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Characterization of Novel Synthesized Small Molecular Compounds Against Non-Small Cell Lung Cancer [ORIGINAL ARTICLES: GENERAL THORACIC]

With the exception of surgery, the standard platinum-based chemotherapeutic agents are the preferred treatment for non-small cell lung cancer (NSCLC); however little improvement (5-year survival) has been made. Therefore it is highly desirable to develop innovative therapeutic agents for NSCLC treatment.

 Methods

Highly enantioselective synthetic methods were developed and a broad compound library was established. Cell toxicity, cell sensitivity, cell proliferation, cell invasion, and three-dimensional colony formation assays were used to assess the anticancer potential of these compounds in non–small-cell lung cancer (NSCLC) cell lines.

 Results

We found that the S-form of compound PL54 (PL54S, 5-20 µM) exhibited strong anticancer activity in 5 tested NSCLC cell lines. We further synthesized a highly pure R-form enantiomer of PL54 (PL54R) and its racemate (PL54Rac) and characterized their anticancer activities. The results showed that PL54S is more potent than PL54R and PL54Rac against the tested cell lines. Furthermore, less cellular toxicity was observed in the normal human lung fibroblasts. Similarly, PL54S displayed greater anti–colony formation activity compared with PL54R and PL54Rac. The cellular sensitivity assay revealed that PL54S and PL54Rac significantly suppressed cologenic formation compared with PL54R and dimethyl sulfoxide controls (p < 0.01). All PL54 compounds (5 to 20 µM) significantly inhibited cell proliferation and invasion of the A549 cell line (p < 0.01). A soft agar colony formation assay revealed that PL54S and PL54Rac (10 mM), but not PL54R, significantly inhibited colony formation of tested NSCLC cells (p < 0.01).

 Conclusions

The stereospecific compounds may prove to be a novel technique for the treatment of NSCLC.

Creating Scenarios of the Impact of COPD and Their Relationship to COPD Assessment Test (CAT) Scores

The COPD Assessment Test (CAT™) is a new short health status measure for routine use. New questionnaires require reference points so that users can understand the scores; descriptive scenarios are one way of doing this. A novel method of creating scenarios is described.

Methods: A Bland and Altman plot showed a consistent relationship between CAT scores and scores obtained with the St George's Respiratory Questionnaire for COPD (SGRQ-C) permitting a direct mapping process between CAT and SGRQ items. The severity associated with each CAT item was calculated using a probabilistic model and expressed in logits (log odds of a patient of given severity affirming that item 50% of the time). Severity estimates for SGRQ-C items in logits were also available, allowing direct comparisons with CAT items. CAT scores were categorised into Low, Medium, High and Very High Impact. SGRQ items of corresponding severity were used to create scenarios associated with each category.

Results: Each CAT category was associated with a scenario comprising 12 to 16 SGRQ-C items. A severity 'ladder' associating CAT scores with exemplar health status effects was also created. Items associated with 'Low' and 'Medium' Impact appeared to be subjectively quite severe in terms of their effect on daily life.

Conclusions: These scenarios provide users of the CAT with a good sense of the health impact associated with different scores. More generally they provide a surprising insight into the severity of the effects of COPD, even in patients with apparently mild-moderate health status impact.

How do COPD patients respond to exacerbations?

Although timely treatment of COPD exacerbations seems clinically important, nearly half of these exacerbations remain unreported and subsequently untreated. Recent studies have investigated incidence and impact of failure to seek medical treatment during exacerbations. Yet, little is known about type and timing of other self-management actions in periods of symptom deterioration.

The current prospective study aims at determining the relative incidence, timing and determinants of three types of patient responses.

Methods: In a multicentre observational study, 121 patients (age 67+/-11 years, FEV1pred. 48+/-19) were followed for 6 weeks by daily diary symptom recording. Three types of action were assessed daily: planning periods of rest, breathing techniques and/or sputum clearing (type-A), increased bronchodilator use (type-B) and contacting a healthcare provider (type-C).

Results: Type-A action was taken in 70.7%, type-B in 62.7% and type C in 17.3% of exacerbations (n=75). Smokers were less likely to take type-A and B actions. Type-C actions were associated with more severe airflow limitation and increased number of hospital admissions in the last year.

Conclusions: Our study shows that most patients are willing to take timely self-management actions during exacerbations. Future research is needed to determine whether the low incidence of contacting a healthcare provider is due to a lack of self-management or healthcare accessibility.

Acute Inhalation of Hypertonic Saline does not Improve Mucociliary Clearance in all Children with Cystic Fibrosis

Little is known of how mucociliary clearance (MCC) in children with cystic fibrosis (CF) and normal pulmonary function compares with healthy adults, or how an acute inhalation of 7% hypertonic saline (HS) aerosol affects MCC in these same children.

Methods: We compared MCC in 12 children with CF and normal pulmonary function after an acute inhalation of 0.12% saline (placebo), or HS, admixed with the radioisotope 99mtechnetium sulfur colloid in a double-blind, randomized, cross-over study. Mucociliary clearance on the placebo day in the children was also compared to MCC in 10 healthy, non-CF adults. Mucociliary clearance was quantified over a 90 min period, using gamma scintigraphy, and is reported as MCC at 60 min (MCC60) and 90 min (MCC90).

Results: Median [interquartile range] MCC60 and MCC90 in the children on the placebo visit were 15.4 [12.4-24.5]% and 19.3 [17.3-27.8%]%, respectively, which were similar to the adults with 17.8 [6.4-28.7]% and 29.6 [16.1-43.5]%, respectively. There was no significant improvement in MCC60 (2.2 [-6.2-11.8]%) or MCC90 (2.3 [-1.2-10.5]%) with HS, compared to placebo. In addition, 5/12 and 4/12 of the children showed a decrease in MCC60 and MCC90, respectively, after inhalation of HS. A post hoc subgroup analysis of the change in MCC90 after HS showed a significantly greater improvement in MCC in children with lower placebo MCC90 compared to those with higher placebo MCC90 (p = 0.045).

Conclusions: These data suggest that percent MCC varies significantly between children with CF lung disease and normal pulmonary functions, with some children demonstrating MCC values within the normal range and others showing MCC values that are below normal values. In addition, although MCC did not improve in all children after inhalation of HS, improvement did occur in children with relatively low MCC values after placebo. This finding suggests that acute inhalation of hypertonic saline may benefit a subset of children with low MCC values.

Discrimination between COPD with and without alpha 1‐antitrypsin deficiency using an electronic nose

CONCLUSIONS : An electronic nose can detect differences in smell‐prints in COPD patients with or without AAT deficiency. Augmentation therapy changes the volatile organic compound pattern. The electronic nose may be helpful in the diagnosis of AAT deficiency.

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