Case–control studies on risk factors for chronic obstructive pulmonary disease: how does the sampling of the cases and controls affect the results?

Introduction: Sampling is regarded as crucial to the validity of case–control studies. Ideally, cases and controls should be selected from the same source population, but deviations from this approach are often seen. Objective: Our objective was to examine how exposure–disease relationships in a study on chronic obstructive pulmonary disease (COPD) were affected by the sampling sources of cases and controls. Methods: A Norwegian case–control study on COPD including 1909 subjects used three sources of recruitment for cases (general population, hospital registry and volunteers) and two sources for controls (general population and volunteers). This resulted in six sampling combinations of cases and controls (groups A–F). We examined how the risk factors gender, age, smoking, educational level and comorbidity were associated with COPD in these six sampling groups. Results: Several exposure–disease associations were dependent on variation in sampling source, thereby demonstrating the possibility of selection bias. The theoretically most ideal sampling group is likely group A, where both cases and controls are recruited from a general population. When using group A as a reference, the groups containing either voluntary controls and/or hospital‐based cases deviated the most, suggesting higher susceptibility to selection bias in these groups. Conclusion: Recruitment from several sources made our study design vulnerable to selection bias. Our findings should bring about increased awareness to the sampling process, and encourage sampling of cases and controls from the same source population in future studies. Please cite this paper as: Sørheim I‐C, Johannessen A, Grydeland TB, Omenaas ER, Gulsvik A and Bakke PS. Case–control studies on risk factors for COPD: how does the sampling of the cases and controls affect the results? The Clinical Respiratory Journal 2010; 4: 89–96.     

Targeting glioblastoma with NK cells and mAb against NG2/CSPG4 prolongs animal survival

Glioblastoma (GBM) is the most malignant brain tumor where patients'' survival is only 14.6 months, despite multimodal therapy with debulking surgery, concurrent chemotherapy and radiotherapy. There is an urgent, unmet need for novel, effective therapeutic strategies for this devastating disease. Although several immunotherapies are under development for the treatment of GBM patients, the use of natural killer (NK) cells is still marginal despite this being a promising approach to treat cancer. In regard of our knowledge on the role of NG2/CSPG4 in promoting GBM aggressiveness we investigated the potential of an innovative immunotherapeutic strategy combining mAb9.2.27 against NG2/CSPG4 and NK cells in preclinical animal models of GBM. Multiple immune escape mechanisms maintain the tumor microenvironment in an anti-inflammatory state to promote tumor growth, however, the distinct roles of resident microglia versus recruited macrophages is not elucidated. We hypothesized that exploiting the cytokine release capabilities of activated NK cells to reverse the anti-inflammatory axis combined with mAb9.2.27 targeting the NG2/CSPG4 may favor tumor destruction by editing pro-GBM immune responses. Combination treatment with NK+mAb9.2.27 diminished tumor growth that was associated with reduced tumor proliferation, increased cellular apoptosis and prolonged survival compared to vehicle and monotherapy controls. The therapeutic efficacy was mediated by recruitment of CCR2^low macrophages into the tumor microenvironment, increased ED1 and MHC class II expression on microglia that might render them competent for GBM antigen presentation, as well as elevated IFN-γ and TNF-α levels in the cerebrospinal fluid compared to controls. Depletion of systemic macrophages by liposome-encapsulated clodronate decreased the CCR2^low macrophages recruited to the brain and abolished the beneficial outcomes. Moreover, mAb9.2.27 reversed tumor-promoting effects of patient-derived tumor-associated macrophage/ microglia (TAM) ex vivo. Taken together, these findings indicate that NK+mAb9.2.27 treatment may be an amenable therapeutic strategy to treat NG2/CSPG4 expressing GBMs. We provide a novel conceptual approach of combination immunotherapy for glioblastoma. The results traverse beyond the elucidation of NG2/CSPG4 as a therapeutic target, but demonstrate a proof of concept that this antibody may hold potential for the treatment of GBM by activation of tumor infiltrated microglia/macrophages.     

Eptinezumab improved patient-reported outcomes and quality of life in patients with migraine and prior preventive treatment failures

Background and purpose

In the phase 3b, randomized, double-blind, placebo-controlled DELIVER clinical trial, eptinezumab reduced migraine frequency and headache in adults with two to four prior preventive treatment failures. Here, the effect of eptinezumab on coinciding patient-reported outcomes is reported.

Methods

Adults were randomized to receive eptinezumab 100, 300 mg or placebo intravenously at weeks 12 and 24. The EQ-5D-5L, measuring overall patient health, and the six-item Headache Impact Test were completed every 4 weeks. The Patient Global Impression of Change was completed at weeks 4, 12 and 24. Patient-identified most bothersome symptom and the Migraine-Specific Quality of Life Questionnaire were administered at weeks 12 and 24.

Results

Eptinezumab improved patient-reported outcomes more than placebo, starting at week 4 and at all subsequent time points. By week 12, patients’ overall health (EQ-5D-5L visual analog scale score) improved with eptinezumab treatment (difference from placebo in change from baseline: 100 mg, 5.1, 95% confidence interval [CI] 2.2, 8.1, p < 0.001; 300 mg, 7.5, 95% CI 4.5, 10.4, p < 0.0001). At week 12, eptinezumab improved headache-related quality of life (difference from placebo in change from baseline in Headache Impact Test total score: 100 mg, −3.8, 95% CI −5.0, −2.5, p < 0.0001; 300 mg, −5.4, 95% CI −6.7, −4.2, p < 0.0001), including each Migraine-Specific Quality of Life Questionnaire domain (p ≤ 0.0001, all comparisons). Over twice as many patients receiving eptinezumab than placebo reported much or very much improvement on the Patient Global Impression of Change and patient-identified most bothersome symptom.

Conclusion

Patients with two to four prior preventive treatment failures receiving eptinezumab versus placebo reported greater improvements in well-being, quality of life and most bothersome symptoms compared to placebo.

Trial registration

ClinicalTrials.gov identifier: NCT04418765; EudraCT identifier: 2019-004497-25.     

Navigated laparoscopic ultrasound in abdominal soft tissue surgery: technological overview and perspectives

Purpose  

Two-dimensinal laparoscopic ultrasound (LUS) is commonly used for many laparoscopic procedures, but 3D LUS and navigation technology are not conventional tools in the clinic. Navigated LUS can help the user understand and interpret the ultrasound images in relation to the laparoscopic view and preoperative images. When combined with information from MRI or CT, navigated LUS has the potential to provide information about anatomic shifts during the procedure. In this paper, we present an overview of the ongoing technological research and development related to LUS combined with navigation technology, The purpose of this overview is threefold: (1) an introduction for those new to the field of navigated LUS; (2) an overview for those working in the field and; and (3) as a reference for those searching for literature on technological developments related to navigation in ultrasound-guided laparoscopic surgery.     

Patterns of hematologic malignancies and solid tumors among 37,838 first‐degree relatives of 13,896 patients with multiple myeloma in Sweden

There are emerging data to suggest a role for genetic factors in the pathogenesis of multiple myeloma (MM). Based on small numbers, certain solid tumors have been reported to occur more frequently among blood relatives of patients with MM. Using population‐based data, we assessed risks for hematologic malignancies, monoclonal gammopathy of undetermined significance (MGUS), and solid tumors among first‐degree relatives of patients with MM. We included 13,896 patients with MM and 54,365 matched controls. Also we identified first‐degree relatives of patients with MM (n = 37,838) and controls (n = 151,068). Using a marginal survival model, we estimated relative risks (RRs) and 95% confidence intervals (CIs) for hematologic and solid tumors among family members of patients with MM and controls as measures of familial aggregation. Compared with relatives of controls, relatives of patients with MM had an increased risk of developing MM (RR = 2.1; 95% CI 1.6–2.9), MGUS (2.1; 1.5–3.1), acute lymphoblastic leukemia (ALL) (2.1; 1.0–4.2), any solid tumor (1.1; 1.0–1.1) and bladder cancer (1.3; 1.0–1.5). No significantly increased risk was found for other hematologic or solid malignancies. Our findings support a role for a shared susceptibility (genetic, environmental or both) that predisposes to MM, MGUS, ALL and bladder cancer. © 2009 UICC     

Induction of increased cAMP levels in articular chondrocytes blocks matrix metalloproteinase–mediated cartilage degradation,but not aggrecanase‐mediated cartilage degradation

Objective

Calcitonin has been suggested to have chondroprotective effects. One signaling pathway of calcitonin is via the second messenger cAMP. We undertook this study to investigate whether increased cAMP levels in chondrocytes would be chondroprotective.

Methods

Cartilage degradation was induced in bovine articular cartilage explants by 10 ng/ml oncostatin M (OSM) and 20 ng/ml tumor necrosis factor (TNF). In these cultures, cAMP levels were augmented by treatment with either forskolin (4, 16, or 64 μM) or 3‐isobutyl‐1‐methyl xanthine (IBMX; 4, 16, or 64 μM). Cartilage degradation was assessed by 1) quantification of C‐terminal crosslinking telopeptide of type II collagen fragments (CTX‐II), 2) matrix metalloproteinase (MMP)–mediated aggrecan degradation by ³⁴²FFGV‐ G2 assay, 3) aggrecanase‐mediated degradation by ³⁷⁴ARGS‐G2 assay, 4) release of sulfated glycosaminoglycans (sGAG) into culture medium, 5) immunohistochemistry with a monoclonal antibody recognizing the CTX‐II epitope, and 6) toluidine blue staining of proteoglycans. MMP expression and activity were assessed by gelatin zymography.

Results

OSM and TNF induced an 8,000% increase in CTX‐II compared with control (P < 0.001). Both forskolin and IBMX dose‐dependently inhibited release of CTX‐II (P < 0.001). OSM and TNF induced a 6‐fold increase in ³⁴²FFGV‐G2, which was abrogated by forskolin and IBMX (by >80%). OSM and TNF stimulated MMP expression as visualized by zymography, and MMP expression was dose‐dependently inhibited by forskolin and IBMX. The highest concentration of IBMX lowered cytokine‐induced release of sGAG by 72%.

Conclusion

Levels of cAMP in chondrocytes play a key role in controlling catabolic activity. Increased cAMP levels in chondrocytes inhibited MMP expression and activity and consequently strongly inhibited cartilage degradation. Specific cAMP modulators in chondrocytes may be potential treatments for cartilage degenerative diseases.

     

The comparative effectiveness of tumor necrosis factor–blocking agents in patients with rheumatoid arthritis and patients with ankylosing spondylitis: A six‐month,longitudinal, observational,multicenter study

Objective

To compare the effectiveness of tumor necrosis factor (TNF)–blocking agents (etanercept and infliximab) in patients with rheumatoid arthritis (RA) and patients with ankylosing spondylitis (AS).

Methods

Data from an ongoing longitudinal, observational study in Norway were used to assess changes in health‐related quality of life (HRQOL) in patients with RA (n = 291) and AS (n = 62). Patients received anti‐TNF therapy, and changes in scores on the Short Form 36 (SF‐36), SF‐6D, modified Health Assessment Questionnaire, and visual analog scales for patients' assessments of pain, fatigue, and global status from baseline to followup examinations at 3 and 6 months were compared. Data were adjusted for age, sex, and baseline values and are presented as crude estimates as well as standardized response means.

Results

Both groups had improvements in all measures at 3 and 6 months. At 3 months, the changes were significantly better in the AS group compared with the RA group for all measures except the SF‐36 social functioning scores. At 6 months, all changes were numerically greater in the AS group. Differences were significant for the SF‐36 role emotional scores and were borderline significant for the SF‐36 physical functioning, role physical, and vitality scores and for the SF‐6D scores.

Conclusion

In this real‐life setting, patients with AS experienced improvement in HRQOL that was comparable to, and sometimes greater than, that observed in RA patients. These results support the idea that patients with AS should have the same access to TNF‐blocking agents as patients with RA.