Lung function and exercise capacity in young adults born prematurely

RATIONALE: Limited information is available about the long-term outcome of lung function and exercise capacity in young adults born prematurely. OBJECTIVE: To determine long-term effects of prematurity on lung function (volumes, diffusing capacity) and exercise capacity in ex-preterms compared with healthy peers. METHODS: In a prospective cohort study, children born with a gestational age of less than 32 wk and/or a birth weight under 1,500 g were followed up for 19 yr. Participants (n=42; mean gestational age, 30 wk, and mean birth weight, 1,246 g) and healthy term control subjects (n=48) were recruited for lung function and exercise tests. MEASUREMENTS: Spirometry, bodybox (TLC(box)), diffusing capacity (Dl(CO)), bicycle ergometer test. MAIN RESULTS: Preterm birth was associated with lower FEV(1) (preterms, 95% predicted, vs. controls, 110% predicted; p<0.001), DL(CO)sb (88% predicted vs. 96% predicted, p=0.003), and exercise capacity (load, 185 vs. 216 W; p<0.001; anaerobic threshold: mean, 1,546 vs. 1,839 ml/min; p<0.001) compared with control subjects at follow-up. No differences between the groups were found in TLC(box), peak oxygen consumption (Vo(2)), and breathing reserve. No significant differences in lung function and exercise parameters were found between preterms with and without bronchopulmonary dysplasia. CONCLUSIONS: Long-term effects of prematurity were airway obstruction and a lower CO diffusing capacity compared with control subjects, although mean lung function parameters were within the normal range. Ex-preterms had a lower exercise level, which could not be explained by impaired lung function or smoking habits, but might be due to impaired physical fitness.     

Nebulized antithrombin limits bacterial outgrowth and lung injury in Streptococcus pneumoniae pneumonia in rats

Introduction  

Disturbed alveolar fibrin turnover is a cardinal feature of severe pneumonia. Clinical studies suggest that natural inhibitors of coagulation exert lung-protective effects via anticoagulant and possibly also anti-inflammatory pathways. Intravenous infusion of the natural anticoagulants increases the risk of bleeding. Local administration may allow for higher treatment dosages and increased local efficacy while at the same time reducing the risk of bleeding. We evaluated the effect of nebulized anticoagulants on pulmonary coagulopathy and inflammation in a rat model of Streptococcus pneumoniae pneumonia.     

The six-minute walk test predicts cardiorespiratory fitness in individuals with aneurysmal subarachnoid hemorrhage

Background: Peak oxygen uptake (VO_2peak) established during progressive cardiopulmonary exercise testing (CPET) is the “gold-standard” for cardiorespiratory fitness. However, CPET measurements may be limited in patients with aneurysmal subarachnoid hemorrhage (a-SAH) by disease-related complaints, such as cardiovascular health-risks or anxiety. Furthermore, CPET with gas-exchange analyses require specialized knowledge and infrastructure with limited availability in most rehabilitation facilities.

Objectives: To determine whether an easy-to-administer six-minute walk test (6MWT) is a valid clinical alternative to progressive CPET in order to predict VO_2peak in individuals with a-SAH.

Methods: Twenty-seven patients performed the 6MWT and CPET with gas-exchange analyses on a cycle ergometer. Univariate and multivariate regression models were made to investigate the predictability of VO_2peak from the six-minute walk distance (6MWD).

Results: Univariate regression showed that the 6MWD was strongly related to VO_2peak (r = 0.75, p < 0.001), with an explained variance of 56% and a prediction error of 4.12 ml/kg/min, representing 18% of mean VO_2peak. Adding age and sex to an extended multivariate regression model improved this relationship (r = 0.82, p < 0.001), with an explained variance of 67% and a prediction error of 3.67 ml/kg/min corresponding to 16% of mean VO_2peak.

Conclusions: The 6MWT is an easy-to-administer submaximal exercise test that can be selected to estimate cardiorespiratory fitness at an aggregated level, in groups of patients with a-SAH, which may help to evaluate interventions in a clinical or research setting. However, the relatively large prediction error does not allow for an accurate prediction in individual patients.     

Quality assurance of the PREOPANC trial (2012-003181-40) for preoperative radiochemotherapy in pancreatic cancer

Background

The Dutch Pancreatic Cancer Group initiated the national, multicentre, controlled PREOPANC trial, randomising between preoperative radiochemotherapy and direct explorative laparotomy for patients with (borderline) resectable pancreatic cancer. The aim of this dummy run is to evaluate compliance with the radiotherapy protocol of this trial, and the quality of delineation and radiation plans.

Methods

Eleven radiation oncology departments open for accrual of patients in the PREOPANC trial were provided with all necessary information of a selected ‘dummy’ patient. Each institute was asked to delineate the target volumes, including gross tumour volume, internal gross tumour volume (iGTV), internal clinical target volume, and planning target volume. The institutions were also asked to provide a radiation treatment plan in accordance with the PREOPANC trial protocol.

Results

The range of the iGTV was 19.3–77.2?cm³ with a mean iGTV of 41.5?cm³ (standard deviation 14.8?cm³). Nine institutions made a treatment plan using an arc technique for treatment delivery, one an intensity modulated technique and one a 3-field conformal technique. All institutions reached the prescribed target coverage, without exceeding the organs at risk constraints. The institution with the 3?field conformal technique was advised to use a more sophisticated technique (e.?g. volumetric modulated arc therapy) to reduce the dose to the spinal cord.

Conclusion

All institutions showed acceptable deviations from the PREOPANC trial protocol and achieved an acceptable quality of delineation and radiation technique. All institutions were allowed to continue participation in the PREOPANC trial.

     

Mcl‐1 and Bcl‐xL levels predict responsiveness to dual MEK/Bcl‐2 inhibition in B‐cell malignancies

Most patients with chronic lymphocytic leukemia (CLL) initially respond to targeted therapies, but eventually relapse and develop resistance. Novel treatment strategies are therefore needed to improve patient outcomes. Here, we performed direct drug testing on primary CLL cells and identified synergy between eight different mitogen‐activated protein kinase kinase (MEK) inhibitors and the B‐cell lymphoma 2 (Bcl‐2) antagonist venetoclax. Drug sensitivity was independent of immunoglobulin heavy‐chain gene variable region (IGVH) and tumor protein p53 (TP53) mutational status, and CLL cells from idelalisib‐resistant patients remained sensitive to the treatment. This suggests that combined MEK/Bcl‐2 inhibition may be an option for high‐risk CLL. To test whether sensitivity could be detected in other B‐cell malignancies, we performed drug testing on cell line models of CLL (n = 4), multiple myeloma (MM; n = 8), and mantle cell lymphoma (MCL; n = 7). Like CLL, MM cells were sensitive to the MEK inhibitor trametinib, and synergy was observed with venetoclax. In contrast, MCL cells were unresponsive to MEK inhibition. To investigate the underlying mechanisms of the disease‐specific drug sensitivities, we performed flow cytometry‐based high‐throughput profiling of 31 signaling proteins and regulators of apoptosis in the 19 cell lines. We found that high expression of the antiapoptotic proteins myeloid cell leukemia‐1 (Mcl‐1) or B‐cell lymphoma‐extra large (Bcl‐xL) predicted low sensitivity to trametinib + venetoclax. The low sensitivity could be overcome by combined treatment with an Mcl‐1 or Bcl‐xL inhibitor. Our findings suggest that MEK/Bcl‐2 inhibition has therapeutic potential in leukemia and myeloma, and demonstrate that protein expression levels can serve as predictive biomarkers for treatment sensitivities.     

Eight years of experience with vismodegib for advanced and multiple basal cell carcinoma patients in the Netherlands: a retrospective cohort study

Background Vismodegib has been used for the treatment of locally advanced basal cell carcinoma (laBCC) and metastatic BCC (mBCC) since 2011. Most efficacy and safety data are provided by clinical trials. This study evaluates the effectiveness of vismodegib for the treatment of laBCC, mBCC and basal cell nevus syndrome (BCNS) patients, and the tumour characteristics associated with a higher probability of achieving a complete response in the Netherlands.Methods A retrospective cohort study that included all patients ≥18 years with histologically proven basal cell carcinoma that received ≥1 dose of vismodegib between July 2011 and September 2019 in the Netherlands.Results In total, 48 laBCC, 11 mBCC and 19 BCNS patients were included. Median progression-free survival was 10.3 months (95% confidence interval (CI), 7.5–22.6) for laBCC, 11.7 (95% CI, 5.2–17.5) for mBCC and 19.1 (95% CI, 7.4–20.2) for BCNS. Larger laBCCs were associated with a lower probability of complete response (hazard ratio (HR) 0.77 per increase in cm, p = 0.02). Of all BCNS patients, 63% received ≥2 treatment sequences with vismodegib; all achieved partial responses.Conclusions Half of the aBCC patients progress within 1 year after the start of vismodegib treatment. More research is needed to investigate other treatment strategies after vismodegib progression and to evaluate long-term effects of repetitive vismodegib treatment.Subject terms: Basal cell carcinoma, Metastasis     

Electrochemical profiling and liquid chromatography–mass spectrometry characterization of synthetic cathinones: From methodology to detection in forensic samples

The emergence of new psychoactive drugs in the market demands rapid and accurate tools for the on-site classification of illegal and legal compounds with similar structures. Herein, a novel method for the classification of synthetic cathinones (SCs) is presented based on their electrochemical profile. First, the electrochemical profile of five common SC (i.e., mephedrone, ethcathinone, methylone, butylone, and 4-chloro-alpha-pyrrolidinovalerophenone) is collected to build calibration curves using square wave voltammetry on graphite screen-printed electrodes (SPEs). Second, the elucidation of the oxidation pathways, obtained by liquid chromatography–high-resolution mass spectrometry, allows the pairing of the oxidation products to the SC electrochemical profile, providing a selective and robust classification. Additionally, the effect of common adulterants and illicit drugs on the electrochemical profile of the SC is explored. Interestingly, a cathodic pretreatment of the SPE allows the selective detection of each SC in presence of electroactive adulterants. Finally, the electrochemical approach is validated with gas chromatography–mass spectrometry by analyzing 26 confiscated samples from seizures and illegal webshops. Overall, the electrochemical method exhibits a successful classification of SC including structural derivatives, a crucial attribute in an ever-diversifying drug market.