Aleksandar Grgic

FDG-PET-BASED RADIOTHERAPY PLANNING IN LUNG CANCER: OPTIMUM BREATHING PROTOCOL AND PATIENT POSITIONING—AN INTRAINDIVIDUAL COMPARISON

PURPOSE Fluoro-2-deoxy-d-glucose (FDG)-positron emission tomography (PET) and PET/computed tomography (CT) are increasingly used for radiotherapy (RT) planning in patients with non-small-cell lung carcinoma. The planning process often is based on separately acquired FDG-PET/CT and planning CT scans. We compared intraindividual differences between PET acquired in diagnostic (D-PET) and RT treatment position (RT-PET) coregistered with planning CTs acquired using different breathing protocols. METHODS AND MATERIALS Sixteen patients with non-small-cell lung carcinoma underwent two PET acquisitions (D-PET and RT-PET) and three planning CT acquisitions (expiration [EXP], inspiration [INS], and mid-breath hold [MID]) on the same day. All scans were rigidly coregistered, resulting in six fused data sets: D-INS, D-EXP, D-MID, RT-INS, RT-EXP, and RT-MID. Fusion accuracy was assessed by three readers at eight anatomic landmarks, lung apices, aortic arch, heart, spine, sternum, carina, diaphragm, and tumor, by using an alignment score ranging from 1 (no alignment) to 5 (exact alignment). RESULTS The RT-PET showed better alignment with any CT than D-PET (p < 0.001). With regard to breathing, RT-MID showed the best mean alignment score (3.7 +/- 1.0), followed by RT-EXP (3.5 +/- 0.9) and RT-INS (3.0 +/- 0.8), with all differences significant (p < 0.001). Comparing alignment scores with regard to anatomic landmarks, the largest deviations were found at the diaphragm, heart, and apices. Overall, there was fair agreement (kappa = 0.48; p < 0.001) among the three readers. CONCLUSIONS Significantly better fusion of PET and planning CT can be reached with PET acquired in the RT position. The best intraindividual fusion results are obtained with the planning CT performed during mid-breath hold. Our data justify the acquisition of a separate planning PET in RT treatment position if only a diagnostic PET scan is available.

F-18-FDG-PET Confined Radiotherapy of Locally Advanced NSCLC With Concomitant Chemotherapy: Results of the PET-PLAN Pilot Trial

PURPOSE The integration of fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) in the process of radiotherapy (RT) planning of locally advanced non-small-cell lung cancer (NSCLC) may improve diagnostic accuracy and minimize interobserver variability compared with target volume definition solely based on computed tomography. Furthermore, irradiating only FDG-PET-positive findings and omitting elective nodal regions may allow dose escalation by treating smaller volumes. The aim of this prospective pilot trial was to evaluate the therapeutic safety of FDG-PET-based RT treatment planning with an autocontour-derived delineation of the primary tumor. METHODS AND MATERIALS Eligible patients had Stages II-III inoperable NSCLC, and simultaneous, platinum-based radiochemotherapy was indicated. FDG-PET and computed tomography acquisitions in RT treatment planning position were coregistered. The clinical target volume (CTV) included the FDG-PET-defined primary tumor, which was autodelineated with a source-to-background algorithm, plus FDG-PET-positive lymph node stations. Limited by dose restrictions for normal tissues, prescribed total doses were in the range of 66.6 to 73.8 Gy. The primary endpoint was the rate of out-of-field isolated nodal recurrences (INR). RESULTS As per intent to treat, 32 patients received radiochemotherapy. In 15 of these patients, dose escalation above 66.6 Gy was achieved. No Grade 4 toxicities occurred. After a median follow-up time of 27.2 months, the estimated median survival time was 19.3 months. During the observation period, one INR was observed in 23 evaluable patients. CONCLUSIONS FDG-PET-confined target volume definition in radiochemotherapy of NSCLC, based on a contrast-oriented source-to-background algorithm, was associated with a low risk of INR. It might provide improved tumor control because of dose escalation.

Functional Characterization of Patients with Chronic Thromboembolic Disease

Background: Patients with chronic thromboembolic pulmonary disease (CTED) have persistent pulmonary vascular obstruction and exercise intolerance without pulmonary hypertension at rest and may benefit from pulmonary endarterectomy. However, up to now, CTED has been poorly characterized. Objectives: This study aimed to analyze the exercise capacity and limiting factors in CTED. Methods: We compared right heart catheterization and cardiopulmonary exercise test results of patients with CTED [mean pulmonary artery pressure (mPAP) at rest <25 mm Hg, n = 10], chronic thromboembolic pulmonary hypertension (CTEPH, n = 31) and a control group (n = 41) presenting with dyspnea but normal pulmonary vascular imaging and excluded pulmonary hypertension. Results: Subjects with CTED show a reduced oxygen uptake [median 76/interquartile range (IQR) 22% pred.] and work rate (median 76/IQR 21 W). The work rate was significantly lower compared to control subjects (p = 0.04) but not significantly different from CTEPH patients (p = 0.66). Oxygen pulse and breathing reserve were normal. CTED subjects showed decreased end-tidal CO2 at anaerobic threshold (28.4/4.3 mm Hg), an elevated VE/VCO2 slope (42.5/23.5), breathing equivalents (EQO2 32.0/8.7, EQCO2 39.5/8.8), alveolar-capillary oxygen gradient (34.7/15.5 mm Hg) and capillary end-tidal carbon dioxide gradient (8.8/5.7 mm Hg) compared to control subjects (p < 0.001). The degree of limitation was similar to that in CTEPH. Conclusions: Despite an mPAP of <25 mm Hg, subjects with CTED show objective functional impairment and similar limitations to patients with CTEPH. Functional limitation is characterized by gas exchange disturbance and ineffective ventilation.

Nonrigid Versus Rigid Registration of Thoracic 18F-FDG PET and CT in Patients with Lung Cancer: An Intraindividual Comparison of Different Breathing Maneuvers

In lung cancer, 18F-FDG PET, CT, and 18F-FDG PET/CT are used for noninvasive staging and therapy planning. Even with improved image registration techniques—especially in the modern hybrid PET/CT scanners—inaccuracies in the fusion process may occur, leading to errors in image interpretation. The aim of this study was to investigate by an intraindividual analysis whether, in comparison with a rigid algorithm, a nonrigid registration algorithm improves the quality of fusion between 18F-FDG PET and CT. Methods: Sixteen patients with histologically proven non–small cell lung cancer underwent a thoracic 18F-FDG PET acquisition in radiotherapy treatment position and 3 CT acquisitions (expiration, inspiration, and mid breath-hold) on the same day. All scans were registered with rigid and nonrigid procedures, resulting in 6 fused datasets: rigid inspiration, rigid expiration, rigid mid breath-hold, nonrigid inspiration, nonrigid expiration, and nonrigid mid breath-hold. The quality of alignment was assessed by 3 experienced readers at 8 anatomic landmarks: lung apices, aortic arch, heart, spine, sternum, carina, diaphragm, and tumor using an alignment score ranging from 1 (no alignment) to 5 (exact alignment). Results: Nonrigid PET/CT showed better alignment than rigid PET/CT (3.5 ± 0.7 vs. 3.3 ± 0.7, P < 0.001). Regarding the breathing maneuver, no difference between nonrigid mid breath-hold and rigid mid breath-hold was observed. In contrast, the alignment quality significantly improved from rigid expiration to nonrigid expiration (3.4 ± 0.7 vs. 3.6 ± 0.7, P < 0.001) and from rigid inspiration to nonrigid inspiration (3.1 ± 0.7 vs. 3.3 ± 0.7, P < 0.001). With regard to individual landmarks, an improvement in fusion quality through the use of nonrigid registration was obvious at the lung apices, carina, and aortic arch. Conclusion: The alignment quality of thoracic 18F-FDG PET/CT exhibits a marked dependence on the breathing maneuver performed during the CT acquisition, as demonstrated in an intraindividual comparison. Nonrigid registration is a significant improvement over rigid registration if the CT is performed during full inspiration or full expiration. The best fusion results are obtained with the CT performed at mid breath-hold using rigid registration, without an improvement using nonrigid algorithms.

Progression of Fibrosis in Usual Interstitial Pneumonia: Serial Evaluation of the Native Lung after Single Lung Transplantation

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a poor prognosis. Usual interstitial pneumonia (UIP) is the histopathological pattern identifying patients with the clinical entity of IPF. Despite aggressive immunosuppressive therapy the clinical course is usually dismal. For selected patients only lung transplantation improves prognosis and quality of life. After lung transplantation patients often receive a potent cyclosporine-based immunosuppressive therapy. Some reports suggest that cyclosporine has the potential to prevent progression of fibrosis. Objective: In patients with single lung transplantation (sLTx) for UIP we evaluated the effect of cyclosporine-based immunosuppressive therapy on progression of fibrosis using a high-resolution computed tomography (HRCT) scoring system. Methods: This retrospective observational study included 13 patients (24–64 years old) with histologically confirmed UIP who had HRCT scans preceding and following sLTx and who survived at least 6 months after sLTx. All patients were initially treated with cyclosporin A, prednisone and azathioprine. Three radiologists analyzed HRCT scans by setting a score regarding fibrosis [fibrosis score (FS); range 0–5 for each lobe] and ground-glass opacity [ground-glass score (GGS); range 0–5 for each lobe]. A comparison of serial changes (interval: 12–96 months posttransplant, 2–4 HRCT examinations/patient) was performed with the sign test. Results: Mean pretransplant FS and GGS of the nontransplanted lung were 1.80 and 1.61, respectively. Comparing pre- and posttransplant HRCT scans, mean lung FS significantly increased (0.35 ± 0.15/year; p = 0.00024), while GGS tended to decrease (0.06 ± 0.26/year; p = 0.5). Conclusion: A cyclosporin A based triple immunosuppressive regimen following sLTx does not seem to prevent progression of the fibrotic changes of the native lung in patients with IPF.

Combining 153Sm-lexidronam and docetaxel for the treatment of patients with hormone-refractory prostate cancer: first experience.

PURPOSE 153Sm-lexidronam has been used for the palliation of symptoms from painful bone metastases for years, while docetaxel has recently been shown to improve the survival of patients with hormone-refractory prostate cancer (HRPC). The first clinical experience with the combination of both treatment modalities is reported. METHODS Between 2005 and 2006, 12 patients with muliple bone metastases from HRPC were treated with a single application of 37 MBq/kg body weight 153Sm-lexidronam and 6 weekly infusions of 35 mg/m2 docetaxel. Data on survival, prostate-specific antigen (PSA) response, symptom palliation, toxicity, and scintigraphic follow-up are provided. RESULTS Mean follow-up was 11.4 (range, 1.1-25.8) months, overall 1-year survival was 48.6%, and median survival was 11.5 months. A PSA response of >50% was documented in 50% of patients. The average pain score (visual analog scale: 1-10) was reduced from 5.1 to 1.4 (p = 0.016) with decrease of > or =2 in 58.3% of patients. The average World Health Organization medication level dropped from 1.6 to 1.1 (p = 0.5). Overall toxicity was moderate, but 1 patient died due to neutropenic sepsis. CONCLUSIONS Our analysis demonstrates feasibility and therapeutic potential for the combination treatment and merits prospective investigation. Further studies will be planned with respect to the potentially synergistic hematologic toxicity of bone-seeking radiopharmaceuticals and chemotherapy.

Successful treatment of disseminated aspergillosis with the combination of voriconazole, caspofungin, granulocyte transfusions, and surgery followed by allogeneic blood stem cell transplantation in a patient with primary failure of an autologous stem cell graft

Abstract:  The treatment of disseminated aspergillus infections in neutropenic patients remains a major challenge in spite of several new antifungal drugs. We report the case of a patient with multiple myeloma in prolonged neutropenia after primary failure of an autologous stem cell graft who developed invasive aspergillosis despite voriconazole monotherapy. He responded to a combination of voriconazole and caspofungin, supported by granulocyte transfusions and surgery. A subsequent allogeneic peripheral blood stem cell transplantation did not lead to recurring aspergillus infection. The patient is well and free of clinical disease with respect to the fungal infection and myeloma more than 18 months after the allogeneic transplantation.

Low-dose MDCT for surveillance of patients with severe homogeneous emphysema after bronchoscopic airway bypass.

OBJECTIVE The purpose of this study was to evaluate the usefulness of low-dose MDCT for radiologic monitoring of patients who have undergone placement of bronchial stents for airway bypass. SUBJECTS AND METHODS In a prospective study, seven patients underwent MDCT according to a low-dose protocol (40 mAs, 120 kVp) before and after stent placement. The positions of the stents in the segmental bronchi were analyzed and compared with the bronchoscopic findings, which were reference standard. Patency versus lack of patency of stents was classified with five levels of confidence, and a definitive diagnosis was assigned to each stent. Prediction of stent dislodgment, follow-up findings, and complications occurring during the observation period were recorded. Consensus reading was performed by two radiologists. Statistical analysis was conducted by receiver operating characteristic analysis or four-field table. RESULTS Seven patients underwent implantation of 37 stents (mean, 5 +/- 2 [SD] stents per patient; range, 2-8 stents). The area under the curve for differentiating patent from occluded stents was 0.995 with resulting sensitivity and specificity of 86.5% and 98.1%. The correct diagnosis of patency was established with MDCT for all but one stent (sensitivity, 94.7%; specificity, 100%). Sensitivity and specificity for prediction of dislodgment were 80% and 91%. Five stents were not identified during inspection bronchoscopy but were found in a regular position at MDCT. Three instances of minor bleeding and one of pneumothorax resolved spontaneously. The mean effective dose of the scan was 1.3 +/- 0.6 mSv. CONCLUSION Low-dose MDCT is feasible for radiologic monitoring after airway bypass procedure.

In Silico Oncology: Quantification of the In Vivo Antitumor Efficacy of Cisplatin-Based Doublet Therapy in Non-Small Cell Lung Cancer (NSCLC) through a Multiscale Mechanistic Model

The 5-year survival of non-small cell lung cancer patients can be as low as 1% in advanced stages. For patients with resectable disease, the successful choice of preoperative chemotherapy is critical to eliminate micrometastasis and improve operability. In silico experimentations can suggest the optimal treatment protocol for each patient based on their own multiscale data. A determinant for reliable predictions is the a priori estimation of the drugs’ cytotoxic efficacy on cancer cells for a given treatment. In the present work a mechanistic model of cancer response to treatment is applied for the estimation of a plausible value range of the cell killing efficacy of various cisplatin-based doublet regimens. Among others, the model incorporates the cancer related mechanism of uncontrolled proliferation, population heterogeneity, hypoxia and treatment resistance. The methodology is based on the provision of tumor volumetric data at two time points, before and after or during treatment. It takes into account the effect of tumor microenvironment and cell repopulation on treatment outcome. A thorough sensitivity analysis based on one-factor-at-a-time and latin hypercube sampling/partial rank correlation coefficient approaches has established the volume growth rate and the growth fraction at diagnosis as key features for more accurate estimates. The methodology is applied on the retrospective data of thirteen patients with non-small cell lung cancer who received cisplatin in combination with gemcitabine, vinorelbine or docetaxel in the neoadjuvant context. The selection of model input values has been guided by a comprehensive literature survey on cancer-specific proliferation kinetics. The latin hypercube sampling has been recruited to compensate for patient-specific uncertainties. Concluding, the present work provides a quantitative framework for the estimation of the in-vivo cell-killing ability of various chemotherapies. Correlation studies of such estimates with the molecular profile of patients could serve as a basis for reliable personalized predictions.

European Respiratory Society International Congress 2017: highlights from the Clinical Assembly

This article contains highlights and a selection of the scientific advances from the European Respiratory Societys Clinical Assembly (Assembly 1 and its six respective groups) that were presented at the 2017 European Respiratory Society International Congress in Milan, Italy. The most relevant topics from each of the groups will be discussed, covering a wide range of areas including clinical problems, rehabilitation and chronic care, thoracic imaging, interventional pulmonology, diffuse and parenchymal lung diseases, and general practice and primary care. In this comprehensive review, the newest research and actual data as well as award-winning abstracts and highlight sessions will be discussed. A highlights review of selected presentations from #ERSCongress 2017 by the @ERStalk Clinical Assembly http://ow.ly/p3fB30gSb24