Cecilia Wassberg

In Vivo Visualization of Amyloid Deposits in the Heart with 11C-PIB and PET

Cardiac amyloidosis is a differential diagnosis in heart failure and is associated with high mortality. There is currently no noninvasive imaging test available for specific diagnosis. N-[methyl-11C]2-(4′-methylamino-phenyl)-6-hydroxybenzothiazole (11C-PIB) PET is used in the evaluation of brain amyloidosis. We evaluated the potential use of 11C-PIB PET in systemic amyloidosis affecting the heart. Methods: Patients (n = 10) diagnosed with systemic amyloidosis—including heart involvement of either monoclonal immunoglobulin light-chain (AL) or transthyretin (ATTR) type—and healthy volunteers (n = 5) were investigated with PET/CT using 11C-PIB to study cardiac amyloid deposits and with 11C-acetate to measure myocardial blood flow to study the impact of global and regional perfusion on PIB retention. Results: Myocardial 11C-PIB uptake was visually evident in all patients 15–25 min after injection and was not seen in any volunteer. A significant difference in 11C-PIB retention in the heart between patients and healthy controls was found. The data indicate that myocardial amyloid deposits in patients diagnosed with systemic amyloidosis could be visualized with 11C-PIB. No correlation between 11C-PIB retention index and myocardial blood flow as measured with 11C-acetate was found on the global level, whereas a positive correlation on the segmental level was seen in a single patient. Conclusion: 11C-PIB and PET could be a method to study systemic amyloidosis of type AL and ATTR affecting the heart and should be investigated further both as a diagnostic tool and as a noninvasive method for treatment follow-up.

Increasing Incidence Rates of Squamous Cell Carcinoma of the Skin in Sweden

The incidence of squamous cell carcinoma of the skin is increasing world-wide, and in Sweden this tumour is one of the most rapidly increasing malignancies. The aim of this study was to investigate incidence trends of squamous cell carcinoma in Sweden. For the 39,805 tumours registered in the Swedish Cancer Registry 1961-1995, incidence rates were calculated according to gender, age, anatomical site and unit surface area. Multivariate analysis was performed with the age-period-cohort model. Age-standardized incidence rates increased substantially in both men (+425%) and women (+146%) during this period. The highest rates per unit surface area were seen for chronically sun-exposed head-neck sites. Age-specific incidence rates increased in ages > or =60 years during the study period. Multivariate analyses showed that age, period and cohort effects in men could best explain the incidence rates, while in women the age-period effects model was adequate. In conclusion, a rapidly increasing incidence trend for squamous cell carcinoma was found, probably explained by increased accumulated sun exposure and increasing incidence among the elderly.

Similar UV responses are seen in a skin organ culture as in human skin in vivo

Abstract: Ultraviolet radiation (UVR) plays an important role in the development of non‐melanoma skin cancer. Most tumors develop in chronically sun‐exposed skin, most often in cosmetically sensitive locations, where in vivo experiments may be difficult to perform. In this study, we describe a skin organ culture model with preserved normal morphology and intact response to UVR. Skin explants from chronically sun‐exposed and non‐sun‐exposed skin were irradiated with artificial UVA+UVB with and without topical sunscreen. UV‐induced DNA damage, epidermal p53 response and repair kinetics were analyzed using immunohistochemistry. Four hours after UV‐irradiation epidermal keratinocytes showed a strong immunoreactivity for thymine‐dimers. Gradual repair during an incubation time resulted in few residual thymine‐dimers after 48 h. Repair appeared to be more efficient in chronically sun‐exposed skin compared with non‐sun‐exposed skin. There was also an accumulation of p53 protein in epidermal keratinocytes, peaking at 4–24 h after irradiation. Large interindividual differences with respect to formation and repair of thymine‐dimers as well as induction and duration of the p53 response were observed. Skin explants treated with topical sunscreen prior to UV‐irradiation showed a clear reduction of thymine‐dimers and p53 expression. The epidermal UV‐responses and repair kinetics in organ‐cultured skin were similar to what was found in vivo. Our data suggest that organ‐cultured skin provides a valuable tool for studies of UV‐induced epidermal responses in chronically sun‐exposed skin.

Streptozocin and 5-Fluorouracil for the Treatment of Pancreatic Neuroendocrine Tumors: Efficacy, Prognostic Factors and Toxicity

Background: In our center, the combination of streptozocin (STZ) and 5-fluorouracil (5-FU) has been used as the first-line treatment in the majority of patients with pancreatic neuroendocrine tumors (pNETs) over the past few decades. The objective of the current study was to assess the efficacy, prognostic factors and safety of the combination of STZ and 5-FU. Patients and Methods: Medical records and radiological reports of 133 patients with pNETs who received the combination of STZ and 5-FU during the period 1981-2014 were retrospectively evaluated. Results: The median survival from the start of treatment was 51.9 months in the whole group. In the radiologically evaluable patients (n = 100), progression-free survival was 23 months. Complete response was reached in 3 patients (3%), partial response in 25 patients (25%), 64 patients (64%) had stable disease, and 8 patients (8%) had progressive disease. In a multivariate analysis, surgery of the primary tumor and having a G3 tumor were significant positive and negative prognostic factors of survival from the start of treatment, respectively. Having either a G3 tumor or a stage IV tumor were significant prognostic factors for a shorter progression-free survival. Chemotherapy had to be discontinued in 29 patients due to side effects, of which kidney toxicity (mainly grades 1-2) was the most frequent. Conclusion: As shown in recent reports, the combination of STZ and 5-FU is effective in the treatment of pNETs in terms of survival and radiological response and has an acceptable toxicity profile.

11C-Hydroxyephedrine Positron Emission Tomography Imaging of Pheochromocytoma: A Single Center Experience over 11 Years

CONTEXT Localization of the primary tumor and detection of metastases are essential for preoperative planning and postoperative management of pheochromocytoma. When computed tomography (CT) and magnetic resonance imaging are inadequate, functional imaging adds important information in this respect. OBJECTIVE In this study the efficacy of positron emission tomography (PET) and PET/CT with (11)C-hydroxyephedrine (HED) was evaluated. DESIGN HED-PET (n = 69) and PET/CT (n = 101) examinations of 134 patients were analyzed, of which 103 were performed before surgery and 67 postoperatively. Image findings were evaluated and tracer uptake in tumors measured as the maximum standardized uptake value (SUVmax), which was compared with histopathological and clinical data. RESULTS Sixty HED-PET and PET/CT examinations were positive, with no false-positive and six false-negative examinations (sensitivity 91%, specificity 100%). Sensitivity of HED-PET in multiple endocrine neoplasia type II patients was lower (73%) with 100% specificity. The mean SUVmax was significantly higher when sympathetic symptoms were present and in metastases compared with primary tumors. The SUVmax correlated significantly with plasma normetanephrine and urinary norepinephrine. The mean SUVmax in HED-positive primary tumors was significantly higher than in normal adrenal glands. CONCLUSION HED-PET and PET/CT demonstrated 91% sensitivity and maximum specificity but with lower sensitivity in multiple endocrine neoplasia type II patients. The degree of HED accumulation (SUVmax) in the tumors correlated to malignancy and biochemical data.

Enhanced epidermal ultraviolet responses in chronically sun-exposed skin are dependent on previous sun exposure.

The p53 protein plays a key role in protecting cells from acquiring manifest mutations by inducing cell cycle arrest or apoptosis. The mechanisms for differences in epidermal responses to ultraviolet irradiation are unclear, although they have been shown to be related to both genetic events and environmental factors. In this study, we compared epidermal ultraviolet responses in chronically sun-exposed and non-sun-exposed skin using immunohistochemistry with antibodies recognizing thymine dimers and p53 protein. Six healthy volunteers were subjected to both artificial ultraviolet irradiation and natural sunlight, with and without photoprotection. A smaller number of thymine dimer-positive keratinocytes were detected 24 h after ultraviolet exposure in chronically sun-exposed skin compared to non-sun-exposed skin. Further, the p53 response was more variable in chronically sun-exposed skin. A significant correlation between total ultraviolet dose and number of p53-immunoreactive keratinocytes was found after natural sun exposure. Our findings suggest that repair of DNA damage is more efficient in chronically sun-exposed skin than in non-sun-exposed skin.

Laparoscopic extended pelvic lymph node (LN) dissection as validation of the performance of [11C]-acetate positron emission tomography/computer tomography in the detection of LN metastasis in intermediate- and high-risk prostate cancer

To evaluate the accuracy of the radiopharmaceutical [11C]‐acetate combined with positron emission tomography/computer tomography (acetate‐PET/CT) in lymph node (LN) staging in newly diagnosed prostate cancer cases. A second aim was to evaluate the potential discriminative properties of acetate‐PET/CT in clinical routine.

Assessment of Whether Patients' Knowledge, Satisfaction, and Experience Regarding Their 18F-Fluoride PET/CT Examination Affects Image Quality.

The aim of this study was to investigate patients’ previous knowledge, satisfaction, and experience regarding an 18F-fluoride PET/CT examination and to explore whether any discomfort or pain during the examination was associated with reduced image quality. A further aim was to explore whether patients’ health-related quality of life (HRQoL) was associated with their satisfaction and experience regarding the examination. Methods: Between November 2011 and April 2013, 50 consecutive patients with a histopathologic diagnosis of prostate cancer who were scheduled for 18F-fluoride PET/CT were asked to participate in the study. A questionnaire was used to collect information on the patients’ previous knowledge and experience regarding the examination. Image quality was assessed according to an arbitrary scale. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and the prostate cancer–specific module (QLQ-PR25) were used to assess HRQoL. Results: Forty-six patients (96%) completed the questionnaire. Twenty-six percent did not at all know what a 18F-fluoride PET/CT examination was. Most (52%–70%) were satisfied to a very high degree with the care provided by the nursing staff but were less satisfied with the information given before the examination. Image quality was similar between patients who were exhausted or claustrophobic during the examination and those who were not. No correlations between HRQoL and the patients’ experience regarding 18F-fluoride PET/CT were found. Conclusion: Most patients were satisfied with the care provided by the nursing staff, but there is still room for improvement, especially regarding the information provided before the examination. A long examination time may be strenuous for the patient, but there was no difference in image quality between patients who felt discomfort or pain during the examination and those who did not.

A novel oral insulin-like growth factor-1 receptor pathway modulator and its implications for patients with non-small cell lung carcinoma: A phase I clinical trial

Background. A phase Ia/b dose-escalation study was performed to characterize the safety, efficacy and pharmacokinetic properties of the oral small molecule insulin-like growth factor-1-receptor pathway modulator AXL1717 in patients with advanced solid tumors. Material and methods. This was a prospective, single-armed, open label, dose-finding phase Ia/b study with the aim of single day dosing (phase Ia) to define the starting dose for multi-day dosing (phase Ib), and phase Ib to define and confirm recommended phase II dose (RP2D) and if possible maximum tolerated dose (MTD) for repeated dosing. Results and Conclusion. Phase Ia enrolled 16 patients and dose escalations up to 2900 mg BID were successfully performed without any dose limiting toxicity (DLT). A total of 39 patients were treated in phase Ib. AXL1717 was well tolerated with neutropenia as the only dose-related, reversible, DLT. RP2D dose was found to be 390 mg BID for four weeks. Some patients, mainly with NSCLC, demonstrated signs of clinical benefit, including four partial tumor responses (one according to RECIST and three according to PET). The 15 patients with NSCLC with treatment duration longer than two weeks with single agent AXL1717 in third or fourth line of therapy showed a median progression-free survival of 31 weeks and overall survival of 60 weeks. Down-regulation of IGF-1R on granulocytes and increases of free serum levels of IGF-1 were seen in patients treated with AXL1717. AXL1717 had an acceptable safety profile and demonstrated promising efficacy in this heavily pretreated patient cohort, especially in patients with NSCLC. RP2D was concluded to be 390 mg BID for four weeks. Trial number is NCT01062620.

An Intraprostatic Modified Release Formulation of Antiandrogen 2-Hydroxyflutamide for Localized Prostate Cancer

Purpose: We investigated the tolerability, safety and antitumor effects of a novel intraprostatic depot formulation of antiandrogen 2‐hydroxyflutamide (in NanoZolid®) in men with localized prostate cancer. Materials and Methods: Two clinical trials, LPC‐002 and LPC‐003, were performed in a total of 47 men. The formulation was injected transrectally into the prostate under ultrasound guidance. In LPC‐002 the effects on prostate specific antigen and prostate volume were measured for 6 months in 24 patients. In LPC‐003 antitumor effects were evaluated by histopathology and magnetic resonance imaging including spectroscopy during 6 or 8 weeks in 23 patients. In each study testosterone and 2‐hydroxyflutamide in plasma were measured as well as quality of life parameters. Results: In LPC‐002 (mean dose 690 mg) a reduction was observed in prostate specific antigen and prostate volume. Average nadir prostate specific antigen and prostate volume were 24.9% and 14.0% below baseline, respectively. When increasing the dose in LPC‐003 to 920 and 1,740 mg, average prostate specific antigen decreased 16% and 23% after 6 and 8 weeks, respectively. Magnetic resonance imaging and magnetic resonance spectroscopy showed morphological changes and a global reduction in metabolite concentrations following treatment, indicating an antitumor response. Injections did not result in hormone related side effects. Three serious adverse events were reported and all resolved with oral antibiotic treatment. Conclusions: Intraprostatic injections of 2‐hydroxyflutamide depot formulations showed antitumor effects, and proved to be safe and tolerable. However, for better anticancer effects higher doses and better dose distribution are suggested.