Drug‐Related Pneumonitis During Mammalian Target of Rapamycin Inhibitor Therapy: Radiographic Pattern‐Based Approach in Waldenström Macroglobulinemia as a Paradigm

Background.

This study determined the frequency of drug-related pneumonitis during mammalian target of rapamycin (mTOR) inhibitor therapy in Waldenström macroglobulinemia patients and investigated the imaging characteristics and radiographic patterns of pneumonitis.

Materials and Methods.

A total of 40 patients (23 men, 17 women; 43–84 years old) with Waldenström macroglobulinemia treated in 2 trials of the mTOR inhibitor everolimus were retrospectively studied. Chest computed tomography (CT) scans during therapy were reviewed for abnormalities suspicious for drug-related pneumonitis by the consensus of three radiologists, evaluating the extent, distributions, and specific findings. The radiographic patterns of pneumonitis were classified using the American Thoracic Society/European Respiratory Society classification of interstitial pneumonia.

Results.

Drug-related pneumonitis was noted in 23 patients (58%). The median time from the initiation of therapy to the onset of pneumonitis was 5.7 months. Lower lungs were involved in all 23 patients, with a higher extent than in the other zones (p < .001). The distribution was peripheral and lower in 11 patients (48%) and mixed and multifocal in 10 (44%). The findings were bilateral in 20 patients (87%). Ground glass opacities (GGOs) and reticular opacities were present in all 23 patients, with consolidation in 12, traction bronchiectasis in 2, and centrilobular nodularity in 1. The pattern of pneumonitis was classified as cryptogenic organizing pneumonia (COP) in 16 (70%) and nonspecific interstitial pneumonia (NSIP) in 7 (30%), with overlapping features of COP and NSIP in 7 patients.

Conclusion.

Drug-related pneumonitis was noted on CT in 58% of Waldenström macroglobulinemia patients treated with mTOR inhibitor therapy. Most common findings were bilateral GGOs and reticular opacities, with or without consolidation, in peripheral and lower lungs, demonstrating COP and NSIP patterns.

Implications for Practice:

The present study has demonstrated that drug-related pneumonitis during mammalian target of rapamycin (mTOR) inhibitor therapy is highly frequent, occurring in 58% of patients with Waldenström macroglobulinemia. The radiographic patterns of pneumonitis demonstrated cryptogenic organizing pneumonia and nonspecific interstitial pneumonia patterns, with overlapping features in 30% of the patients. The present study describes an initial attempt of a radiographic pattern-based approach to drug-related pneumonitis in the era of molecular targeting therapy, with a cohort of patients with Waldenström macroglobulinemia receiving mTOR inhibitor therapy as a paradigm, which might contribute to further understanding and in-depth interpretation of lung toxicity during novel cancer therapy.     

Clinical application of pharmacokinetic analysis as a biomarker of solitary pulmonary nodules: Dynamic contrast-enhanced MR imaging

The purpose of this study is to evaluate perfusion indices and pharmacokinetic parameters in solitary pulmonary nodules (SPNs). Thirty patients of 34 enrolled with SPNs (15–30 mm) were evaluated in this study. T1 and T2‐weighted structural images and 2D turbo FLASH perfusion images were acquired with shallow free breathing. B‐spline nonrigid image registration and optimization by χ² test against pharmacokinetic model curve were performed on dynamic contrast‐enhanced MRI. This allowed voxel‐by‐voxel calculation of k_ep, the rate constant for tracer transport to and from plasma and the extravascular extracellular space. Mean transit time, time‐to‐peak, initial slope, and maximum enhancement (E_max) were calculated from time–intensity curves fitted to a gamma variate function. After blinded data analysis, correlation with tissue histology from surgical resection or biopsy samples was performed. Histologic evaluation revealed 25 malignant and five benign SPNs. All benign SPNs had k_ep < 1.0 min^?1. Nineteen of 25 (76%) malignant SPNs showed k_ep > 1.0 min^?1. Sensitivity to diagnose malignant SPNs at a cutoff of k_ep = 1.0 min^?1 was 76%, specificity was 100%, positive predictive value was 100%, negative predictive value was 45%, and accuracy was 80%. Of all indices studied, k_ep was the most significant in differentiating malignant from benign SPNs. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.     

Ovarian fibroma: findings by contrast-enhanced MRI

Ovarian fibromas are solid neoplasms that are difficult to differentiate radiologically from uterine leiomyomas. In this report, we describe the contrast-enhanced magnetic resonance imaging features of a 13-cm-diameter solid pelvic mass that allowed us to make the prospective diagnosis of ovarian fibroma. Received: 16 April 1996/Accepted: 7 June 1996     

Fibrolamellar hepatocellular carcinoma: MR appearance

We report two cases of fibrolamellar hepatocellular carcinoma, each of which had lower signal intensity than normal liver on short repetition time (TR), short echo time (TE) spin-echo (SE) images and demonstrated a central scar-like area of low signal intensity which did not become hyperintense on long time TR/TE SE images.     

Potent plasmodicidal activity of a heat-induced reformulation of deoxycholate-amphotericin B (Fungizone) against Plasmodium falciparum

The emergence and spread of drug-resistant Plasmodium falciparum continue to pose problems in malaria chemotherapy. Therefore, it is necessary to identify new antimalarial drugs and therapeutic strategies. In the present study, the activity of a heat-treated form of amphotericin B (HT-AMB) against P. falciparum was evaluated. The efficacy and toxicity of HT-AMB were also compared with those of the standard formulation (AMB). HT-AMB showed significant activity against a chloroquine-resistant strain (strain K-1) and a chloroquine-susceptible strain (strain FCR-3) in vitro. The 50% inhibitory concentrations of HT-AMB were 0.32 +/- 0.03 mug/ml for strain K-1 and 0.33 +/- 0.03 mug/ml for strain FCR-3. In the presence of 1.0 mug of HT-AMB per ml, only pyknotic parasites were observed after 24 h of incubation of early trophozoites (ring forms). However, when late trophozoites and schizonts were cultured with 1.0 mug of HT-AMB per ml, those forms multiplied to ring forms but the number of infected erythrocytes did not increase. These results indicate that HT-AMB possesses potent antiplasmodial activity and that the drug is more effective against the ring-form stage than against the late trophozoite and schizont stages. HT-AMB was observed to have little cytotoxic effect against a human liver cell line (Chang liver cells). In conclusion, the results suggest that HT-AMB has promising properties and merits further in vivo investigations as a treatment for falciparum malaria.     

Pulmonary ventilation: dynamic MRI with inhalation of molecular oxygen

We have recently demonstrated a non-invasive technique to visualize pulmonary ventilation in humans with inhalation of molecular oxygen as a paramagnetic contrast agent. In the current study, T1 shortening of lung tissue by inhalation of oxygen was observed (P<0.001). The T1 values of lung tissue were also correlated with arterial blood oxygen pressure (PaO(2)) in a pig, resulting in excellent correlation (r(2)=0.997). Dynamic wash-in and wash-out MR ventilation images as well as dynamic wash-in wash-out signal intensity versus time curves were obtained. The mean wash-in decay constants were 26.8+/-10.5 s in the right lung, and 26.3+/-9.5 s in the left lung. The mean wash-out decay constants were 23.3+/-11.3 s in the right lung, and 20.8+/-10.5 s in the left lung. Dynamic assessment of pulmonary ventilation is feasible using oxygen-enhanced MR imaging, which could provide dynamic MR ventilation-perfusion imaging in combination with recently developed MR perfusion imaging technique, and thus a robust tool for the study of pulmonary physiology and pathophysiology.     

Assessment of pulmonary perfusion using a subtracted HASTE image between diastole and systole

The MR signal intensity change in the pulmonary parenchyma during the cardiac cycle was studied using HASTE sequence in volunteers. In addition, the potential to assess pulmonary perfusion abnormality by subtraction between diastolic and systolic HASTE images was tested in a pig model of pulmonary embolism. Signal intensity decreased in systole while it increased gradually in diastole. In a pig model with pulmonary embolism, subtracted images could identify the perfusion abnormality. Thus, subtraction of diastolic and systolic HASTE images has the potential to detect pulmonary perfusion abnormality. The technique may provide a new simple method for evaluating pulmonary perfusion.     

Kurtosis and skewness of density histograms on inspiratory and expiratory CT scans in smokers

The aim of this study is to evaluate the relationship between lung function and kurtosis or skewness of lung density histograms on computed tomography (CT) in smokers. Forty-six smokers (age range 46?81 years), enrolled in the Lung Tissue Research Consortium, underwent pulmonary function tests (PFT) and chest CT at full inspiration and full expiration. On both inspiratory and expiratory scans, kurtosis and skewness of the density histograms were automatically measured by open-source software. Correlations between CT measurements and lung function were evaluated by the linear regression analysis. Although no significant correlations were found between inspiratory kurtosis or skewness and PFT results, expiratory kurtosis significantly correlated with the following: the percentage of predicted value of forced expiratory volume in the first second (FEV(1)), the ratio of FEV(1) to forced vital capacity (FVC), and the ratio of residual volume (RV) to total lung capacity (TLC) (FEV(1)%predicted, R = -0.581, p < 0.001; FEV(1)/FVC, R = -0.612, p < 0.001; RV/TLC, R = 0.613, p < 0.001, respectively). Similarly, expiratory skewness showed significant correlations with PFT results (FEV(1)%predicted, R = -0.584, p < 0.001; FEV(1)/FVC, R = -0.619, p < 0.001; RV/TLC, R = 0.585, p < 0.001, respectively). Also, the expiratory/inspiratory (E/I) ratios of kurtosis and skewness significantly correlated with FEV(1)%predicted (p < 0.001), FEV(1)/FVC (p < 0.001), RV/TLC (p < 0.001), and the percentage of predicted value of diffusing capacity for carbon monoxide (kurtosis E/I ratio, p = 0.001; skewness E/I ratio, p = 0.03, respectively). We conclude therefore that expiratory values and the E/I ratios of kurtosis and skewness of CT densitometry reflect airflow limitation and air-trapping. Higher kurtosis or skewness on expiratory CT scan indicates more severe conditions in smokers.