Eric Verbeken

The impact of 18F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) lymph node staging on the radiation treatment volumes in patients with non-small cell lung cancer

Abstract Purpose : 18 F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) combined with computer tomography (PET-CT) is superior to CT alone in mediastinal lymph node (LN) staging in non-small cell lung cancer (NSCLC). We studied the potential impact of this non-invasive LN staging procedure on the radiation treatment plan of patients with NSCLC. Patients and methods : The imaging and surgical pathology data from 105 patients included in two previously published prospective LN staging protocols form the basis for the present analysis. For 73 of these patients, with positive LNs on CT and/or on PET, a theoretical study was performed in which for each patient the gross tumour volume (GTV) was defined based on CT and on PET-CT data. For each GTV, the completeness of tumour coverage was assessed, using the available surgical pathology data as gold standard. A more detailed analysis was done for the first ten consecutive patients in whom the PET-CT-GTV was smaller than the CT-GTV. Theoretical radiation treatment plans were constructed based on both CT-GTV and PET-CT-GTV. Dose-volume histograms for the planning target volume (PTV), for the total lung volume and the lung volume receiving more than 20 Gy ( V lung(20) ), were calculated. Results : Data from 988 assessed LN stations were available. In the subgroup of 73 patients with CT or PET positive LNs, tumour coverage improved from 75% when the CT-GTV was used to 89% with the PET-CT-GTV ( P =0.005). In 45 patients (62%) the information obtained from PET would have led to a change of the treatment volumes. For the ten patients in the dosimetry study, the use of PET-CT to define the GTV, resulted in an average reduction of the PTV by 29±18% (±1 SD) ( P =0.002) and of the V lung(20) of 27±18% (±1 SD) ( P =0.001). Conclusion : In patients with NSCLC considered for curative radiation treatment, assessment of locoregional LN tumour extension by PET will improve tumour coverage, and in selected patients, will reduce the volume of normal tissues irradiated, and thus toxicity. This subgroup of patients could then become candidates for treatment intensification.

Head and Neck Squamous Cell Carcinoma: Value of Diffusion-weighted MR Imaging for Nodal Staging

PURPOSE To evaluate diffusion-weighted (DW) magnetic resonance (MR) imaging, as compared with turbo spin-echo MR imaging, for the detection of nodal metastases in head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS The study was approved by the ethics committee, and patients gave written informed consent. Before undergoing surgery, 33 consecutive patients underwent 1.5-T MR imaging, including DW imaging performed with a wide range of b values (0-1000 sec/mm(2)). The apparent diffusion coefficients (ADCs) of lymph nodes 4 mm or greater in short-axis diameter depicted on images obtained with b values of 0 and 1000 sec/mm(2) were calculated. After topographic correlation, the lymph nodes were evaluated microscopically with prekeratin immunostaining. The optimal ADC thresholds for discriminating between metastatic and benign lymph nodes were determined. The sensitivity, specificity, and accuracy of DW imaging were calculated separately-on per-lymph-node and per-neck-level bases-for all lymph nodes and for supracentimeter and subcentimeter lymph nodes and were compared with corresponding turbo spin-echo MR imaging values. RESULTS Correlation of histopathologic and radiologic findings was possible for 301 lymph nodes. The ADC derived from the signal intensity averaged across images obtained with b values of 0 and 1000 sec/mm(2) (ADC(b0-1000)) was 1.19 x 10(-3) mm(2)/sec +/- 0.22 (standard deviation) for benign lymph nodes and 0.85 x 10(-3) mm(2)/sec +/- 0.27 for malignant lymph nodes (P < .0001). With an optimal ADC(b0-1000) threshold of 0.94 x 10(-3) mm(2)/sec, 84% sensitivity, 94% specificity, and 91% accuracy for differentiation of malignant versus benign status of each lymph node and 94% sensitivity, 97% specificity, and 97% accuracy for differentiation at each neck level were achieved. Compared with turbo spin-echo imaging, DW imaging had higher sensitivity (76% vs 7%) but slightly lower specificity (94.0% vs 99.5%) for detection of subcentimeter nodal metastases. CONCLUSION DW imaging performed with ADC(b0-1000) values had higher accuracy than turbo spin-echo MR imaging in nodal staging, providing added value in the detection of subcentimeter nodal metastases.

Bronchoalveolar Lavage Fluid Galactomannan for the Diagnosis of Invasive Pulmonary Aspergillosis in Patients with Hematologic Diseases

BACKGROUND Prompt diagnosis of invasive pulmonary aspergillosis (IPA) remains a challenge. Galactomannan (GM) detection in bronchoalveolar lavage (BAL) fluid by the Platelia enzyme immunoassay aims to further improve upon the tests utility by applying it directly to specimens from the target organ. METHODS A retrospective analysis of the Platelia assay was performed on BAL samples from 99 evaluable high-risk hematology patients, including 58 with proven or probable IPA. RESULTS BAL GM demonstrated an improved sensitivity profile (91.3% with an optical density [OD] index cutoff of >or=1.0) in comparison with culture and microscopy (50% and 53.3%, respectively). The diagnostic accuracy as given by the area under the receiver operating characteristic curve was 0.93 (95% confidence interval, 0.88-0.99); further decreasing the OD index cutoff to 0.5 compromised specificity more than it improved sensitivity. Estimates of the positive and negative predictive value of the Platelia assay on BAL samples (OD index, >or=1.0) were 76% and 96%, respectively. The mean BAL GM OD index was not different in neutropenic versus nonneutropenic case patients (3.9 and 4.5, respectively; P = .3); however, a trend toward decreased sensitivity in patients receiving mold-active prophylaxis was noted. CONCLUSION BAL GM is a valuable adjunctive diagnostic tool to other conventional microbiologic and radiologic studies.

Defining the Transmurality of a Chronic Myocardial Infarction by Ultrasonic Strain-Rate Imaging Implications for Identifying Intramural Viability: An Experimental Study

Background—In a correlative functional/histopathologic study, we investigated the regional deformation characteristics of both chronic nontransmural and transmural infarctions before and after a dobutamine challenge. Methods and Results—After stenosing copper-coated stent implantation to produce circumflex artery endothelial proliferation, 18 pigs were followed up for 5 weeks. Posteuthanasia histology showed 10 to have a nontransmural and 8 a transmural infarction. Eight nonstented animals served as controls. Regional radial function was monitored by measuring ultrasound-derived peak systolic strain rates (SRSYS) and systolic strains (&egr;SYS) (1) before stent implantation and (2) at 5 weeks, at baseline (bs) and during an incremental dobutamine infusion. In controls, dobutamine induced a linear increase in SRSYS (dobutamine: bs, 4.8±0.4 s−1; 20 &mgr;g · kg−1 · min−1, 9.9±0.7 s−1;P <0.0001) and an initial increase of &egr;SYS at low dose (bs, 58±5%; at 5 &mgr;g · kg−1 · min−1, 78±6%;P <0.05) but a subsequent decrease during higher infusion rates. In the nontransmural group, bs SRSYS and &egr;SYS were significantly lower than prestent values (SRSYS, 2.9±0.5 s−1 and &egr;SYS, 32±6%, P <0.05 versus prestent). During dobutamine infusion, SRSYS increased slightly at 5 &mgr;g · kg−1 · min−1 (4.7±0.6 s−1, P <0.05) but fell during higher infusion rates, whereas &egr;SYS showed no change. For nontransmural infarctions, transmural scar extension correlated closely with &egr;SYS at bs (r =0.88). For transmural infarctions, SRSYS at bs was significantly reduced and &egr;SYS was almost not measurable (SRSYS, 1.8±0.3 s−1; &egr;SYS, 3±4%). Both deformation parameters showed no further change during the incremental dobutamine infusion. Conclusions—Ultrasonic deformation values could clearly differentiate chronic nontransmural from transmural myocardial infarction. The transmural extension of the scar could be defined by the regional deformation response.

FDG-PET scan in potentially operable non-small cell lung cancer : Do anatometabolic PET-CT fusion images improve the localisation of regional lymph node metastases?

Abstract Exact localisation of thoracic lymph nodes (LNs) on fluorine-18 fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) can be hampered by the paucity of anatomical landmarks. In non-small cell lung cancer (NSCLC) patients referred for locoregional LN staging, we prospectively examined to what extent localisation of LNs at PET reading could be improved by visual correlation with computed tomography (CT), or by anatometabolic PET+CT fusion images. Fifty-six patients with potentially operable NSCLC underwent CT, PET and surgical staging. Prospective reading was performed for CT, PET without CT, PET+CT visual correlation and PET+CT fusion. Reading was blinded to surgical pathology data and noted on a standard LN map. Surgical staging was available for 493 LN stations. In the evaluation per individual LN station, CT was accurate in 87%, PET in 91% and visual correlation and fusion in 93%. In the identification of the nodal stage, CT was correct in 28/56 patients (50%), PET in 37/56 (66%), visual correlation in 40/56 (71%), and fusion in 41/56 (73%). It is concluded that in the exact localisation of metastatic thoracic LNs, the accuracy of reading of PET is increased if the PET images can be visually correlated with CT images. PET+CT anatometabolic fusion images add only a marginal benefit compared with visual correlation.

Mucormycosis in allogeneic bone marrow transplant recipients: report of five cases and review of the role of iron overload in the pathogenesis

In a 10-year consecutive series of 263 allogeneic bone marrow transplant recipients, we identified five cases (1.9%) of invasive mucormycosis. Only one infection occurred within the first 100 days after transplantation, while the remainder complicated the late post-transplant course (median day of diagnosis: 343). Sites of infection were considered ‘non-classical’ and included pulmonary, cutaneous and gastric involvement. No case of fungal dissemination was observed. Mucormycosis was the primary cause of death in three of the five patients. Corticosteroid-treated graft-versus-host disease, either acute or chronic, or severe neutropenia were present in all cases. However, compared with a matched control population, the most striking finding was the demonstration of severe iron overload in each of the mucormycosis patients. The mean level of serum ferritin, transferrin saturation and number of transfused units of red cells (2029 μg/l, 92% and 52 units, respectively) in the study group is significantly higher compared with the control group (P < 0.05). the difference with other risk groups for mucormycosis, including deferoxamine-treated dialysis patients and acidotic diabetics, was analyzed in view of the possible pathogenic role of iron. although these infections are often fatal, limited disease may have a better prognosis if diagnosed early and treated aggressively.

The role of interleukin-17 during acute rejection after lung transplantation

Acute rejection (AR) is an important complication that can occur after lung transplantation and constitutes a risk factor for bronchiolitis obliterans syndrome, which is characterised by a neutrophilic airway inflammation. The specific aim of this study was to investigate the role of interleukin (IL)-17, which promotes chemotaxis of neutrophils by inducing IL-8 production, in AR. Cell differentials, mRNA and protein levels were quantified in bronchoalveolar lavages (BALs) taken from patients at 28 and 90 days after lung transplantation. The patients rejection status was assessed by transbronchial biopsy. An AR was found in nine out of the 26 patients examined, 28 days after transplantation. The number of BAL neutrophils and lymphocytes were increased in these patients. IL-17 mRNA and protein levels in the BAL were increased in patients with AR. Analysis of BAL obtained at day 90 after transplantation, demonstrated that the increase in IL-17 had disappeared, whereas the increase in neutrophils and lymphocytes persisted. These data showed that interleukin-17 is temporarily upregulated in bronchoalveolar lavage during acute rejection. The number of lymphocytes and neutrophils are increased in bronchoalveolar lavage during acute rejection and may persist up to 2 months after acute rejection. These findings suggest that interleukin-17 is important in the pathophysiology of acute lung rejection.

Potential use of FDG-PET scan after induction chemotherapy in surgically staged IIIa–N2 non-small-cell lung cancer: A prospective pilot study

BACKGROUND Clearance of viable tumour cells in mediastinal lymph nodes (MLN) by induction chemotherapy (IC)--so-called MLN downstaging--is an important aspect of combined-modality treatment of N2-NSCLC. Reassessment of MLN after IC by CT is far from accurate, while re-mediastinoscopy is often technically difficult. Based on our previous results with FDG-PET in the initial staging of N2 disease, we investigated whether PET after IC could be helpful in predicting MLN downstaging and therapeutic outcome. PATIENTS AND METHODS Patients underwent a first PET before IC. After three cycles of platinum-based IC, a second PET was performed before locoregional therapy, either surgery or radiotherapy. PET results were correlated with pathology of the MLN when available, and with survival. RESULTS Fifteen surgically staged N2-NSCLC patients were prospectively included. Locoregional therapy after IC consisted of surgery in nine and radiotherapy in six. Correlation with pathology of the nine resection specimens revealed that the accuracy of PET in predicting MLN downstaging was 100% (six true negatives; three true positives), whereas for CT it was only 67% (two false pos; one false neg). Reassessment with PET after IC was correlated with the outcome after the entire combined modality treatment. Survival was significantly better in patients with mediastinal clearance (P = 0.01) or with a greater than 50% decrease in the Standardised Uptake Value (SUV) of the primary tumour (P = 0.03) after IC. CONCLUSIONS Mediastinal PET after IC accurately assesses pathologic MLN downstaging in N2-NSCLC. The data suggest a possible correlation of early survival with mediastinal clearance and an important decrease of SUV in the primary tumour. Confirmation of these preliminary findings would establish PET as a useful non-invasive tool to select patients for intensive locoregional treatment after IC.

Prospective clinical evaluation of lower cut‐offs for galactomannan detection in adult neutropenic cancer patients and haematological stem cell transplant recipients

The recent advent of an improved commercial serum enzyme‐linked immunosorbent assay (ELISA) for the detection of circulating galactomannan (GM), a major constituent of Aspergillus cell walls, has contributed to the diagnosis of invasive aspergillosis (IA) in many haematology and transplant centres. However, the optimal threshold for positivity remains a matter of debate. We prospectively evaluated the impact of lowering the cut‐off in 124 neutropenic episodes with a high pretest probability for IA. Two new cut‐off points, lower than previously accepted, are proposed: (a) a ‘static’ cut‐off at 0·8 and (b) a ‘dynamic’ cut‐off at 0·5. A single assay with an optical density (OD) index ≥0·8 warrants the initiation of anti‐Aspergillus therapy. A further lowering of the ‘static’ threshold seems not clinically feasible given the drop in positive predictive value (PPV). However, the demonstration of at least two sequential sera with an OD ≥0·5 (‘dynamic’ threshold) increased the specificity and the PPV to 98·6% and the efficiency to 98%. Applying both cut‐offs to a subgroup of 21 ‘possible’ fungal infections further identified and upgraded six cases of IA. However, the clinical benefit of lower cut‐offs (particularly for earlier diagnosis) depends upon the kinetics of antigenaemia and the intensity of serum sampling.

A dichotomy in bronchiolitis obliterans syndrome after lung transplantation revealed by azithromycin therapy

Bronchiolitis obliterans syndrome (BOS) is the most important cause of late mortality following lung transplantation, resulting in major morbidity and a huge burden on healthcare resources. Treatment options are limited, resulting in a mere stabilisation of the lung function decline. Recent introduction of the macrolide antibiotic azithromycin raised new hope after demonstrating lung function improvement in subsets of patients. The present study aimed to provide an overview of the clinical effects on azithromycin in the setting of BOS after lung transplantation, with special emphasis on the anti-inflammatory actions. Moreover, the authors proposed a new frame of thinking centred on a dichotomy in the pathogenesis and clinical phenotype of BOS. Subsets of BOS patients were identified who do or do not respond to azithromycin (regarding forced expiratory volume in one second (FEV1), bronchoalveolar lavage (BAL) neutrophilia/interleukin-8). These observations have shed new light on the current belief that BOS represents a homogenous clinical entity in which the neutrophil is the main culprit. Recent clinical observations, supported by research findings, have revealed a dichotomy in the clinical spectrum of BOS with neutrophilic (partially) reversible allograft dysfunction (responding to azithromycin) and fibroproliferative BOS (not responding to azithromycin). This concept is reinforced by unique data obtained in BOS patients, consisting of histology specimens, physical and radiological examination, FEV1 and BAL examination. The acceptance of this dichotomy can improve understanding of the heterogeneous pathological condition that constitutes bronchiolitis obliterans syndrome, thus encouraging a more accurate diagnosis and, ultimately, better tailored treatment for each bronchiolitis obliterans syndrome patient.