Malene Hildebrandt

Gender differences in severity, symptomatology and distribution of melancholia in major depression

Background: Studies of gender differences in the clinical presentation of depression have provided divergent results. This study aimed at analyzing gender differences in severity, symptomatology and distribution of melancholia in major depression. Sampling and Methods: The study comprised 930 in- and out-patients (652 women, 278 men) from 6 randomized controlled trials. All patients fulfilled DSM-III or DSM-III-R criteria for major depression. The 17-item Hamilton Depression Scale (HDS) was applied to all patients. A multi-axial evaluation was completed using the Newcastle 1 Depression Rating Scale from 1965 for melancholia (N1) in a subsample of patients (n = 439). A factor analysis on the HDS was performed. Non-parametric statistical tests were used and only gender differences greater than 20% were considered clinically relevant. Results: The median on the HDS total score was 22 and the median number of symptoms was 13 for both men and women. Presentation of specific symptoms was similar for men and women. The factor analysis revealed no gender differences, and neither did analyses on symptoms of Axes II and IV. According to the N1, 80% of the men and 66% of the women suffered from melancholic depression (p = 0.004). Conclusions: In a large and broad sample of in- and out-patients with major depression, the severity and symptomatology of depression were similar for men and women. Melancholic depression was significantly more frequent among male than female patients. Inclusion and exclusion criteria in the randomized controlled trials provided a selected group of patients, which limited the generalisability of the results to an exclusive subgroup of patients treated for depression in routine clinical practice.

Gender and depression: a study of severity and symptomatology of depressive disorders (ICD-10) in general practice

Objective:  Gender differences in severity and symptomatology of depression in a large and representative sample of depressive patients from general practice were examined.

[18F]Fluorodeoxyglucose (FDG)-Positron Emission Tomography (PET)/Computed Tomography (CT) in Suspected Recurrent Breast Cancer: A Prospective Comparative Study of Dual-Time-Point FDG-PET/CT, Contrast-Enhanced CT, and Bone Scintigraphy

PURPOSE To prospectively investigate the diagnostic accuracy of [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) with dual-time-point imaging, contrast-enhanced CT (ceCT), and bone scintigraphy (BS) in patients with suspected breast cancer recurrence. PATIENTS AND METHODS One hundred women with suspected recurrence of breast cancer underwent 1-hour and 3-hour FDG-PET/CT, ceCT, and BS within approximately 10 days. The study was powered to estimate the precision of the individual imaging tests. Images were visually interpreted using a four-point assessment scale, and readers were blinded to other test results. The reference standard was biopsy along with treatment decisions and clinical follow-up (median, 17 months). RESULTS FDG-PET/CT resulted in no false negatives and fewer false positives than the other imaging techniques. Accuracy of results were similar for 1-hour and 3-hour FDG-PET/CT. For distant recurrence, the area under the receiver operating curve was 0.99 (95% CI, 0.97 to 1) for FDG-PET/CT, 0.84 (95% CI, 0.73 to 0.94) for ceCT, and 0.86 (95% CI, 0.77 to 0.94) for the combined ceCT+BS. Of 100 patients, 22 (22%) were verified with distant recurrence, and 18 of these had bone involvement. Nineteen patients (19%) had local recurrence only. In exploratory analyses, diagnostic accuracy of FDG-PET/CT was better than ceCT alone or ceCT combined with BS in diagnosing distant, bone, and local recurrence, shown by a greater area under the receiver operating curve and higher sensitivity, specificity, and superior likelihood ratios. CONCLUSION FDG-PET/CT was accurate in diagnosing recurrence in breast cancer patients. It allowed for distant recurrence to be correctly ruled out and resulted in only a small number of false-positive cases. Exploratory findings suggest that FDG-PET/CT has greater accuracy than conventional imaging technologies in this patient group.

[18F]Fluorodeoxyglucose PET/Computed Tomography in Breast Cancer and Gynecologic Cancers: A Literature Review

In this literature review, an update is provided on the role of [(18)F]fluorodeoxyglucose PET/computed tomography in different clinical settings of the 4 most frequent female-specific cancer types: breast, endometrial, ovarian, and cervical cancer. The most recent knowledge regarding primary diagnosis, staging, response evaluation, prognostic and predictive values, recurrence detection, and radiotherapy planning is evaluated, including, when clinically relevant, considerations with respect to the epidemiology, treatment, and course of the diseases.

Diagnosing recurrent breast cancer: Accuracy and inter-rater agreement of FDG-PET/CT and bone scintigraphy

European Journal of Nuclear Medicine and Molecular Imaging Volume 44, Supplement 2 10.1007/s00259-017-3822-1 This supplement was not sponsored by outside commercial interests. It was funded entirely by the association’s own resources DOI 10.1007/s00259-017-3822-1 S119 Eur J Nucl Med Mol Imaging (2017) 44 (Suppl 2):S119–S956

Group-sequential analysis may allow for early trial termination: illustration by an intra-observer repeatability study

Background: Group-sequential testing is widely used in pivotal therapeutic, but rarely in diagnostic research, although it may save studies, time, and costs. The purpose of this paper was to demonstrate a group-sequential analysis strategy in an intra-observer study on quantitative FDG-PET/CT measurements, illuminating the possibility of early trial termination which implicates significant potential time and resource savings. Methods: Primary lesion maximum standardised uptake value (SUVmax) was determined twice from preoperative FDG-PET/CTs in 45 ovarian cancer patients. Differences in SUVmax were assumed to be normally distributed, and sequential one-sided hypothesis tests on the population standard deviation of the differences against a hypothesised value of 1.5 were performed, employing an alpha spending function. The fixed-sample analysis (N = 45) was compared with the group-sequential analysis strategies comprising one (at N = 23), two (at N = 15, 30), or three interim analyses (at N = 11, 23, 34), respectively, which were defined post hoc. Results: When performing interim analyses with one third and two thirds of patients, sufficient agreement could be concluded after the first interim analysis and the final analysis. Other partitions did not suggest early stopping after adjustment for multiple testing due to one influential outlier and our small sample size. Conclusions: Group-sequential testing may enable early stopping of a trial, allowing for potential time and resource savings. The testing strategy must, though, be defined at the planning stage, and sample sizes must be reasonably large at interim analysis to ensure robustness against single outliers. Group-sequential testing may have a place in accuracy and agreement studies.

Stewart-Treves Syndrome on the Lower Extremity Associated to Idiopathic Chronic Lymphedema Visualized on FDG PET/CT

Angiosarcomas are highly malignant and rare tumors of vascular or lymphatic endothelial cell origin with a poor prognosis. Lymphangiosarcoma associated with chronic lymphedema is known as Stewart-Treves syndrome. Stewart-Treves syndrome is primarily described in patients with lymphedema of an upper extremity occurring after breast cancer surgery including radical axillary lymph node dissection and subsequent radiotherapy. It is rarely described in the presence of idiopathic chronic lymphedema of the lower extremities. We present a case of lymphangiosarcoma visualized on F-FDG PET/CT, where Stewart-Treves syndrome is secondary to probably a combination of idiopathic chronic lymphedema of the lower extremities and systemic immunosuppressive treatment.

FDG-PET/CT in the primary assessment of operability of women with ovarian cancer: experiences with incidental findings

Hypothesis: We assessed in in vitro and in vivo models of ovarian cancer the therapeutic efficacy of 16F12 mAbs directed against Mullerian Inhibiting Substance type II receptor (MISRII) radiolabeled with 213Bi Methods: In vitro, both direct and bystander cytotoxic effects were measured using clonogenic assay and standard medium transfer protocol. Typically, Clonogenic survival was assessed in SK-OV-3 donor cells expressing MISRII and exposed for 90 min to 0.06-0.5MBq/mL of 16F12 213Bi-mAbs. Bystander cytotoxicity was measured in recipient cells grown in non-radioactive culture medium preconditioned for 2 hours in the presence of donor cells. DNA double strand breaks (DSBs) were measured in both donor and recipients cells using immunofluorescent detection of gamma-H2AX and of 53BP1. In vivo we explored in athymic nude mice bearing intraperitoneal (IP) MISRII-expressing AN3CA tumor the therapeutic efficacy of brief-intraperitoneal radioimmunotherapy (BIP-RIT, 12.95 37 MBq; 37MBq/mg) or of intraperitoneal RIT (IP-RIT; 2.96-12.95 MBq; 37MBq/mg) using 213Bi-16F12. BIP-RIT mimics hyperthermic intraperitoneal chemotherapy as used in clinic. It consists of intraperitoneal injection of high activities of radiolabeled mAbs followed 30 min later by wash of the peritoneal cavity with saline solution to remove unbound radioactivity. The biodistribution of radiolabeled antibodies following IP-RIT (12.95 MBq; 37MBq/mg) or BIP-RIT (37 MBq; 37MBq/mg) was assessed. Results: In vitro we showed in donor cells a strong direct cytotoxicity of 16F12 213Bi-mAbs. A significant bystander cytotoxicity was also measured in recipient cells. Genotoxic effects were also demonstrated as measured by the formation of DNA DSBs in both donor and recipient cells. In vivo, results of biodistribution indicated that tumour uptake of 213Bi-16F12 during BIP RIT was higher than after IP RIT. The tumour-to-blood uptake ratio was 9 versus 3, respectively, one hour post RIT while it decreased down to 3 and 1, respectively, three hours post-RIT. Finally, a similar delay in tumor growth was observed in mice treated with 12.95 MBq of 213Bi-16F12 following IP-RIT or treated with 37 MBq using BIP-RIT. Conclusions: We confirmed in vitro the therapeutic efficacy of newly developed 16F12 213Bi-mAbs. in vivo results indicate that similar therapeutic efficacy and lower toxicity could be obtained with BIP-RIT compared with IP-RIT. BIP-RIT could be a new tool in the therapy of peritoneal carcinomatosis. URI: Authors: LADJOHOUNLOU Riad PICHARD Alexandre DEHAYES E BOUDOUSQ Vincent BRUCHERTSEIFER Frank MORGENSTERN Alfred NAVARRO-TEULON Isabelle POUGET Jean-Pierre Publication Year: 2016 Science Areas: Health and consumer protection [1]European Journal of Nuclear Medicine and Molecular Imaging Volume 43, Supplement 1 10.1007/s00259-016-3484-4 This supplement was not sponsored by outside commercial interests. It was funded entirely by the association’s own resources. ABSTRACT DOI 10.1007/s00259-016-3484-4 Eur J Nucl Med Mol Imaging (2016) 43 (Suppl 1):S1–S734Background: In the context of the EORTC LungTech trial, a QA procedure including a PET/CT credentialing has been developed. This procedure will ultimately allow us to pool data from 23 institutions with the overall goal of investigating the impact of tumour motion on quantification. As no standardized procedure exists under respiratory conditions, we investigated the variability of 14 SUV metrics to assess their robustness over respiratory noise. Methods: The customized CIRS-008A phantom was scanned at 13 institutions. This phantom consists of a 18 cm long body, a rod attached to a motion actuator, and a sphere of either 1.5 or 2.5cm diameters. Body, rods and spheres were filled with homogeneous 18FDG solutions representative of activity concentrations in mediastinum, lung and tumour for a 70kg patient. Three respiratory patterns with peak-to-peak amplitudes and periods of 15mm/3sec, 15mm/6sec and 25mm/4sec were tested. Prior to scanning in respiratory condition, a 3D static PET/CT was acquired as reference. During motion, images were acquired using 3D or 4D gated PET(average image) according to institutional settings. 14 SUV(mean) metrics were obtained per acquisition varying VOI/ ROI shape and location. Three ROIs and three VOIs with respective radii of 0.5, 0.6 and 0.8cm were investigated. These ROIs/VOIs were first centred on the maximum activity voxel; a second analysis was made changing the location from the voxel to the region (ROI5voxels) or the volume (VOI7voxels) with the maximum value. Two additional VOIs were defined as 3D isocontours respectively at 70% and 50% of the maximum voxel value. The SUV metrics were normalized by the corresponding 3D static SUV. Converting to recovery coefficients (RC) allowed us to pool data from all institutions, while maintaining focus solely on motion. For each RC from each motion setting we calculated the mean over institutions, we then looked at the standard deviation (Sd) and spread of each averaged RC over each motion setting (formula [1], [2], Figure1). Results: For the institutions visited we found that RCVOI70% and RCVOI50%, yielded over the 14 metrics the lowest variability to motion with Sd of 0.04 and 0.03 respectively. The RCs based on ROIs/VOIs centered on a single voxel were less impacted by motion (Sd: 0.08) compared to region RCs (Sd: 0.14). The averaged Sd over the RCs based on VOIs and ROIs was 0.12 and 0.11 respectively. Conclusion: Quantification over breathing types depends on ROI/VOI definition. Variables based on SUV max thresholds were found the most robust against respiratory noise.

FDG-PET/CT in early stage uterine cervical cancer: can SUVmax discriminate between malignant and benign lymph nodes?

Hypothesis: We assessed in in vitro and in vivo models of ovarian cancer the therapeutic efficacy of 16F12 mAbs directed against Mullerian Inhibiting Substance type II receptor (MISRII) radiolabeled with 213Bi Methods: In vitro, both direct and bystander cytotoxic effects were measured using clonogenic assay and standard medium transfer protocol. Typically, Clonogenic survival was assessed in SK-OV-3 donor cells expressing MISRII and exposed for 90 min to 0.06-0.5MBq/mL of 16F12 213Bi-mAbs. Bystander cytotoxicity was measured in recipient cells grown in non-radioactive culture medium preconditioned for 2 hours in the presence of donor cells. DNA double strand breaks (DSBs) were measured in both donor and recipients cells using immunofluorescent detection of gamma-H2AX and of 53BP1. In vivo we explored in athymic nude mice bearing intraperitoneal (IP) MISRII-expressing AN3CA tumor the therapeutic efficacy of brief-intraperitoneal radioimmunotherapy (BIP-RIT, 12.95 37 MBq; 37MBq/mg) or of intraperitoneal RIT (IP-RIT; 2.96-12.95 MBq; 37MBq/mg) using 213Bi-16F12. BIP-RIT mimics hyperthermic intraperitoneal chemotherapy as used in clinic. It consists of intraperitoneal injection of high activities of radiolabeled mAbs followed 30 min later by wash of the peritoneal cavity with saline solution to remove unbound radioactivity. The biodistribution of radiolabeled antibodies following IP-RIT (12.95 MBq; 37MBq/mg) or BIP-RIT (37 MBq; 37MBq/mg) was assessed. Results: In vitro we showed in donor cells a strong direct cytotoxicity of 16F12 213Bi-mAbs. A significant bystander cytotoxicity was also measured in recipient cells. Genotoxic effects were also demonstrated as measured by the formation of DNA DSBs in both donor and recipient cells. In vivo, results of biodistribution indicated that tumour uptake of 213Bi-16F12 during BIP RIT was higher than after IP RIT. The tumour-to-blood uptake ratio was 9 versus 3, respectively, one hour post RIT while it decreased down to 3 and 1, respectively, three hours post-RIT. Finally, a similar delay in tumor growth was observed in mice treated with 12.95 MBq of 213Bi-16F12 following IP-RIT or treated with 37 MBq using BIP-RIT. Conclusions: We confirmed in vitro the therapeutic efficacy of newly developed 16F12 213Bi-mAbs. in vivo results indicate that similar therapeutic efficacy and lower toxicity could be obtained with BIP-RIT compared with IP-RIT. BIP-RIT could be a new tool in the therapy of peritoneal carcinomatosis. URI: Authors: LADJOHOUNLOU Riad PICHARD Alexandre DEHAYES E BOUDOUSQ Vincent BRUCHERTSEIFER Frank MORGENSTERN Alfred NAVARRO-TEULON Isabelle POUGET Jean-Pierre Publication Year: 2016 Science Areas: Health and consumer protection [1]European Journal of Nuclear Medicine and Molecular Imaging Volume 43, Supplement 1 10.1007/s00259-016-3484-4 This supplement was not sponsored by outside commercial interests. It was funded entirely by the association’s own resources. ABSTRACT DOI 10.1007/s00259-016-3484-4 Eur J Nucl Med Mol Imaging (2016) 43 (Suppl 1):S1–S734Background: In the context of the EORTC LungTech trial, a QA procedure including a PET/CT credentialing has been developed. This procedure will ultimately allow us to pool data from 23 institutions with the overall goal of investigating the impact of tumour motion on quantification. As no standardized procedure exists under respiratory conditions, we investigated the variability of 14 SUV metrics to assess their robustness over respiratory noise. Methods: The customized CIRS-008A phantom was scanned at 13 institutions. This phantom consists of a 18 cm long body, a rod attached to a motion actuator, and a sphere of either 1.5 or 2.5cm diameters. Body, rods and spheres were filled with homogeneous 18FDG solutions representative of activity concentrations in mediastinum, lung and tumour for a 70kg patient. Three respiratory patterns with peak-to-peak amplitudes and periods of 15mm/3sec, 15mm/6sec and 25mm/4sec were tested. Prior to scanning in respiratory condition, a 3D static PET/CT was acquired as reference. During motion, images were acquired using 3D or 4D gated PET(average image) according to institutional settings. 14 SUV(mean) metrics were obtained per acquisition varying VOI/ ROI shape and location. Three ROIs and three VOIs with respective radii of 0.5, 0.6 and 0.8cm were investigated. These ROIs/VOIs were first centred on the maximum activity voxel; a second analysis was made changing the location from the voxel to the region (ROI5voxels) or the volume (VOI7voxels) with the maximum value. Two additional VOIs were defined as 3D isocontours respectively at 70% and 50% of the maximum voxel value. The SUV metrics were normalized by the corresponding 3D static SUV. Converting to recovery coefficients (RC) allowed us to pool data from all institutions, while maintaining focus solely on motion. For each RC from each motion setting we calculated the mean over institutions, we then looked at the standard deviation (Sd) and spread of each averaged RC over each motion setting (formula [1], [2], Figure1). Results: For the institutions visited we found that RCVOI70% and RCVOI50%, yielded over the 14 metrics the lowest variability to motion with Sd of 0.04 and 0.03 respectively. The RCs based on ROIs/VOIs centered on a single voxel were less impacted by motion (Sd: 0.08) compared to region RCs (Sd: 0.14). The averaged Sd over the RCs based on VOIs and ROIs was 0.12 and 0.11 respectively. Conclusion: Quantification over breathing types depends on ROI/VOI definition. Variables based on SUV max thresholds were found the most robust against respiratory noise.

Dual-time-point FDG-PET/CT: prognostic value of total metabolic tumour volume in patients with recurrent breast cancer

Hypothesis: We assessed in in vitro and in vivo models of ovarian cancer the therapeutic efficacy of 16F12 mAbs directed against Mullerian Inhibiting Substance type II receptor (MISRII) radiolabeled with 213Bi Methods: In vitro, both direct and bystander cytotoxic effects were measured using clonogenic assay and standard medium transfer protocol. Typically, Clonogenic survival was assessed in SK-OV-3 donor cells expressing MISRII and exposed for 90 min to 0.06-0.5MBq/mL of 16F12 213Bi-mAbs. Bystander cytotoxicity was measured in recipient cells grown in non-radioactive culture medium preconditioned for 2 hours in the presence of donor cells. DNA double strand breaks (DSBs) were measured in both donor and recipients cells using immunofluorescent detection of gamma-H2AX and of 53BP1. In vivo we explored in athymic nude mice bearing intraperitoneal (IP) MISRII-expressing AN3CA tumor the therapeutic efficacy of brief-intraperitoneal radioimmunotherapy (BIP-RIT, 12.95 37 MBq; 37MBq/mg) or of intraperitoneal RIT (IP-RIT; 2.96-12.95 MBq; 37MBq/mg) using 213Bi-16F12. BIP-RIT mimics hyperthermic intraperitoneal chemotherapy as used in clinic. It consists of intraperitoneal injection of high activities of radiolabeled mAbs followed 30 min later by wash of the peritoneal cavity with saline solution to remove unbound radioactivity. The biodistribution of radiolabeled antibodies following IP-RIT (12.95 MBq; 37MBq/mg) or BIP-RIT (37 MBq; 37MBq/mg) was assessed. Results: In vitro we showed in donor cells a strong direct cytotoxicity of 16F12 213Bi-mAbs. A significant bystander cytotoxicity was also measured in recipient cells. Genotoxic effects were also demonstrated as measured by the formation of DNA DSBs in both donor and recipient cells. In vivo, results of biodistribution indicated that tumour uptake of 213Bi-16F12 during BIP RIT was higher than after IP RIT. The tumour-to-blood uptake ratio was 9 versus 3, respectively, one hour post RIT while it decreased down to 3 and 1, respectively, three hours post-RIT. Finally, a similar delay in tumor growth was observed in mice treated with 12.95 MBq of 213Bi-16F12 following IP-RIT or treated with 37 MBq using BIP-RIT. Conclusions: We confirmed in vitro the therapeutic efficacy of newly developed 16F12 213Bi-mAbs. in vivo results indicate that similar therapeutic efficacy and lower toxicity could be obtained with BIP-RIT compared with IP-RIT. BIP-RIT could be a new tool in the therapy of peritoneal carcinomatosis. URI: Authors: LADJOHOUNLOU Riad PICHARD Alexandre DEHAYES E BOUDOUSQ Vincent BRUCHERTSEIFER Frank MORGENSTERN Alfred NAVARRO-TEULON Isabelle POUGET Jean-Pierre Publication Year: 2016 Science Areas: Health and consumer protection [1]European Journal of Nuclear Medicine and Molecular Imaging Volume 43, Supplement 1 10.1007/s00259-016-3484-4 This supplement was not sponsored by outside commercial interests. It was funded entirely by the association’s own resources. ABSTRACT DOI 10.1007/s00259-016-3484-4 Eur J Nucl Med Mol Imaging (2016) 43 (Suppl 1):S1–S734Background: In the context of the EORTC LungTech trial, a QA procedure including a PET/CT credentialing has been developed. This procedure will ultimately allow us to pool data from 23 institutions with the overall goal of investigating the impact of tumour motion on quantification. As no standardized procedure exists under respiratory conditions, we investigated the variability of 14 SUV metrics to assess their robustness over respiratory noise. Methods: The customized CIRS-008A phantom was scanned at 13 institutions. This phantom consists of a 18 cm long body, a rod attached to a motion actuator, and a sphere of either 1.5 or 2.5cm diameters. Body, rods and spheres were filled with homogeneous 18FDG solutions representative of activity concentrations in mediastinum, lung and tumour for a 70kg patient. Three respiratory patterns with peak-to-peak amplitudes and periods of 15mm/3sec, 15mm/6sec and 25mm/4sec were tested. Prior to scanning in respiratory condition, a 3D static PET/CT was acquired as reference. During motion, images were acquired using 3D or 4D gated PET(average image) according to institutional settings. 14 SUV(mean) metrics were obtained per acquisition varying VOI/ ROI shape and location. Three ROIs and three VOIs with respective radii of 0.5, 0.6 and 0.8cm were investigated. These ROIs/VOIs were first centred on the maximum activity voxel; a second analysis was made changing the location from the voxel to the region (ROI5voxels) or the volume (VOI7voxels) with the maximum value. Two additional VOIs were defined as 3D isocontours respectively at 70% and 50% of the maximum voxel value. The SUV metrics were normalized by the corresponding 3D static SUV. Converting to recovery coefficients (RC) allowed us to pool data from all institutions, while maintaining focus solely on motion. For each RC from each motion setting we calculated the mean over institutions, we then looked at the standard deviation (Sd) and spread of each averaged RC over each motion setting (formula [1], [2], Figure1). Results: For the institutions visited we found that RCVOI70% and RCVOI50%, yielded over the 14 metrics the lowest variability to motion with Sd of 0.04 and 0.03 respectively. The RCs based on ROIs/VOIs centered on a single voxel were less impacted by motion (Sd: 0.08) compared to region RCs (Sd: 0.14). The averaged Sd over the RCs based on VOIs and ROIs was 0.12 and 0.11 respectively. Conclusion: Quantification over breathing types depends on ROI/VOI definition. Variables based on SUV max thresholds were found the most robust against respiratory noise.