Helle Westergren Hendel

Circulating levels of TNF-alpha and IL-6-relation to truncal fat mass and muscle mass in healthy elderly individuals and in patients with type-2 diabetes

The purpose of the current study was to test the hypothesis that an altered fat distribution in elderly healthy subjects and in patients with type-2 diabetes contributes to high circulating levels of interleukin (IL)-6 and tumor necrotic factor (TNF)-alpha, which secondly is related to lower muscle mass. Twenty young controls, (20-35 yr), 20 healthy elderly subjects (65-80 yr) and 16 elderly patients with type 2 diabetes (65-80 yr) were included in a cross sectional study. Plasma levels of TNF-alpha and IL-6 were measured after an overnight fast. Dual-energy X-ray absorptiometry and total body potassium counting measured truncal fat, appendicular skeletal muscle mass (ASM) and body cell mass (BCM), respectively. TNF-alpha, IL-6 and the relative truncal fat mass were higher in elderly compared with young controls. ASM was lower in diabetic men than in young controls and BCM was lower in elderly men compared with young men. TNF-alpha and IL-6 were correlated with the absolute as well as the relative truncal fat mass in univariate regression analyses. Similar results were found in multivariate linear regression analyses after adjusting for the effect of age and gender. TNF-alpha was related to lower ASM and BCM in elderly men both in a univariate regression analysis and a multivariate regression analysis. In conclusion, high plasma levels of TNF-alpha and IL-6 in elderly healthy people and in patients with type 2 diabetes are associated with increased truncal fat mass, suggesting that cytokines are partly derived from this adipose tissue bed. Furthermore, TNF-alpha was related to lower ASM and BCM, suggesting that TNF-alpha contributes to sarcopenia in ageing.

Electrochemotherapy for large cutaneous recurrence of breast cancer: A phase II clinical trial

Abstract Background. Cutaneous recurrences of breast cancer may cause considerable discomfort due to ulceration, oozing, and pain and can also be difficult to treat. Electrochemotherapy is a localised anticancer treatment using electric pulses to make cell membranes permeable, augmenting uptake of chemotherapeutic drugs, and thus enabling highly efficient tumour cell kill. This is the first systematic investigation of electrochemotherapy for larger cutaneous recurrences of breast cancer. Patients and methods. We conducted a phase II trial for patients with cutaneous recurrences where no further treatment options were available. Primary endpoint was objective response evaluated by clinical examination. Secondary endpoints included response evaluated by PET/CT, change in lung diffusion capacity, patient reported symptoms, and distress related to bodily appearance. Treatment consisted of bleomycin injection followed by application of electric pulses. Results. Seventeen heavily pre-treated patients received electrochemotherapy. Twelve patients were evaluable (follow-up > 8 weeks). CT showed four (33%) patients achieving over 50% tumour volume reduction, clinical examination showed one CR and one PR (OR 17%). Symptomatic relief included decreasing exudates, odour, and bleeding. Treatment was well tolerated; the main side effect was post-treatment pain. Conclusion. This first phase II study indicates that electrochemotherapy is a promising treatment alternative for cutaneous recurrences of breast cancer.

Comparison of EORTC Criteria and PERCIST for PET/CT Response Evaluation of Patients with Metastatic Colorectal Cancer Treated with Irinotecan and Cetuximab

The study aim was to compare European Organization for Research and Treatment of Cancer (EORTC) criteria with PET Response Criteria in Solid Tumors (PERCIST) for response evaluation of patients with metastatic colorectal cancer treated with a combination of the chemotherapeutic drug irinotecan and the monoclonal antibody cetuximab. Methods: From 2006 to 2009, patients with metastatic colorectal cancer were prospectively included in a phase II trial evaluating the combination of irinotecan and cetuximab every second week, as third-line treatment. 18F-FDG PET/CT was performed between 1 and 14 d before the first treatment and after every fourth treatment cycle until progression was identified by CT with Response Evaluation Criteria in Solid Tumors (RECIST). Response evaluation with 18F-FDG PET/CT was retrospectively performed according to both EORTC criteria and PERCIST, classifying the patients into 4 response categories: complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD). Individual best overall metabolic response (BOmR) was registered with both sets of criteria, as well as survival within response categories, and compared. Results: A total of 61 patients and 203 PET/CT scans were eligible for response evaluation. With EORTC criteria, 38 had PMR, 16 had SMD, and 7 had PMD as their BOmR. With PERCIST, 34 had PMR, 20 had SMD, and 7 had PMD as their BOmR. None of the patients had CMR. There was agreement between EORTC criteria and PERCIST in 87% of the patients, and the corresponding κ-coefficient was 0.76. Disagreements were confined to PMR and SMD. Median overall survival (OS) in months with EORTC criteria was 14.2 in the PMR group and 7.2 in the combined SMD + PMD group. With PERCIST, it was 14.5 in the PMR group and 7.9 in the SMD + PMD group. Conclusion: Response evaluation with EORTC criteria and PERCIST gave similar responses and OS outcomes with good agreement on BOmR (κ-coefficient, 0.76) and similar significant differences in median OS between response groups. Compared with EORTC criteria, we find PERCIST unambiguous because of clear definitions and therefore more straightforward to use.

Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen.

Purpose: Adoptive cell transfer therapy (ACT) based on autologous tumor-infiltrating lymphocytes (TIL) has achieved impressive clinical results in several phase I and II trials performed outside of Europe. Although transient, the toxicities associated with high-dose (HD) bolus IL2 classically administered together with TILs are severe. To further scrutinize whether similar results can be achieved with lower doses of IL2, we have carried out a phase I/II trial of TIL transfer after classical lymphodepleting chemotherapy followed by an attenuated IL2 regimen. Experimental Design: Twenty-five patients with progressive treatment-refractory metastatic melanoma, good clinical performance, age < 70 years, and at least one resectable metastasis were eligible. TIL infusion was preceded by standard lymphodepleting chemotherapy and followed by attenuated doses of IL2 administered in an intravenous, continuous decrescendo regimen (ClinicalTrials.gov Identifier: NCT00937625). Results: Classical IL2-related toxicities were observed but patients were manageable in a general oncology ward without the need for intervention from the intensive care unit. RECIST 1.0 evaluation displayed three complete responses and seven partial responses (ORR 42%). Median overall survival was 21.8 months. Tumor regression was associated with a higher absolute number of infused tumor-reactive T cells. Moreover, induction and persistence of antimelanoma T-cell responses in the peripheral blood was strongly correlated to clinical response to treatment. Conclusions: TIL-ACT with a reduced IL2 decrescendo regimen results in long-lasting complete responses in patients with treatment-refractory melanoma. Larger randomized trials are needed to elucidate whether clinical efficacy is comparable with TIL-ACT followed by HD bolus IL2. Clin Cancer Res; 22(15); 3734–45. ©2016 AACR.

Assessment of Volume Measurement of Breast Cancer-Related Lymphedema by Three Methods: Circumference Measurement, Water Displacement, and Dual Energy X-Ray Absorptiometry

BACKGROUND Following treatment for breast cancer 12%-60% develop breast cancer-related lymphedema (BCRL). There are several ways of assessing BCRL. Circumference measurement (CM) and water displacement (WD) for volume measurements (VM) are frequently used methods in practice and research, respectively. The aim of this study was to evaluate CM and WD for VM of the BCRL arm and the contralateral arm, comparing the results with regional dual energy X-ray absorptiometry (DXA). METHODS AND RESULTS Twenty-four women with unilateral BCRL were included in the study. Blinded duplicate VM were obtained from both arms using the three methods mentioned above. CM and DXA were performed by two observers. WD was performed by a group of observers. Mean differences (d) in duplicated volumes, limits of agreement (LOA), and 95% confidence intervals (CI) were calculated for each method. The repeatability expressed as d (95% CI) between the duplicated VM of the BCRL arm and the contralateral arm was for DXA 3 ml (-6-11) and 3 ml (1-7), respectively. For CM and WD, the d (95% CI) of the BCRL arm were 107 ml (86-127) and 26 ml (-26-79), respectively and in the contralateral arm 100 ml (78-122) and -6 ml (-29-17), respectively. CONCLUSIONS DXA is superior in repeatability when compared to CM and WD for VM, especially for the BCRL arm but also the contralateral arm.

Skeletal muscle mitochondrial function and exercise capacity in HIV-infected patients with lipodystrophy and elevated p-lactate levels

Objective To investigate the skeletal muscle mitochondrial function in HIV-infected patients with lipdystrophy or elevated p-lactate levels. Design Eight HIV patients treated with highly active antiretroviral therapy, with lipodystrophy or elevated p-lactate, and eight healthy controls were exposed to incremental exercise until exhaustion. Methods Blood samples and gas analysis were performed at rest, during exercise and in recovery. Oxygen consumption, workload and blood lactate were assessed. Before and immediately after exercise muscle biopsies were obtained, in which citrate synthase (CS), hydroxyacyl-coenzyme A dehydrogenase (HD), glycogen and nucleotides were measured. Results Maximal workload was significantly lower in patients compared with controls [171 Watt (88–206) versus 235 Watt (118–294) P = 0.05]. A trend towards lower maximal oxygen consumption (VO2max) was detected in patients [2136 ml/min (1221–2598) versus 2985 ml/min (1506–3959) P = 0.11]. Patients had significantly elevated levels of blood lactate at rest [1.55 mmol/l (1–2.5) versus 0.8 mmo/l (0.37–1.1) P < 0.01), but no significant difference in maximal blood-lactate values was found. The decline in blood lactate in the recovery period was similar between groups. There was no significant difference in CS, HD, glycogen or nucleotides. Conclusion The significantly lower working capacity and the trend towards reduced VO2max in patients could be caused by mitochondrial dysfunction, but may also be caused by impaired physical fitness. The similar levels of nucleotides, CS, HD, and glycogen and the normal increase in blood lactate during exercise indicates a normal oxidative phosphorylation. No evidence of serious damage to skeletal muscle mitochondrial function was found.

Are soft tissue composition of bone and non-bone pixels in spinal bone mineral measurements by DXA similar? Impact of weight loss.

Weight loss seems associated with a decrease in bone mineral density (BMD) as measured by absorptiometry, which may be the result of accuracy errors caused by differences in soft tissue between non‐bone and bone pixels. The aim was to study the abdominal fat% and thickness in regions corresponding to non‐bone, soft tissue‐only and bone pixels for spinal BMD measurements by dual energy X‐ray absorptiometry (DXA), and to calculate the theoretical errors in measurement of changes in BMD by DXA as a result of changes in soft tissue heterogeneity with weight loss. Abdominal computed tomography (CT) and DXA scans were performed in 34 obese subjects (42·1 ± 10·1 years (mean ± SD), wt: 102·1 ± 12·8 kg and BMI: 36·6 ± 3·8 kg m–2) before and after weight loss (11·3 ± 6·9 kg after 1 year). There were some significant differences in fat% and thickness of soft tissue between abdominal regions corresponding to non‐bone and bone pixels, respectively, for spinal BMD measurements by DXA, both before and after weight loss. With weight loss there were some changes in the soft tissue heterogeneity, which caused a minor theoretical error (apparent, but false decrease of 1–2%) of borderline significance for the anterior–posterior (AP) spinal BMD by DXA.

Observer variability in a phase II trial – assessing consistency in RECIST application

Abstract Objective. To assess the consistency of Response Evaluation Criteria in Solid Tumours (RECIST) application in a phase II trial. Material and methods. Patients with metastatic non-resectable colorectal cancer treated with a combination of an antibody and a chemotherapeutic drug, were included. Computed tomography (CT) scans (thorax, abdomen and pelvis) were performed at baseline and after every fourth treatment cycle. RECIST was intended for response evaluation. The scans were consecutively read by a heterogeneous group of radiologists as a part of daily work and hereafter retrospectively reviewed by a dedicated experienced radiologist. Agreement on best overall response (BOR) between readers and reviewer was quantified using κ-coefficients and the discrepancy rate was correlated with the number of different readers per patient using a χ2-test. Results. One hundred patients with 396 CT scans were included. Discrepancies between the readers and the reviewer were found in 47 patients. The majority of discrepancies concerned the application of RECIST. With the review, BOR changed in 17 patients, although, only in six patients the change was potentially treatment altering. Overall, the κ-coefficient of agreement between readers and reviewer was 0.71 (good). However, in the subgroup of responding patients the κ-coefficient was 0.21 (fair). The number of patients with discrepancies was significantly higher with three or more different readers per patient than with less (p =0.0003). Conclusion. RECIST was not consistently applied and the majority of the reader discrepancies were RECIST related. Post review, 17 patients changed BOR; six patients in a potentially treatment altering manner. Additionally, we found that the part of patients with discrepancies increased significantly with more than three different readers per patient. The findings support a peer-review approach where a few dedicated radiologists perform double blinded readings of all the on-going cancer trial patients’ CT scans.

CT versus FDG‐PET/CT response evaluation in patients with metastatic colorectal cancer treated with irinotecan and cetuximab

We compared morphologic computed tomography (CT)‐based to metabolic fluoro‐deoxy‐glucose (FDG) positron emission tomography (PET)/CT‐based response evaluation in patients with metastatic colorectal cancer and correlated the findings with survival and KRAS status. From 2006 to 2009, patients were included in a phase II trial and treated with cetuximab and irinotecan every second week. They underwent FDG‐PET/CT examination at baseline and after every fourth treatment cycle. Response evaluation was performed prospectively according to Response Evaluation Criteria in Solid Tumors (RECIST 1.0) and retrospectively according to Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST). Best overall responses were registered. Sixty‐one patients were eligible for response evaluation. Partial response (PR) rate was 18%, stable disease (SD) rate 64%, and progressive disease (PD) rate 18%. Partial metabolic response (PMR) rate was 56%, stable metabolic disease rate 33%, and progressive metabolic disease (PMD) rate 11%. Response agreement was poor, κ‐coefficient 0.19. Hazard ratio for overall survival for responders (PR/PMR) versus nonresponders (PD/PMD) was higher for CT‐ than for FDG‐PET/CT evaluation. Within patients with KRAS mutations, none had PR but 44% had PMR. In conclusion, morphologic and metabolic response agreement was poor primarily because a large part of the patients shifted from SD with CT evaluation to PMR when evaluated with FDG‐PET/CT. Furthermore, a larger fraction of the patients with KRAS mutations had a metabolic treatment response.

Dual time point imaging fluorine-18 flourodeoxyglucose positron emission tomography for evaluation of large loco-regional recurrences of breast cancer treated with electrochemotherapy

Abstract Background. Electrochemotherapy is a local anticancer treatment very efficient for treatment of small cutaneous metastases. The method is now being investigated for large cutaneous recurrences of breast cancer that are often confluent masses of malignant tumour with various degrees of inflammation. To this end 18-Flourine- Flourodeoxyglucose-Positron Emission Tomography/Computed Tomography (FDG-PET/CT) could be a method for response evaluation. However, a standard FDG-PET/CT scan cannot differentiate inflammatory tissue from malignant tissue. Dual point time imaging (DTPI) FDG-PET has the potential of doing so. The purpose of this study was to investigate if DTPI FDG-PET/CT could assess response to electrochemotherapy and to assess the optimal timing of imaging. Patients and methods. Within a phase II clinical trial 11 patients with cutaneous recurrences had FDG-PET/CT scans at three time points: 60 min, 120 min and 180 min after FDG injection. The scans were performed before and 3 weeks after electrochemotherapy. Results. A significant reduction in maximum standard uptake value at 60 min post injection was seen after treatment. Furthermore a change in the FDG uptake pattern was observed; from increasing uptake in up to 180 min post injection before treatment to stabilization of FDG uptake at 120 min post injection after treatment. The change in FDG uptake pattern over time lead to change of response in three target lesions; two lesions changed from stable metabolic disease to partial metabolic response and one lesion changed from partial metabolic response to stable metabolic disease. To ensure detection of the change in uptake pattern, scanning 60 and 180 min post injection seems optimal. Conclusions. The present study shows that FDG-PET/CT 60 and 180 min after tracer injection is a promising tool for response evaluation of cutaneous recurrences of breast cancer treated with electrochemotherapy.