Change of Apoptosis and Glucose Metabolism in Lung Cancer Xenografts during Cytotoxic and Anti-Angiogenic Therapy Assessed by Annexin V Based Optical Imaging and 18F-FDG-PET/CT.

Methods: For apoptosis imaging, the near-infrared probe Annexin Vivo750 was used in combination with fluorescence molecular tomography and microcomputed tomography (FMT/µCT). Glucose metabolism was assessed using 18F-FDG-PET/CT. Five groups of nude mice bearing lung cancer xenografts (A549) were investigated: (i) untreated controls and two groups after (ii) cytotoxic (carboplatin) or (iii) anti-angiogenic (sunitinib) treatment for four and nine days, respectively. Imaging data were validated by immunohistochemistry. Results: In response to carboplatin treatment, an inverse relation was found between the change in glucose metabolism and apoptosis in A549 tumors. Annexin Vivo showed a continually increasing tumor accumulation, while the tumor-to-muscle ratio of 18F-FDG continuously decreased during therapy. Immunohistochemistry revealed a significantly higher tumor apoptosis (p=0.007) and a minor but not significant reduction in vessel density only at day 9 of carboplatin therapy. Interestingly, during anti-angiogenic treatment there was an early drop in the tumor-to-muscle ratio between days 0 and 4, followed by a subsequent minor decrease (18F-FDG tumor-to-muscle-ratio: 1.9 ± 0.4; day 4: 1.1 ± 0.2; day 9: 1.0 ± 0.2; p=0.021 and p=0.001, respectively). The accumulation of Annexin Vivo continuously increased over time (Annexin Vivo: untreated: 53.7 ± 36.4 nM; day 4: 87.2 ± 53.4 nM; day 9: 115.1 ± 103.7 nM) but failed to display the very prominent early induction of tumor apoptosis that was found by histology already at day 4 (TUNEL: p=0.0036) together with a decline in vessel density (CD31: p=0.004), followed by no significant changes thereafter. Conclusion: Both molecular imaging approaches enable visualizing the effects of cytotoxic and anti-angiogenic therapy in A549 tumors. However, the early and strong tumor apoptosis induced by the anti-angiogenic agent sunitinib was more sensitively and reliably captured by monitoring of the glucose metabolism as compared to Annexin V-based apoptosis imaging.

What patients with pulmonary fibrosis and their partners think: a live, educative survey in the Netherlands and Germany.

Pulmonary fibrosis greatly impacts patients and their partners. Unmet needs of patients are increasingly acknowledged; the needs of partners often remain unnoticed. Little is known about the best way to educate patients and partners. We investigated pulmonary fibrosis patients' and partners' perspectives and preferences in care, and the differences in these between the Netherlands and Germany. Additionally, we evaluated whether interactive interviewing could be a novel education method in this population. Patients and partners were interviewed during pulmonary fibrosis patient information meetings. In the Netherlands, voting boxes were used and results were projected directly. In Germany, questionnaires were used. In the Netherlands, 278 patients and partners participated; in Germany, 51. Many participants experienced anxiety. Almost all experienced misunderstanding, because people do not know what pulmonary fibrosis is. All expressed a need for information, psychological support and care for partners. Use of the interactive voting system was found to be pleasant (70%) and informative (94%). This study improves the knowledge of care needs of patients with pulmonary fibrosis and their partners. There were no major differences between the Netherlands and Germany. Interactive interviewing could be an attractive method to acquire insights into the needs and preferences of patients and partners, while providing them with information at the same time.

Spontaneous Pneumomediastinum as a Potential Predictor of Mortality in Patients with Idiopathic Pulmonary Fibrosis.

BACKGROUND: Spontaneous pneumomediastinum (PM) is a rare event in patients with idiopathic pulmonary fibrosis (IPF) with unknown prognostic implications. OBJECTIVES: To analyze the incidence and prognostic impact of PM in a cohort of patients with IPF. METHODS: PM diagnosed by computed tomography was identified retrospectively in the clinical and radiological records of 182 patients with IPF who were admitted to our center between August 2006 and July 2013. PM patients were compared to matched IPF patients not affected by PM and analyzed for survival. RESULTS: PM occurred in 9/182 IPF patients [5%; 6 males; median age: 63 years; median percent predicted of vital capacity (VC%) at baseline: 53%]. The median time between IPF diagnosis and PM occurrence was 3 months (interquartile range: 0-33). The control group included 36 IPF patients (28 males; median age: 69 years; VC% at baseline: 57%). In a multivariate Cox regression analysis, PM was a significant predictor of mortality [hazard ratio (HR): 3.0; p = 0.032]. Considering only patients experiencing PM at the time of IPF diagnosis (n = 4), PM was a strongly significant predictor of mortality in multivariate analysis (HR: 6.4; p = 0.007). CONCLUSIONS: Spontaneous PM is a rare but serious complication in patients with IPF and may be considered as a potential predictor of mortality.

Impact of Comorbidities on Mortality in Patients with Idiopathic Pulmonary Fibrosis.

INTRODUCTION: Comorbidities significantly influence the clinical course of idiopathic pulmonary fibrosis (IPF). However, their prognostic impact is not fully understood. We therefore aimed to determine the impact of comorbidities, as individual and as whole, on survival in IPF. METHODS: The database of a tertiary referral centre for interstitial lung diseases was reviewed for comorbidities, their treatments, their frequency and survival in IPF patients. RESULTS: 272 patients were identified of which 12% had no, 58% 1-3 and 30% 4-7 comorbidities, mainly cardiovascular, pulmonary and oncologic comorbidities. Median survival according to the frequency of comorbidities differed significantly with 66 months for patients without comorbidities, 48 months when 1-3 comorbidities were reported and 35 months when 4-7 comorbidities were prevalent (p = 0.004). A multivariate Cox proportional hazard analyses identified other cardiac diseases and lung cancer as significant predictors of death, gastro-oesophageal reflux disease (GERD) and diastolic dysfunction had a significant positive impact on survival. A significant impact of comorbidities associated therapies on survival was not discovered. This included the use of proton pump inhibitors at baseline, which was not associated with a survival benefit (p = 0.718). We also established a predictive tool for highly prevalent comorbidities, termed IPF comorbidome which demonstrates a new relationship of IPF and comorbidities. CONCLUSION: Comorbidities are frequent in IPF patients. Some comorbidities, especially lung cancer, mainly influence survival in IPF, while others such as GERD may inherit a more favourable effect. Moreover, their cumulative incidence impacts survival.

Optical coherence tomography detects structural abnormalities of the nasal mucosa in patients with cystic fibrosis.

BACKGROUND: Chronic inflammation and remodeling of the airways remain a hallmark of cystic fibrosis (CF). However, knowledge of the associated mucosal micro-anatomical changes is limited. We evaluated the potential of optical coherence tomography (OCT) for in vivo imaging of the upper airway mucosa in CF patients. METHODS: A flexible OCT probe was used for cross-sectional imaging of the nasal mucosa in 25 CF patients and 25 healthy controls. RESULTS: OCT images showed mucosal details including epithelium, basement membrane, lamina propria with seromucinous glands, and underlying cartilaginous structures. Mean nasal mucosa and epithelial layer thickness were increased in CF compared to controls. In CF patients, antibiotic therapy was associated with reduced nasal mucosa thickening. CONCLUSIONS: OCT detected mucosal changes associated with upper airway inflammation and response to antibiotic therapy in CF patients. OCT may be a useful tool for quantitative in vivo assessment of structural changes of the airway mucosa.

Pleuroparenchymal fibroelastosis in association with carcinomas.

PPFE is a rare disease characterized by upper lobe pleural fibrosis and parenchymal fibroelastosis. Its aetiology is considered idiopathic, although possible causative factors have been described. An association of PPFE with solid tumours is unknown and has not been considered previously. We identified six patients with PPFE, four of them with a coexisting malignancy. The case series suggests that PPFE might be an implication of varying factors rather than being an exclusively idiopathic condition.

Screening for Helicobacter pylori in Idiopathic Pulmonary Fibrosis Lung Biopsies.

BACKGROUND: Increasing evidence suggests a role of gastro-oesophageal reflux (GER) in idiopathic pulmonary fibrosis (IPF) pathogenesis. Recently, an association between serum Helicobacter pylori (HP) antibody positivity and more severe disease was described, but HP has not been directly analysed in lung tissue so far. OBJECTIVE: To investigate the presence of HP in the lung tissue of IPF patients. METHODS: Two tertiary interstitial lung disease care centre databases were screened for available lung biopsy material from IPF patients. Clinical and radiological data, including presence of GER and antiacid medication, were evaluated. HP-specific PCR was carried out on the IPF lung biopsy specimens. RESULTS: A total of 39 IPF patients were included, of whom 85% were male. The patients' median age was 66 years, their vital capacity was 79% predicted, and their diffusing capacity for carbon monoxide was 53% predicted. In all, 82% of the lung biopsies were surgical and 18% transbronchial. Comorbidities were GER disease in 23% (n = 9), sleep apnoea in 13% (n = 5) and hiatal hernia in 38% of the cases (n = 15). Proton pump inhibitors were prescribed at the time of biopsy in 21% of the cases (n = 9). After a median follow-up of 25 months (range 6-69), there were 1 death, 1 lung transplantation and 8 acute exacerbations without relevant differences between the GER and non-GER subgroups. HP DNA was not detected in any of the lung tissue samples. CONCLUSION: The fact that no HP DNA was detected in the lung tissues calls into question the proposed relevance of HP to the direct pathogenesis of IPF.

Visual vs Fully Automatic Histogram-Based Assessment of Idiopathic Pulmonary Fibrosis (IPF) Progression Using Sequential Multidetector Computed Tomography (MDCT).

OBJECTIVES: To describe changes over time in extent of idiopathic pulmonary fibrosis (IPF) at multidetector computed tomography (MDCT) assessed by semi-quantitative visual scores (VSs) and fully automatic histogram-based quantitative evaluation and to test the relationship between these two methods of quantification. METHODS: Forty IPF patients (median age: 70 y, interquartile: 62-75 years; M:F, 33:7) that underwent 2 MDCT at different time points with a median interval of 13 months (interquartile: 10-17 months) were retrospectively evaluated. In-house software YACTA quantified automatically lung density histogram (10th-90th percentile in 5th percentile steps). Longitudinal changes in VSs and in the percentiles of attenuation histogram were obtained in 20 untreated patients and 20 patients treated with pirfenidone. Pearson correlation analysis was used to test the relationship between VSs and selected percentiles. RESULTS: In follow-up MDCT, visual overall extent of parenchymal abnormalities (OE) increased in median by 5%/year (interquartile: 0%/y; +11%/y). Substantial difference was found between treated and untreated patients in HU changes of the 40th and of the 80th percentiles of density histogram. Correlation analysis between VSs and selected percentiles showed higher correlation between the changes (Δ) in OE and Δ 40th percentile (r=0.69; p<0.001) as compared to Δ 80th percentile (r=0.58; p<0.001); closer correlation was found between Δ ground-glass extent and Δ 40th percentile (r=0.66, p<0.001) as compared to Δ 80th percentile (r=0.47, p=0.002), while the Δ reticulations correlated better with the Δ 80th percentile (r=0.56, p<0.001) in comparison to Δ 40th percentile (r=0.43, p=0.003). CONCLUSIONS: There is a relevant and fully automatically measurable difference at MDCT in VSs and in histogram analysis at one year follow-up of IPF patients, whether treated or untreated: Δ 40th percentile might reflect the change in overall extent of lung abnormalities, notably of ground-glass pattern; furthermore Δ 80th percentile might reveal the course of reticular opacities.

Erythropoietin improves the accumulation and therapeutic effects of carboplatin by enhancing tumor vascularization and perfusion.

Recombinant human erythropoietin (rhuEpo) is currently under debate for the treatment of chemotherapy-induced anemia due to clinical trials showing adverse effects in Epo-treated patients and the discovery of the erythropoietin-receptor (EpoR) in tumor and endothelial cells. Here, using Epo-Cy5.5 as theranostic near-infrared fluorescent probe we analyzed the effects of rhuEpo as co-medication to carboplatin in non-small-cell-lung-cancer (NSCLC)-xenografts with different tumor cell EpoR-expression (H838 ~8-fold higher than A549). Nude mice bearing subcutaneous A549 and H838 NSCLC-xenografts received either only carboplatin or carboplatin and co-medication of rhuEpo in two different doses. Tumor sizes and relative blood volumes (rBV) were longitudinally measured by 3D-contrast-enhanced ultrasound (3D-US). Tumoral EpoR-levels were determined by combined fluorescence molecular tomography (FMT)/ micro computed tomography (µCT) hybrid imaging. We found that rhuEpo predominantly acted on the tumor endothelium. In both xenografts, rhuEpo co-medication significantly increased vessel densities, diameters and the amount of perfused vessels. Accordingly, rhuEpo induced EpoR-phoshorylation and stimulated proliferation of endothelial cells. However, compared with solely carboplatin-treated tumors, tumor growth was significantly slower in the groups co-medicated with rhuEpo. This is explained by the Epo-mediated vascular remodeling leading to improved drug delivery as obvious by a more than 2-fold higher carboplatin accumulation and significantly enhanced tumor apoptosis. In addition, co-medication of rhuEpo reduced tumor hypoxia and diminished intratumoral EpoR-levels which continuously increased during carboplatin (Cp) -treatment. These findings suggest that co-medication of rhuEpo in well balanced doses can be used to improve the accumulation of anticancer drugs. Doses and indications may be personalized and refined using theranostic EpoR-probes.

Treatment and outcome of lung cancer in idiopathic interstitial pneumonias.

BACKGROUND: Idiopathic interstitial pneumonias (IIP) are associated with an increased lung cancer (LC) risk. However, data on the prognostic and therapeutic impact are limited. We therefore aimed to analyze the outcome of IIP patients with LC under different treatment modalities. METHODS: Patients with IIPs diagnosed in a tertiary interstitial lung diseases (ILD) center were reviewed for LC diagnosis. RESULTS: Of 265 patients with idiopathic pulmonary fibrosis (IPF), 142 with non-specific interstitial pneumonia (NSIP), and 71 with cryptogenic organizing pneumonia (COP), 16%, 4%, and 6% were affected byLC, respectively. Patient characteristics were: IPF: 93% male, median age 67 years, forced vital capacity (FVC) 82%, diffusion capacity for Carbon monoxide (DLCO) 41%, mean survival 20 months. NSIP: 67% male, median age 70 years, FVC 72%, DLCO 43%, mean survival 35 months. COP: 50% male, median age 66 years, FVC 93%, DLCO 77%, mean survival 88 months. Significant treatment-related toxicities occurred in 55% IPF, 20% NSIP und 0% COP patients. 30-days postoperative mortality was 25% in IPF, and 0% in NSIP/COP while rate of radiation pneumonitis was 24% in IPF. CONCLUSIONS: LC is a frequent comorbidity in IIP, with a higher incidence and reduced survival in IPF compared to other IIPs. LC treatment is associated with significant toxicity, specifically in IPF. Interdisciplinary evaluation of therapeutic options in IIP patients diagnosed with LC is therefore mandatory.

Diagnosis of pulmonary embolism: conventional ventilation/perfusion SPECT is superior to the combination of perfusion SPECT and nonenhanced CT.

BACKGROUND: Ventilation/perfusion single-emission photon CT (V/P-SPECT) is widely used to detect pulmonary embolism (PE). Any pathological deficit on P-SPECT with a corresponding unremarkable V-SPECT is considered an embolism. This means that a deficit on P-SPECT with a corresponding deficit on the ventilation scan correlates with other lung pathologies such as pneumonia, bullous emphysema or tumor. In principle, it is possible to identify any of these lung pathologies on nonenhanced chest CT and so this technique has the potential to replace V-SPECT in the diagnosis of PE. Today, SPECT/CT hybrid imaging systems are increasingly applied in clinical routines. OBJECTIVES: We investigated whether embolism can be diagnosed using a combined P-SPECT/CT hybrid imaging approach without V-SPECT. METHODS: Ninety-three patients with clinically suspected embolism were investigated with standard V/P-SPECT and a nonenhanced CT scan on a combined SPECT/CT system. A diagnosis of embolism was based on V/P-SPECT (gold standard). P-SPECT/CT datasets were blinded and analyzed without any knowledge of the V-SPECT data. The accuracy of P-SPECT/CT was compared to the gold standard. RESULTS: Embolism was diagnosed in 24/93 patients using V/P-SPECT. In total, 57 lung lobes were affected. P-SPECT/CT significantly (p < 0.01) overdiagnosed embolism in nonaffected patients. In total, 36 cases with 88 affected lung lobes were shown. The sensitivity was 95.8%, the specificity 82.6%, the false-negative rate 4.2% and the false-positive rate 17.3%. CONCLUSIONS: Our results demonstrate that a nonenhanced CT scan in a novel hybrid imaging system cannot replace V-SPECT in the scintigraphy-based diagnosis of PE. V-SPECT increases specificity and reduces the number of false-positive results when compared to 'perfusion-only' SPECT/CT.

Pirfenidone in idiopathic pulmonary fibrosis: real-life experience from a German tertiary referral center for interstitial lung diseases.

BACKGROUND: Pirfenidone is a novel antifibrotic drug for the treatment of mild-to-moderate idiopathic pulmonary fibrosis (IPF). However, adverse events may offset treatment benefits and compliance. OBJECTIVES: To assess recent course of disease, adverse events and compliance in patients who started pirfenidone. METHODS: In an observational cohort study, 63 patients with mild-to-moderate IPF who started pirfenidone between May 2011 and June 2013 were reviewed. Pulmonary function, adverse events and treatment compliance were recorded at each clinic visit. Disease progression was defined as a reduction of vital capacity ≥10% and/or diffusion capacity (DLCO) ≥15%. RESULTS: Follow-up time on pirfenidone treatment was 11 (±7) months. Sixty-six percent of the patients continued with pirfenidone monotherapy and 34% of the patients received pirfenidone combined with corticosteroids (CCS) and/or N-acetylcysteine (NAC). There was a nonsignificant reduction in mean decline of percent predicted forced vital capacity after treatment start (0.7 ± 10.9%) compared to the pretreatment period (6.6 ± 6.7%, p = 0.098). Sixty-two percent of the patients had stable disease on pirfenidone treatment. Adverse events affected 85% of the patients, leading to discontinuation of pirfenidone in 20%. Adverse events and treatment discontinuation were seen more frequently in patients with concomitant CCS and/or NAC treatment. CONCLUSIONS: Adverse events affect the majority of patients treated with pirfenidone, but are mostly manageable with supportive measures. In this heterogeneous patient group, a nonsignificant effect of pirfenidone treatment on pulmonary function was seen, underlining the need for more data on patient selection criteria and efficacy of pirfenidone, particularly in patients with coexistent emphysema and concomitant NAC/CCS treatment.

Influence of repetitive contrast agent injections on functional and molecular ultrasound measurements.

Quantitative contrast-enhanced ultrasound plays an important role in tumor characterization and treatment assessment. Besides established functional ultrasound techniques, ultrasound molecular imaging using microbubbles targeted to disease-associated markers is increasingly being applied in pre-clinical studies. Often, repeated injections of non-targeted or targeted microbubbles during the same imaging session are administered. However, the influence of repeated injections on the accuracy of the quantitative data is unclear. Therefore, in tumor-bearing mice, we investigated the influence of multiple injections of non-targeted microbubbles (SonoVue) on time to peak and peak enhancement in liver and tumor tissue and of vascular endothelial growth factor receptor 2 (VEGFR2)-targeted contrast agents (MicroMarker) on specific tumor accumulation. We found significantly decreasing values for time to peak and a tendency for increased values for peak enhancement after multiple injections. Repeated injections of VEGFR2-targeted microbubbles led to significantly increased tumor accumulation, which may result from the exposure of additional binding sites at endothelial surfaces caused by mechanical forces from destroyed microbubbles.

A low molecular weight zinc2+-dipicolylamine-based probe detects apoptosis during tumour treatment better than an annexin V-based probe.

OBJECTIVES: Molecular imaging of apoptosis is frequently discussed for monitoring cancer therapies. Here, we compare the low molecular weight phosphatidylserine-targeting ligand zinc2+-dipicolylamine (Zn2+-DPA) with the established but reasonably larger protein annexin V. METHODS: Molecular apoptosis imaging with the fluorescently labelled probes annexin V (750 nm, 36 kDa) and Zn2+-DPA (794 nm, 1.84 kDa) was performed in tumour-bearing mice (A431). Three animal groups were investigated: untreated controls and treated tumours after 1 or 4 days of anti-angiogenic therapy (SU11248). Additionally, µPET with 18 F-FDG was performed. Imaging data were displayed as tumour-to-muscle ratio (TMR) and validated by quantitative immunohistochemistry. RESULTS: Compared with untreated control tumours, TUNEL staining indicated significant apoptosis after 1 day (P < 0.05) and 4 days (P < 0.01) of treatment. Concordantly, Zn2+-DPA uptake increased significantly after 1 day (P < 0.05) and 4 days (P < 0.01). Surprisingly, annexin V failed to detect significant differences between control and treated animals. Contrary to the increasing uptake of Zn2+-DPA, 18 F-FDG tumour uptake decreased significantly at days 1 (P < 0.05) and 4 (P < 0.01). CONCLUSIONS: Increase in apoptosis during anti-angiogenic therapy was detected significantly better with the low molecular weight probe Zn2+-DPA than with the annexin V-based probe. Additionally, significant treatment effects were detectable as early using Zn2+-DPA as with measurements of the glucose metabolism using 18 F-FDG. KEY POINTS: • The detection of apoptosis by non-invasive imaging is important in oncology. • A new low molecular weight probe Zn2+-DPA shows promise in depicting anti-angiogenic effects. • The small Zn2+-DPA ligand appears well suited for monitoring therapy. • Treatment effects are detectable just as early with Zn2+-DPA as with 18F-FDG.

Accuracy of a clinical PET/CT vs. a preclinical µPET system for monitoring treatment effects in tumour xenografts.

PURPOSE: Small animal imaging is of growing importance for preclinical research and drug development. Tumour xenografts implanted in mice can be visualized with a clinical PET/CT (cPET); however, it is unclear whether early treatment effects can be monitored. Thus, we investigated the accuracy of a cPET versus a preclinical µPET using (18)F-FDG for assessing early treatment effects. MATERIALS AND METHODS: The spatial resolution and the quantitative accuracy of a clinical and preclinical PET were evaluated in phantom experiments. To investigate the sensitivity for assessing treatment response, A431 tumour xenografts were implanted in nude mice. Glucose metabolism was measured in untreated controls and in two therapy groups (either one or four days of antiangiogenic treatment). Data was validated by γ-counting of explanted tissues. RESULTS: In phantom experiments, cPET enabled reliable separation of boreholes≥5mm whereas µPET visualized boreholes≥2mm. In animal studies, µPET provided significantly higher tumour-to-muscle ratios for untreated control tumours than cPET (3.41±0.87 vs. 1.60±.0.28, respectively; p<0.01). During treatment, cPET detected significant therapy effects at day 4 (p<0.05) whereas µPET revealed highly significant therapy effects even at day one (p<0.01). Correspondingly, γ-counting of explanted tumours indicated significant therapy effects at day one and highly significant treatment response at day 4. Correlation with γ-counting was good for cPET (r=0.74; p<0.01) and excellent for µPET (r=0.85; p<0.01). CONCLUSION: Clinical PET is suited to investigate tumour xenografts≥5mm at an advanced time-point of treatment. For imaging smaller tumours or for the sensitive assessment of very early therapy effects, µPET should be preferred.

Contrast medium injection protocol adjusted for body surface area in combined PET/CT.

OBJECTIVES: To evaluate the effect of contrast medium dose adjustment for body surface area (BSA) compared with a fixed-dose protocol in combined positron emission tomography (PET) and computed tomography (CT) (PET/CT). METHODS: One hundred and twenty patients were prospectively included for (18)F-2-deoxy-fluor-glucose ((18)F-FDG)-PET/CT consisting of a non-enhanced and a venous contrast-enhanced CT, both used for PET attenuation correction. The first 60 consecutive patients received a fixed 148-ml contrast medium dose. The second 60 patients received a dose that was based on their calculated BSA. Mean and maximum standardised FDG uptake (SUVmean and SUVmax) and contrast enhancement (HU) were measured at multiple anatomical sites and PET reconstructions were evaluated visually for image quality. RESULTS: A decrease in the variance of contrast enhancement in the BSA group compared with the fixed-dose group was seen at all anatomical sites. Comparison of tracer uptake SUVmean and SUVmax between the fixed and the BSA group revealed no significant differences at all anatomical sites (all P > 0.05). Comparison of the overall image quality scores between the fixed and the BSA group showed no significant difference (P = 0.753). CONCLUSIONS: BSA adjustment results in increased interpatient homogeneity of contrast enhancement without affecting PET values. In combined PET/CT, a BSA adjusted contrast medium protocol should be used preferably. KEY POINTS: • Intravenous contrast medium is essential for many applications of PET/CT • Body surface area adjustment of contrast medium helps standardise contrast enhancement • Underdosing or overdosing of contrast medium will be reduced • PET image quality is not influenced • BSA adjusted contrast medium protocol should be used preferably in combined PET/CT.