide with non-small cell lung cancer (NSCLC) making up most of these cases. Males have poorer overall survival compared to women following a lung cancer diagnosis. Many studies have focused on the effects of estrogen to explain higher survival rates among women, but few have looked at the effects of androgens. We describe the expression of the androgen receptor (AR) and Ki67 in lung cancer specimens in the Manitoba Tumor Bank (MTB) and correlate these factors with patient outcome. Using the MTB, we performed immunohistochemistry on lung cancer tissue to determine expression of the AR and Ki67. These were then correlated with patient outcome. Of the 136 cases, 55% were female and 55% were adenocarcinoma. AR expression was not independently associated with outcome. Ki67 was associated with a significantly higher hazard ratio for death and recurrence (HR 2.19, 95% CI 1.30-3.70; HR 1.92, 95% CI 1.07-3.46, respectively). AR expression modified the effect of Ki67 on outcome, such that when both were expressed, there was no association with recurrence or survival (HR 2.39, 95% CI 1.31-4.36 for AR- Ki67+ vs HR 1.54, 95% CI 0.44-5.37 for AR+ Ki67+). Ki67 was associated with poorer outcomes alone. AR status alone was not associated with outcome. Although the mechanism remains unclear, AR status seems to negate the association of a high Ki67 and poor outcome.

Geographical Variation and Factors Associated with Non-Small Cell Lung Cancer in Manitoba.

BACKGROUND: Screening decreases non-small cell lung cancer (NSCLC) deaths and is recommended by the Canadian Task Force on Preventive Health Care. We investigated risk factor prevalence and NSCLC incidence at a small region level to inform resource allocation for lung cancer screening. METHODS: NSCLC diagnoses were obtained from the Canadian Cancer Registry, then geocoded to 283 small geographic areas (SGAs) in Manitoba. Sociodemographic characteristics of SGAs were obtained from the 2006 Canadian Census and Canadian Community Health Survey. Geographical variation was modelled using a Bayesian spatial Poisson model. RESULTS: NSCLC incidence in SGAs ranged from 1 to 343 cases per 100,000 population per year. The highest incidence rates were in the Southeastern, Southwestern, and Central regions of Manitoba, while most of Northern Manitoba had lower rates. Poisson regression suggested areas with higher proportions of Aboriginal people and higher average income, and immigrants had lower NSCLC incidence whereas areas with higher proportions of smokers had higher incidence. CONCLUSION: On an SGA level, smoking rates remain the most significant factor driving NSCLC incidence. Socioeconomic status and proportions of immigrants or Aboriginal peoples independently impact NSCLC rates. We have identified SGAs in Manitoba to target in policy and infrastructure planning for lung cancer screening.

Androgen pathway manipulation and survival in patients with lung cancer.

The epidemiology of lung cancer differs between men and women. The role of androgens in lung cancer remains unclear. This study was performed to determine if exposure to androgen pathway manipulation (APM) is associated with greater survival in male patients diagnosed with lung cancer. Using a retrospective cohort design, all men diagnosed with lung cancer from January 1, 2004 to December 31, 2010 were identified from the population-based Manitoba Cancer Registry and Manitoba Health Administrative Databases. Information from the Drug Program Information Network (DPIN) was used to determine prescriptions filled for antiandrogens, 5-alpha reductase inhibitors, and gonadotropin-releasing hormone (GnRH) agonists. Multivariable Cox proportional hazards analysis with time-varying exposure variables was used to compare survival. A total of 3018 men with lung cancer were identified between 2004 and 2010. Of these, 339 (11.5%) were identified as having used a form of APM. The majority of patients received 5-alpha reductase inhibitors. Patients who received APM prior to the diagnosis of lung cancer had no significant difference in survival (HR 0.97, p = 0.69) compared to those who did not. Patients exposed to APM after their diagnosis were found to have a significantly better survival (HR 0.36, p = 0.0007), as were those exposed both before and after diagnosis (HR 0.53, p < 0.0001). In male patients diagnosed with lung cancer, exposure to APM is associated with significantly better survival when compared with no exposure. The association is only seen when some or all of the exposure has occurred after the diagnosis of lung cancer.

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.

Sex as an independent prognostic factor in a population-based non-small cell lung cancer cohort.

BACKGROUND: Males with non-small cell lung cancer (NSCLC) tend to experience worse outcomes, as do those with nonadenocarcinoma histology; however, the independent effects of these factors remain unclear. OBJECTIVE: To evaluate the independent effect of sex and histology on mortality in a population of patients with NSCLC. METHODS: All patients with NSCLC in Manitoba from 1985 to 2004 were identified from the Manitoba Cancer Registry. Treatment data were extracted from the Manitoba Health administrative databases and linked to the registry. Cox regression analysis was used to determine the independent effect of sex on survival. RESULTS: A total of 10,908 patients (6665 male, 4243 female) with NSCLC were identified. Females had a median overall survival of 9.4 months versus 6.8 months for males (P<0.001). The adjusted HR for death for males compared with females was 1.13 (95% CI 1.04 to 1.23; P=0.004). Sex modified the effect of surgical treatment on survival (HR 1.26 [95% CI 1.13 to 1.40]; P<0.001). Adenocarcinoma histology modified the effect of sex on survival (HR 1.36 [95% CI 1.24 to 1.50]; P<0.001) when treatment was accounted for. CONCLUSION: Females experienced a significantly better survival rate than males independent of treatment, age, year of diagnosis and histology. This was greatest in surgically treated patients and in those with adenocarcinoma.

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.

Survival and treatment pattern of non-small cell lung cancer over 20 years.

INTRODUCTION: The multidisciplinary treatment of non-small cell lung cancer (NSCLC) has evolved, however, the impact on population outcomes remains unclear. We examined the treatment and survival pattern of patients with NSCLC over 20 years in Manitoba, Canada. METHODS: All diagnoses of NSCLC from January 1, 1985, to December 31, 2004, were extracted from the Manitoba Cancer Registry. Treatment and survival data from the registry were combined with administrative medical claims data. Patients were grouped by treatment: surgery, chemotherapy, radiotherapy, or no antineoplastic treatment. Adjuvant therapies were also examined. RESULTS: A total of 10,908 diagnoses of NSCLC were identified. The proportion treated with surgery and radiotherapy declined over time (annual percent change (APC) -0.28, p = 0.009; APC -0.74, p < 0.0001, respectively), while more received chemotherapy or no antineoplastic treatment (APC 0.57, p < 0.0001 and 0.45, p = 0.0002, respectively). Postoperative radiotherapy use declined over time (APC -0.87, p < 0.0001). Median survival time improved for the entire cohort after 1997 (0.46 months per annum (MPA), p = 0.04), and for those treated with primary surgery (post-1994: 2.85 MPA, p = 0.05), chemotherapy (0.49 MPA, p < 0.0001), and concurrent chemoradiotherapy (0.30 MPA, p = 0.03). CONCLUSIONS: The survival of patients with NSCLC has improved over time, driven by improvements in those treated initially with surgery or chemotherapy. This occurred in the setting of fewer surgical resections and increased chemotherapy use suggesting improved patient selection. Coincident with these changes, multidisciplinary case conferences, clinical practice guidelines, and consolidation of service may have contributed to these phenomena.

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.

Isolated pulmonary amyloidosis: case report and review of the literature.

The respiratory tract is rarely the site of localized tracheobronchial or nodular amyloid deposits. We present an unusual case of isolated nodular amyloidosis of the lung and review the current literature related to this disorder.