Kerstin Cederlund

Safety analysis of ex vivo-expanded NK and NK-like T cells administered to cancer patients: a Phase I clinical study

The chimeric state after allogeneic hematopoietic stem cell transplantation provides a platform for adoptive immunotherapy using donor-derived immune cells. The major risk with donor lymphocyte infusions (DLIs) is the development of graft-versus-host disease (GvHD). Development of new DLI products with antitumor reactivity and reduced GvHD risk represents a challenging task in cancer immunotherapy. Although natural killer (NK) and NK-like T cells are promising owing to their antitumor activity, their low concentrations in peripheral blood mononuclear cells reduces their utility in DLIs. We have recently developed a system that allows expansion of clinical-grade NK and NK-like T cells in large numbers. In this study, the safety of donor-derived long-term ex vivo-expanded human NK and NK-like T cells given as DLIs was investigated as immunotherapy for cancer in five patients following allogeneic stem cell infusion. Infusion of the cells was safe whether administered alone or with IL-2 subcutaneously. No signs of acute GvHD were observed. One patient with hepatocellular carcinoma showed markedly decreased serum alpha-fetoprotein levels following cell infusions. These findings suggest that the use of ex vivo-expanded NK and NK-like T cells is safe and appears an attractive approach for further clinical evaluation in cancer patients.

Visual classification of emphysema heterogeneity compared with objective measurements: HRCT vs spiral CT in candidates for lung volume reduction surgery

Abstract. The aim of this study was to investigate whether spiral CT is superior to high-resolution computed tomography (HRCT) in evaluating the radiological morphology of emphysema, and whether the combination of both CT techniques improves the evaluation in patients undergoing lung volume reduction surgery (LVRS). The material consisted of HRCT (with 2-mm slice thickness) and spiral CT (with 10-mm slice thickness) of 94 candidates for LVRS. Selected image pairs from these examinations were evaluated. Each image pair consisted of one image from the cranial part of the lung and one image from the caudal part. The degree of emphysema in the two images was calculated by computer. The difference between the images determined the degree of heterogeneity. Five classes of heterogeneity were defined. The study was performed by visual classification of 95 image pairs (spiral CT) and 95 image pairs (HRCT) into one of five different classes of emphysema heterogeneity. This visual classification was compared with the computer-based classification. Spiral CT was superior to HRCT with 47% correct classifications of emphysema heterogeneity compared with 40% for HRCT-based classification (p<0.05). The combination of the techniques did not improve the evaluation (42%). Spiral CT is superior to HRCT in determining heterogeneity of emphysema visually, and should be included in the pre-operative CT evaluation of LVRS candidates.

Heart rate variability and heat sensation during CT coronary angiography: Low-osmolar versus iso-osmolar contrast media

Background: During computed tomography coronary angiography (CTCA) unexpected changes in heart rate while scanning may affect image quality. Purpose: To evaluate whether an iso-osmolar contrast medium (IOCM, iodixanol) and a low-osmolar contrast medium (LOCM, iomeprol) affect heart rate and experienced heat sensation differently. Material and Methods: One hundred patients scheduled for CTCA were randomized to receive either iodixanol 320 mgI/ml or iomeprol 400 mgI/ml. Depending on their heart rate, the patients were assigned to one of five scanning protocols, each optimized for different heart rate ranges. During scanning the time between each heart beat (hb) was recorded, and the corresponding heart rate was calculated. For each contrast medium (CM) the average heart rate, the variation in heart rate from individual mean heart rate, and the mean deviation from the predefined scanning protocol were calculated. Experience of heat was obtained immediately after scanning by using a visual analog scale (VAS). Examination quality was rated by two radiologists on a three-point scale. Results: The mean variation in heart rate after IOCM was 1.4 hb/min and after LOCM it was 4.4 hb/min (NS). The mean deviations in heart rate from that in the predefined scanning protocol were 2.0 hb/min and 4.7 hb/min, respectively (NS). A greater number of arrhythmic hb were observed after LOCM compared with IOCM (P<0.001). There was no statistically significant difference in image quality. The LOCM group reported a stronger heat sensation after CM injection than the IOCM group (VAS =36 mm and 18 mm, P<0.05). Conclusion: At clinically used concentrations the IOCM, iodixanol 320 mgI/ml, does not increase the heart rate during CTCA and causes less heart arrhythmia and less heat sensation than the LOCM, iomeprol 400 mgI/ml.

Hepatic contrast medium enhancement at computed tomography and its correlation with various body size measures

Background When the same dose of iodine is given to all patients when performing abdominal computed tomography (CT) there may be a wide inter-individual variation in contrast medium (CM) enhancement of the liver. Purpose To evaluate if any of the measures body height (BH), body mass index (BMI), lean body mass (LBM), ideal body weight (IBW), and body surface area (BSA) correlated better than body weight (BW) with hepatic enhancement, and to compare the enhancement when using iodixanol and iomeprol. Material and Methods One hundred patients referred for standard three-phase CT examination of abdomen were enrolled. Body weight and height were measured at the time of the CT examination. Forty grams of iodine (iodixanol 320 mg I/mL or iomeprol 400 mg I/mL) was injected at a rate of 1.6 g-I/s, followed by a 50 mL saline flush. The late arterial phase was determined by using a semi-automatic smart prep technique with a scan delay of 20 s. The hepatic parenchymal phase started automatically 25 s after the late arterial phase. CM concentration was estimated by placement of regions of interest in aorta (native and late arterial phase) and in liver (native and parenchymal phase). Results BW (r = −0.51 and −0.64), LBM (r = −0.54 and −0.59), and BSA (r = −0.54 and −0.65) showed the best correlation coefficients with aortic and hepatic parenchymal enhancement, respectively, without any significant differences between the measures. Comparing iodixanol and iomeprol there was no significant difference in aortic enhancement. The liver enhancement was significantly higher (P < 0.05) using iodixanol than iomeprol. Conclusion To achieve a consistent hepatic enhancement, CM dose may simply be adjusted to body weight instead of using more complicated calculated parameters based on both weight and height.

Coronary Plaque Burden, as Determined by Cardiac Computed Tomography, in Patients with Myocardial Infarction and Angiographically Normal Coronary Arteries Compared to Healthy Volunteers: A Prospective Multicenter Observational Study

Objectives Patients presenting with acute myocardial infarction and angiographically normal coronary arteries (MINCA) represent a diagnostic and a therapeutic challenge. Cardiac computed tomography (CT) allows detection of coronary artery disease (CAD) even in the absence of significant stenosis. We aimed to investigate whether patients suffering from MINCA had a greater coronary plaque burden, as determined by cardiac CT, than a matched group of healthy volunteers. Methods Consecutive patients, aged 45 to 70, with MINCA were enrolled in the Stockholm metropolitan area. Patients with myocarditis were excluded using cardiovascular magnetic resonance imaging. Remaining patients underwent cardiac CT, as did a reference group of healthy volunteers matched by age and gender, with no known cardiovascular disease. Plaque burden was evaluated semi-quantitatively on a per patient and a per segment level. Results Despite a higher prevalence of smoking and hypertension, patients with MINCA did not have more CAD than healthy volunteers. Among 57 MINCA patients and 58 volunteers no signs of CAD were found in 24 (42%) and 25 (43%) respectively. On a per segment level, MINCA patients had less segments with stenosis ≥20% (2% vs. 5%, p<0.01), as well as a smaller proportion of large (2% vs. 4%, p<0.05) and mixed type plaques (1% vs. 4%, p<0.01). The median coronary calcium score did not differ between MINCA patients and healthy volunteers (6 vs. 8, ns). Conclusions MINCA patients with no or minimal angiographic stenosis do not have more coronary atherosclerosis than healthy volunteers, and a large proportion of these patients do not have any signs of CAD, as determined by cardiac CT. The MINCA patient group is probably heterogeneous, with a variety of different underlying mechanisms. Non-obstructive CAD is most likely not the most prevalent cause of myocardial infarction in this patient group.

Is training essential for interpreting cardiac computed tomography

Background: Cardiac computed tomography (CT) has gained increasing acceptance for diagnosing obstructive coronary artery disease (CAD). Several guidelines have been published on required education for proficiency in the interpretation of these examinations. Purpose: To describe the learning-curve effect of the interpretation of 100 consecutive cardiac CT examinations aimed at diagnosing CAD. The diagnostic accuracy of radiologists and radiographers was also compared. Material and Methods: Two radiologists and two radiographers, all with no prior experience in evaluation of cardiac CT, independently underwent a dedicated training program of 100 examinations randomized into 10 blocks (sessions), with 10 cases in each. They independently evaluated the coronary arteries regarding significant obstructive CAD. After every session, individual feedback on diagnostic accuracy and comparison with the corresponding invasive coronary angiography (currently regarded as the gold standard to detect coronary lesions) was given. The time required for interpretation was recorded. Results: The mean review time decreased (P<0.0001) successively during the 10 sessions for all the observers together. The first session had a mean review time of 32 min, and the last session 16 min. No significant improvement in sensitivity, specificity, or negative predictive value (NPV) was observed. For positive predictive value (PPV), there was an improvement for the radiologists (P<0.05), but not for the radiographers. The radiographers had a higher total specificity compared to the radiologists (P<0.01). Conclusion: The review time for novices in cardiac CT was approximately halved during the first 100 cases, with maintained accuracy. There was a learning-curve effect in PPV for the radiologists. The diagnostic accuracy of dedicated radiographers indicates that they might be considered to be included as part of the evaluation team.

Pulmonary function testing and pulmonary Langerhans cell histiocytosis

In a long‐term single‐center follow‐up (median 16‐years), we studied high‐resolution computed tomography (HRCT) and pulmonary function testing (PFT) in pulmonary LCH. Diffusing capacity corrected for alveolar volume (K(CO)) and total lung capacity (TLC) were significantly decreased (P = 0.016 and P = 0.030, respectively) in patients with extensive HRCT abnormalities. Patients with late stage disease on HRCT had increased forced expiratory volume (FEV1.0)(P = 0.037) and vital capacity (VC)(P = 0.036). Disease monitoring is important in pulmonary LCH, and since PFT with diffusing capacity provides a measurement of the current lung function, it may be a valuable tool in monitoring pulmonary LCH, and a good complement to imaging. Pediatr Blood Cancer 2007;49:323–328.

A comparison between low intensity and reduced intensity conditioning in allogeneic hematopoietic stem cell transplantation for solid tumors

Allogeneic hematopoietic stem cell transplantation can produce a graft-versus-tumor-effect in patients with solid tumors. Adjuvant cell therapy with donor lymphocyte infusion may augment this graft-versus-tumor effect. Background Following different types of conditioning, allogeneic hematopoietic stem cell transplantation produces a graft-versus-tumor effect in patients with solid tumors. We performed a non-randomized study comparing low intensity conditioning with reduced intensity conditioning after stem cell transplantation to demonstrate the graft-versus-tumor effect. Design and Methods Allogeneic stem cell transplantation was performed in 48 patients with metastatic renal cell cancer (n=17), colo-rectal cancer (n=15), non-metastatic advanced primary liver cancer after orthotopic liver transplantation (n=11), and other solid tumors (n=5). Tumor response was determined based on the international response evaluation criteria for solid tumors (RECIST). Results No significant difference in the incidence of graft rejection was found between the low intensity conditioning and reduced intensity conditioning groups. Engraftment occurred earlier in the low intensity conditioning group than in the reduced intensity conditioning group (median 0 vs. 16 days, respectively; p<0.001). Complete donor chimerism in B cells occurred earlier after low intensity conditioning than after reduced intensity conditioning (median 28 vs. 97 days, respectively; p<0.001). No significant difference in the incidence of tumor response was found between groups receving the different types of the conditioning. The most favorable tumor response rate was found in patients who received donor lymphocyte infusions and de-veloped chronic graft-versus-host disease (75% vs. 34%, p=0.003). The best graft-versus-tumor effect was demonstrated in patients with advanced primary liver cancer who had previously undergone liver transplantation (p=0.018). Patients receiving reduced intensity conditioning had a tendency to better overall survival compared to the low intensity conditioning group (30% vs. 17%, p=0.005). Conclusions Adjuvant cell therapy with donor lymphocyte infusion may augment the graft-versus-tumor effect of cronic graft-versus-host disease. Patients with limited tumor load are indicated for allogeneic stem cell transplantation and reduced intensity conditioning may be favorable compared to low intensity conditioning.

Decreased invasive fungal disease but no impact on overall survival by posaconazole compared to fluconazole prophylaxis: a retrospective cohort study in patients receiving induction therapy for acute myeloid leukaemia/myelodysplastic syndromes

Posaconazole prophylaxis during induction chemotherapy for acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) has been shown to significantly decrease the incidence of invasive fungal disease (IFD) and increase overall survival in a trial setting, but only small real‐life studies have been published.

Anomalous origin of right coronary artery from the pulmonary artery

A 37-year-old woman with no previous cardiovascular risk factors had sudden onset of transient symptoms of speech impediment. The case was judged as a transient ischaemic attack and brain computed tomography (CT) showed no abnormal findings. Echocardiography revealed no patent foramen ovalis but there was an abnormal arterial flow in the interventricular septum, which raised the suspicious of a coronary fistula. A cardiac computed tomography angiography (CTA) revealed an abnormal origin of the right coronary artery from the pulmonary artery (ARCAPA) with collaterals between the left and right coronary system. In a multidisciplinary conference, it was decided to postpone surgical correction since the patient was at the time asymptomatic and had normal right and left ventricular systolic function and no signs of myocardial ischaemia on exercise test.