Helle Hjorth Johannesen

Voluntary Running Suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell Mobilization and Redistribution

Regular exercise reduces the risk of cancer and disease recurrence. Yet the mechanisms behind this protection remain to be elucidated. In this study, tumor-bearing mice randomized to voluntary wheel running showed over 60% reduction in tumor incidence and growth across five different tumor models. Microarray analysis revealed training-induced upregulation of pathways associated with immune function. NK cell infiltration was significantly increased in tumors from running mice, whereas depletion of NK cells enhanced tumor growth and blunted the beneficial effects of exercise. Mechanistic analyses showed that NK cells were mobilized by epinephrine, and blockade of β-adrenergic signaling blunted training-dependent tumor inhibition. Moreover, epinephrine induced a selective mobilization of IL-6-sensitive NK cells, and IL-6-blocking antibodies blunted training-induced tumor suppression, intratumoral NK cell infiltration, and NK cell activation. Together, these results link exercise, epinephrine, and IL-6 to NK cell mobilization and redistribution, and ultimately to control of tumor growth.

Insular lesions, ECG abnormalities, and outcome in acute stroke

It has been suggested that lesions in the insula may result in abnormal electrocardiographic (ECG) findings and increase the risk of sudden death. We investigated if computed tomography (CT) detected insular lesions due to acute stroke were related to ECG abnormalities and mortality at three months. Acute insular lesions were diagnosed in 43/179 patients (left insular  =  25; right insular  =  17; bilateral  =  1) with acute stroke (cerebral infarcts  =  62 and intracerebral haemorrhage  =  17) based on CT scans from 5–8 days after stroke onset; 12 lead ECGs were recorded on admission and ECG telemetry was done in the first 12–24 hours after admission. Information regarding mortality at three months was obtained. Insular lesions were related to sinus tachycardia with heart rate >120 bpm (p = 0.001), ectopic beats >10% (p = 0.032), and ST elevation (p = 0.011). Right insular lesions were related to atrial fibrillation (p = 0.009), atrioventricular block (p = 0.029), ectopic beats >10% (p = 0.016), and inverted T wave (p = 0.040). Right insular lesions, compared with left or no insular lesions, increased the odds of death within three months (OR 6.2, 95% CI 1.5 to 25.2) independent of stroke severity, lesion volume, and age. As the number of patients in the present study is relatively small, our findings need to be confirmed in studies on other populations of stroke patients.

Serum-cortisol reflects severity and mortality in acute stroke.

BACKGROUND The adrenal glucocorticoid stress response in humans causes catabolism, increasing blood glucose and heart rate, and possibly potentiates ischaemic damage to neurons. These effects could induce secondary brain damage in acute stroke. MATERIALS AND METHODS This prospective study was based on a single determination of s-cortisol in 172 patients included within 24 h of stroke onset, 50% within 12 h of stroke onset. All patients were admitted to hospital within 6 h of stroke onset. We investigated the relations of s-cortisol to neurological deficit measured by Scandinavian Stroke Scale (SSS), lesion volume on CT-scan, blood glucose on admission, pulse rate, blood pressure, body temperature, deteriorating stroke, cytokines and cytokine receptors, and outcome. RESULTS In a multivariate logistic regression analysis, s-cortisol was independently related to death within 7 days of stroke onset, odds ratio (OR) Cortisol(+100 nmol/l) 1.9 (95% CI 1.01-3.8); serum-cortisol was, however, not a predictor of death or dependency within 3 months. S-cortisol correlated to SSS (rho=-0.45, p<0.001), body temperature (rho=0.27, p<0.001), pulse rate (rho=0.26, p<0.001), and lesion volume (rho=0.33, p<0.001). S-cortisol was related to the presence of insular damage. CONCLUSION Acute stroke mortality related to increasing serum-cortisol levels. S-cortisol was associated with stroke severity and markers reflecting stroke severity.

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.

Serum Cardiac Troponin I in Acute Stroke Is Related to Serum Cortisol and TNF-α

Background: Serum cardiac troponin I (cTnI) is a specific marker of myocardial injury related to in-patient fatality and cardiac injury in acute stroke. We investigated whether cTnI in acute stroke is related to serum cortisol, acute inflammatory response, and insular damage. We also investigated whether cTnI predicted outcome at 3 months. Patients and Methods: The study was based on 155 patients with CT-confirmed acute cerebral infarction and study inclusion within 24 h (50% within 12 h) of stroke onset. Blood samples were obtained on inclusion. Stroke severity was assessed by the Scandinavian Stroke Scale (SSS) and outcome was assessed by the modified Rankin Scale (mRS), death or dependency was defined as mRS ≧3 three months after stroke. Results: 35% of all patients and 63% of patients who died within 3 months were troponin positive. Tumor necrosis factor-α (TNF-α) and cortisol were independently related to detection of cTnI: TNF-α+100 pg/ml OR 1.5 (CI 95% 1.1–2.2), cortisol+100 nmol/l OR 1.1 (CI 95% 1.01–1.2). SSS and age were also included in this model and did not reach significance. cTnI positivity was, together with age, stroke severity and prestroke mRS, but not s-cortisol, an independent explanatory variable of outcome at 3 months (death or dependency) with OR 4.1 (CI 95% 1.1–14.5). cTnI did not relate to insular involvement. Conclusion: In this study, cortisol and TNF-α were independently related to cTnI, which was predictive of 3-month prognosis.

Simultaneous Hyperpolarized 13C-Pyruvate MRI and 18F-FDG PET (HyperPET) in 10 Dogs with Cancer

With the introduction of combined PET/MR spectroscopic (MRS) imaging, it is now possible to directly and indirectly image the Warburg effect with hyperpolarized 13C-pyruvate and 18F-FDG PET imaging, respectively, via a technique we have named hyperPET. The main purpose of this present study was to establish a practical workflow for performing 18F-FDG PET and hyperpolarized 13C-pyruvate MRS imaging simultaneously for tumor tissue characterization and on a larger scale test its feasibility. In addition, we evaluated the correlation between 18F-FDG uptake and 13C-lactate production. Methods: Ten dogs with biopsy-verified spontaneous malignant tumors were included for imaging. All dogs underwent a protocol of simultaneous 18F-FDG PET, anatomic MR, and hyperpolarized dynamic nuclear polarization with 13C-pyruvate imaging. The data were acquired using a combined clinical PET/MR imaging scanner. Results: We found that combined 18F-FDG PET and 13C-pyruvate MRS imaging was possible in a single session of approximately 2 h. A continuous workflow was obtained with the injection of 18F-FDG when the dogs was placed in the PET/MR scanner. 13C-MRS dynamic acquisition demonstrated in an axial slab increased 13C-lactate production in 9 of 10 dogs. For the 9 dogs, the 13C-lactate was detected after a mean of 25 s (range, 17–33 s), with a mean to peak of 13C-lactate at 49 s (range, 40–62 s). 13C-pyruvate could be detected on average after 13 s (range, 5–26 s) and peaked on average after 25 s (range, 13–42 s). We noticed concordance of 18F-FDG uptake and production of 13C-lactate in most, but not all, axial slices. Conclusion: In this study, we have shown in a series of dogs with cancer that hyperPET can easily be performed within 2 h. We showed mostly correspondence between 13C-lactate production and 18F-FDG uptake and expect the combined modalities to reveal additional metabolic information to improve prognostic value and improve response monitoring.

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.

Feasibility of Multiparametric Imaging with PET/MR in Head and Neck Squamous Cell Carcinoma

The purpose of this study was to investigate and assess the correlation and reproducibility of multiparametric imaging in head and neck cancer patients. Methods: Twenty-one patients were included in this prospective scan–rescan study. All patients were scanned twice on an integrated PET and MRI scanner. Gross tumor volumes were defined on T2-weighted MR images, and volumes of interest were defined on diffusion-weighted MRI and 18F-FDG PET (VOIDWI, VOIPET). Overlap between volumes was assessed as a percentwise overlap. 18F-FDG uptake and diffusion were measured using SUV and apparent diffusion coefficient, and correlation was tested across and within patients and as a voxel-by-voxel analysis. Results: Seventeen patients were available for correlation analysis, and 12 patients were available for assessment of tumor overlap. The median tumor overlap between VOIDWI and VOIPET was 82% (VOIDWI in VOIPET) and 62% (VOIPET in VOIDWI) on scan 1 and scan 2, respectively. Across patients, the correlation between SUV and apparent diffusion coefficient was weak and nonsignificant. However, in individual patients a weak but significant correlation was identified on a voxel-by-voxel basis. Conclusion: In multiparametric imaging with the integrated PET/MR scanner, the VOIs from DWI and 18F-FDG PET were both within the target volume for radiotherapy and overlapped substantially although not completely. No correlation between 18F-FDG uptake and DWI could be found across patients, but within individual patients a statistically significant, but weak, voxel-by-voxel correlation was found. The findings suggest that information on glucose uptake and diffusion coefficient carries complementary information of interest that may be relevant for radiotherapy treatment planning.

Electrochemotherapy and calcium electroporation inducing a systemic immune response with local and distant remission of tumors in a patient with malignant melanoma – a case report

Hanne Falk, Susanne Lambaa, Helle Hjorth Johannesen, Gitte Wooler, Alessandro Venzo and Julie Gehl Department of Oncology, Herlev and Gentofte Hospital, Center for Experimental Drug and Gene Electrotransfer (CEDGE), University of Copenhagen, Herlev, Denmark; Department of Plastic Surgery, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark; Department of Radiology, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark; Department of Pathology, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark; Department of Plastic Surgery, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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.