Maria Plataki

Proportional assist ventilation with load-adjustable gain factors in critically ill patients: comparison with pressure support.

ObjectivesIt is not known if proportional assist ventilation with load-adjustable gain factors (PAV+) may be used as a mode of support in critically ill patients. The aim of this study was to examine the effectiveness of sustained use of PAV+ in critically ill patients and compare it with pressure support ventilation (PS).Design and settingRandomized study in the intensive care unit of a university hospital.MethodsA total of 208 critically ill patients mechanically ventilated on controlled modes for at least 36 h and meeting certain criteria were randomized to receive either PS (n = 100) or PAV+ (n = 108). Specific written algorithms were used to adjust the ventilator settings in each mode. PAV+ or PS was continued for 48 h unless the patients met pre-defined criteria either for switching to controlled modes (failure criteria) or for breathing without ventilator assistance.ResultsFailure rate was significantly lower in PAV+ than that in PS (11.1 vs. 22.0%, P = 0.040, OR 0.443, 95% CI 0.206–0.952). The proportion of patients exhibiting major patient–ventilator dyssynchronies at least during one occasion and after adjusting the initial ventilator settings, was significantly lower in PAV+ than in PS (5.6 vs. 29.0%, P < 0.001, OR 0.1, 95% CI 0.06–0.4). The proportion of patients meeting criteria for unassisted breathing did not differ between modes.ConclusionsPAV+ may be used as a useful mode of support in critically ill patients. Compared to PS, PAV+ increases the probability of remaining on spontaneous breathing, while it considerably reduces the incidence of patient–ventilator asynchronies.

Severe airway stenosis associated with Crohn's disease: Case report

BackgroundSymptomatic respiratory tract involvement is not common in Crohns disease. Upper-airway obstruction has been reported before in Crohns disease and usually responds well to steroid treatment.Case presentationWe report a case of a 32-year old patient with Crohns disease who presented with progressively worsening dyspnea on exertion. Magnetic Resonance Imaging of the chest and bronchoscopy revealed severe tracheal stenosis and marked inflammation of tracheal mucosa. Histopathology of the lesion showed acute and chronic inflammation and extended ulceration of bronchial mucosa, without granulomas. Tracheal stenosis was attributed to Crohns disease after exclusion of other possible causes and oral and inhaled steroids were administered. Despite steroid treatment, tracheal stenosis persisted and only mild symptomatic improvement was noted after 8 months of therapy. The patient subsequently underwent rigid bronchoscopy with successful dilatation and ablation of the stenosed areas and remission of her symptoms.ConclusionRespiratory involvement in Crohns disease might be more common than appreciated. Interventional pulmonology techniques should be considered in cases of tracheal stenosis due to Crohns disease refractory to steroid treatment.

Active Remodeling in Idiopathic Interstitial Pneumonias: Evaluation of Collagen Types XII and XIV

Fibril-associated collagens with interrupted triple helices (FACITs) XII and XIV act as fibril organizers and assist in the maintenance of uniform fibril size. We investigated the spatial expression patterns of collagens XII and XIV in cryptogenic organizing pneumonia (COP)/organizing pneumonia (OP) and in idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) and compared them to normal human lung. Study subjects included 10 patients with COP/OP, 10 patients with IPF/UIP, and 8 control subjects. Immunostaining for collagens XII and XIV was carried out in paraffin-embedded human lung tissue sections. Picrosirius red histochemical staining for collagen I expression and electron microcopy to evaluate fibril diameter were also performed. In normal lung, collagens XII and XIV were expressed in perivascular and subpleural connective tissue. In COP/OP, both collagens showed intense staining in perivascular connective tissue, thickened alveolar septae, and subpleural areas. In IPF/UIP, XII and XIV were expressed in perivascular connective tissue, in areas of established fibrosis, and in areas of subpleural thickening. Only collagen XII was expressed in granulation tissue plugs in COP/OP and in fibroblastic foci in IPF/UIP. Collagen type I was overexpressed in fibrotic areas. Electron micrographs revealed obvious fibril diameter alteration and fusion in the same areas. FACITs XII and XIV are expressed in normal and fibrotic lung. Unlike collagen XIV, collagen XII was expressed in granulation tissue plugs in COP/OP and in fibroblast foci in IPF/UIP. This may suggest a possible distinct role for both collagens in the modulation of the extracellular matrix during the onset of fibrotic process.

Heterogeneity of circulating tumor cells (CTCs) in patients with recurrent small cell lung cancer (SCLC) treated with pazopanib

OBJECTIVES To investigate the effect of pazopanib on different CTCs subpopulations in patients with recurrent SCLC and evaluate their clinical relevance. METHODS Peripheral blood was obtained before the administration of pazopanib (n=56 patients), after the first cycle (n=35 patients) and at disease progression (n=45 patients). CTCs were detected by CellSearch and double immunofluorescent staining using antibodies against the cytokeratins (CK), TTF-1, CD56 and VEGFR2. RESULTS Before treatment, CTCs could be detected in 50% of patients by CellSearch; phenotypic characterization of CTCs demonstrated that 50%, 46.6% and 27.6% of patients had CD45-/TTF1+, CD45-/CD56+ and TTF-1+/CD56+ CTCs, respectively. Additionally, 59% of CTCs were TTF-1+/VEGFR2+ and 53% CK+/VEGFR2+. One pazopanib cycle resulted to a significant decrease of the number of CTCs (CellSearch: p=0.043) and CK+/VEGFR2+ cells (p=0.027). At the time of PD, both the total number of CTCs (p=0.027) and the number of the different subpopulations were significantly increased compared to post-1st cycle values; this increased CTCs number was associated with a significant increase of TTF-1+/VEGFR2+ (p=0.028) and CK+/VEGFR2+ CTCs (p=0.018). In multivariate analysis, only the number of CTCs as assessed by CellSearch after one treatment cycle was significantly associated with OS (HR: 0.21; p=0.005). CONCLUSIONS Pazopanib has a significant effect on different subpopulations of CTCs in patients with relapsed SCLC; the detection of VEGFR2+ CTCs during treatment could be a surrogate marker associated with resistance to pazopanib.

Is there increasing evidence that the risks of rhAPC may outweigh its benefits

Sir, It is true that the use of rhAPC in critically ill patients with sepsis has raised a lot of controversy and we read with great interest the concerns of Eichacker and Natanson in their editorial in “Intensive Care Medicine” [1]. We believe, however, that their comparisons and conclusions, in view of the recently published surveys by Kanji et al. [2] and Bertolini et al. [3], do not take into consideration significant limitations and differences in the studies on rhAPC published to date. The authors raise concern that the incidence of bleeding with rhAPC is actually higher than that reported in PROWESS and ENHANCE [4, 5]. Although severe bleeding occurred in about 10% of patients in the Canadian and Italian surveys, it is important to note that (a) a significant percentage of patients had relative (> 20%) or even absolute contraindications (2% in the study by Kanji et al.) for rhAPC infusion, (b) the serious bleeding criterion was less strict, and (c) patients were more severely ill than those enrolled in PROWESS and ENHANCE, a fact that places them at greater risk for bleeding, independent of rhAPC. In addition, Eichacker and Natanson [1] cited the “troubling” increase of intracerebral hemorrhages observed in children in RESOLVE [6]. They did not report, however, that these events were associated with age younger than 60 days and weight less than 4 kg (an identifiable population) and major protocol violations (a modifiable factor). The other major point made by the authors is a possible lack of benefit with rhAPC treatment, referring to the results of ADDRESS, RESOLVE, and VHA/UHC [7, 8]; however, ADDRESS was specifically designed to confirm the results of the PROWESS meta-analysis indicating benefit only for patients with APACHE ≥ 25. The lack of benefit in patients with APACHE < 25 and/or single-organ failure was therefore no surprise. In the VHA/UHC study 37% of patients had contraindications that would have precluded them from enrollment in PROWESS and mortality in this subgroup was significantly increased. The RESOLVE study was underpowered to detect any differences in mortality, although a non-significant 12% increase in survival after adjusting for various predictors of death in rhAPC group is noteworthy. In the recent studies by Kanji et al. [2] and Bertolini et al. [3], the severity of illness was greater than PROWESS or ENHANCE, and therefore mortality is not comparable between those studies. Finally, 21 and 8% of patients in the studies by Bertolini [3] and Kanji et al. [2], respectively, received treatment after 48 h, and this delay may have influenced the results. From the recent studies [2, 3] it is evident that in everyday clinical practice rhAPC is being administered in the presence of contraindications or with delay, and this may both increase the incidence of bleeding and reduce the effectiveness of therapy. This calls for education effort in the proper use of the drug. In conclusion, we believe that currently there is no evidence to suggest that the risks of timely rhAPC therapy outweigh benefits in patients with severe sepsis, high risk of death, and no contraindications.

Dynamic changes of phenotypically different circulating tumor cells sub-populations in patients with recurrent/refractory small cell lung cancer treated with pazopanib

The aim of the study was to investigate the effect of 2nd-line pazopanib on the different CTCs subpopulations in SCLC patients and evaluate the clinical relevance of their changes. Different CTCs subpopulations were evaluated before pazopanib initiation (n = 56 patients), after one-cycle (n = 35) and on disease progression (n = 45) by CellSearch and double immunofluorescence using anti-CKs and anti-Ki67, anti-M30 or anti-Vimentin antibodies. Before treatment, CTCs were detected in 50% of patients by CellSearch whereas 53.4%, 15.5% and 74.1% patients had CK+/Ki67+, CK+/M30+ and CK+/Vim+ CTCs, respectively. One pazopanib cycle significantly decreased the number of CTCs as detected by CellSearch (p = 0.043) as well as the number of CK+/Ki67+ (p < 0.001), CK+/M30+ (p = 0.015) and CK+/Vim+ (p < 0.001) cells. On disease progression, both the incidence and CTC numbers were significantly increased (CellSearch, p = 0.027; CK+/Ki67+, p < 0.001; CK+/M30+, p = 0.001 and CK+/Vim+, p < 0.001). In multivariate analysis, the detection of CK+/Vim+ CTCs after one treatment cycle (HR: 7.9, 95% CI: 2.9–21.8; p < 0.001) and CTCs number on disease progression, as assessed by CellSearch, (HR: 2.0, 95% CI: 1.0–6.0; p = 0.005) were emerged as independent factors associated with decreased OS. In conclusion, pazopanib can eliminate different CTC subpopulations in patients with relapsed SCLC. The analysis of CTCs could be used as a dynamic biomarker of treatment efficacy.