Incidence of Idiopathic Intracranial Hypertension in Individuals With Gonadotropin-Releasing Hormone Analogue Treatment for Gender Dysphoria in Sweden.

This cohort study examines the incidence of idiopathic intracranial hypertension (IHH) among individuals in Sweden undergoing gonadotropin-releasing hormone analogue (GnRHa) treatment for gender dysphoria.

Testosterone replacement in prostate cancer survivors with testosterone deficiency: Study protocol of a randomized controlled trial.

BACKGROUND: Most men diagnosed with prostate cancer today have organ-confined disease and low risk of disease recurrence after radical prostatectomy. Testosterone deficiency in prostate cancer survivors contributes to impaired health-related quality of life but testosterone treatment is viewed as a contraindication in this population. OBJECTIVES: We describe the design of the first randomized trial to determine the safety and efficacy of testosterone treatment in men who have undergone prostatectomy for non-aggressive prostate cancer and have symptomatic testosterone deficiency. METHODS: Surviving Prostate cancer while Improving quality of life through Rehabilitation with Testosterone Trial is a randomized, placebo-controlled, double-blind, parallel group trial in 142 men, ≥ 40 years, who have undergone radical prostatectomy for organ-confined prostate cancer, Gleason score ≤ 7 (3+4), Stage pT2, N0, M0 lesions and have symptomatic testosterone deficiency and undetectable prostate specific antigen for > 2 years after surgery. Eligible participants are randomized to weekly intramuscular injections of 100-mg testosterone cypionate or placebo for 12 weeks and followed for another 12 weeks. Primary endpoint is change from baseline in sexual activity. Secondary outcomes include change in sexual desire, erectile function, energy, lean and fat mass, physical and cognitive performance. Safety is assessed by monitoring prostate-specific antigen, lower urinary tract symptoms, hemoglobin, and adverse events. RESULTS: The trial is being conducted at two trial sites in Boston, MA and Baltimore, MD. As of July 30, 2022, 42 participants have been randomized. No prostate-specific antigen or clinical recurrence has been noted to-date. DISCUSSION: Recruitment was slowed by coronavirus disease 2019-related closures, slow subsequent ramp-up of research activities, and patient concerns about safety of testosterone treatment. Despite these challenges, participant retention has been high. CONCLUSION: The Surviving Prostate cancer while Improving quality of life through Rehabilitation with Testosterone Trial, a placebo-controlled, randomized trial, will determine whether testosterone replacement therapy is safe and efficacious in correcting symptoms of testosterone deficiency in prostate cancer survivors, and potentially inform clinical practice.

Long term outcome after toxic nodular goitre.

BACKGROUND: The purpose of treating toxic nodular goitre (TNG) is to reverse hyperthyroidism, prevent recurrent disease, relieve symptoms and preserve thyroid function. Treatment efficacies and long-term outcomes of antithyroid drugs (ATD), radioactive iodine (RAI) or surgery vary in the literature. Symptoms often persist for a long time following euthyroidism, and previous studies have demonstrated long-term cognitive and quality of life (QoL) impairments. We report the outcome of treatment, rate of cure (euthyroidism and hypothyroidism), and QoL in an unselected TNG cohort. METHODS: TNG patients (n = 638) de novo diagnosed between 2003-2005 were invited to engage in a 6-10-year follow-up study. 237 patients responded to questionnaires about therapies, demographics, comorbidities, and quality of life (ThyPRO). Patients received ATD, RAI, or surgery according clinical guidelines. RESULTS: The fraction of patients cured with one RAI treatment was 89%, and 93% in patients treated with surgery. The rate of levothyroxine supplementation for RAI and surgery, at the end of the study period, was 58% respectively 64%. Approximately 5% of the patients needed three or more RAI treatments to be cured. The patients had worse thyroid-related QoL scores, in a broad spectrum, than the general population. CONCLUSION: One advantage of treating TNG with RAI over surgery might be lost due to the seemingly similar incidence of hypothyroidism. The need for up to five treatments is rarely described and indicates that the treatment of TNG can be more complex than expected. This circumstance and the long-term QoL impairments are reminders of the chronic nature of hyperthyroidism from TNG.

Towards definitions of critical illness and critical care using concept analysis.

OBJECTIVE: As 'critical illness' and 'critical care' lack consensus definitions, this study aimed to explore how the concepts' are used, describe their defining attributes, and propose potential definitions. DESIGN AND METHODS: We used the Walker and Avant approach to concept analysis. The uses and definitions of the concepts were identified through a scoping review of the literature and an online survey of 114 global clinical experts. We used the Arksey and O'Malley framework for scoping reviews and searched in PubMed and Web of Science with a strategy including terms around critical illness/care and definitions/etymologies limited to publications in English between 1 January 2008 and 1 January 2020. The experts were selected through purposive sampling and snowballing, with 36.8% in Africa, 25.4% in Europe, 22.8% in North America, 10.5% in Asia, 2.6% in South America and 1.8% in Australia. They worked with anaesthesia or intensive care 59.1%, emergency care 15.8%, medicine 9.5%, paediatrics 5.5%, surgery 4.7%, obstetrics and gynaecology 1.6% and other specialties 3.9%. Through content analysis of the data, we extracted codes, categories and themes to determine the concepts' defining attributes and we proposed potential definitions. To assist understanding, we developed model, related and contrary cases concerning the concepts, we identified antecedents and consequences to the concepts, and defined empirical referents. RESULTS: Nine and 13 articles were included in the scoping reviews of critical illness and critical care, respectively. A total of 48 codes, 14 categories and 4 themes were identified in the uses and definitions of critical illness and 60 codes, 13 categories and 5 themes for critical care. The defining attributes of critical illness were a high risk of imminent death; vital organ dysfunction; requirement for care to avoid death; and potential reversibility. The defining attributes of critical care were the identification, monitoring and treatment of critical illness; vital organ support; initial and sustained care; any care of critical illness; and specialised human and physical resources. The defining attributes led to our proposed definitions of critical illness as, 'a state of ill health with vital organ dysfunction, a high risk of imminent death if care is not provided and the potential for reversibility', and of critical care as, 'the identification, monitoring and treatment of patients with critical illness through the initial and sustained support of vital organ functions.' CONCLUSION: The concepts critical illness and critical care lack consensus definitions and have varied uses. Through concept analysis of uses and definitions in the literature and among experts, we have identified the defining attributes of the concepts and proposed definitions that could aid clinical practice, research and policy-making.

Predicting outcomes of cross-sex hormone therapy in transgender individuals with gender incongruence based on pre-therapy resting-state brain connectivity.

Individuals with gender incongruence (GI) experience serious distress due to incongruence between their gender identity and birth-assigned sex. Sociological, cultural, interpersonal, and biological factors are likely contributory, and for some individuals medical treatment such as cross-sex hormone therapy and gender-affirming surgery can be helpful. Cross-sex hormone therapy can be effective for reducing body incongruence, but responses vary, and there is no reliable way to predict therapeutic outcomes. We used clinical and MRI data before cross-sex hormone therapy as features to train a machine learning model to predict individuals' post-therapy body congruence (the degree to which photos of their bodies match their self-identities). Twenty-five trans women and trans men with gender incongruence participated. The model significantly predicted post-therapy body congruence, with the highest predictive features coming from the cingulo-opercular (R2 = 0.41) and fronto-parietal (R2 = 0.30) networks. This study provides evidence that hormone therapy efficacy can be predicted from information collected before therapy, and that patterns of functional brain connectivity may provide insights into body-brain effects of hormones, affecting one's sense of body congruence. Results could help identify the need for personalized therapies in individuals predicted to have low body-self congruence after standard therapy.

PALLiON - PALLiative care Integrated in ONcology: study protocol for a Norwegian national cluster-randomized control trial with a complex intervention of early integration of palliative care.

BACKGROUND: Several publications have addressed the need for a systematic integration of oncological care focused on the tumor and palliative care (PC) focused on the patient with cancer. The exponential increase in anticancer treatments and the high number of patients living longer with advanced disease have accentuated this. Internationally, there is now a persuasive argument that introducing PC early during anticancer treatment in patients with advanced disease has beneficial effects on symptoms, psychological distress, and survival. METHODS: This is a national cluster-randomized trial (C-RCT) in 12 Norwegian hospitals. The trial investigates effects of early, systematic integration of oncology and specialized PC in patients with advanced cancer in six intervention hospitals compared with conventional care in six. Hospitals are stratified on the size of local catchment areas before randomization. In the intervention hospitals, a three-part complex intervention will be implemented. The backbone of the intervention is the development and implementation of patient-centered care pathways that contain early, compulsory referral to PC and regular and systematic registrations of symptoms. An educational program must be completed before patient inclusion. A total of 680 patients with advanced cancer and one caregiver per patient are included when patients come for start of last line of chemotherapy, defined according to national treatment guidelines. Data registration, clinical variables, and patient- and caregiver-reported outcomes take place every 2 months for 1 year or until death. The primary outcome is use of chemotherapy in the last 3 months of life by comparing the proportion of patients who receive this in the intervention and control groups. Primary outcome is use of chemotherapy in the last 3 months before death, i.e. number of patients. Secondary outcomes are initiation, discontinuation and number of cycles, last 3 months of life, administration of other medical interventions in the last month of life, symptom burden, quality of life (QoL), satisfaction with information and follow-up, and caregiver health, QoL, and satisfaction with care. DISCUSSION: Results from this C-RCT will be used to raise the awareness about the positive outcomes of early provision of specialized palliative care using pathways for patients with advanced cancer receiving medical anticancer treatment. The long-term clinical objective is to integrate these patient-centered pathways in Norwegian cancer care. The specific focus on the patient and family and the organization of a predictable care trajectory is consistent with current Norwegian strategies for cancer care. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03088202. Registered on 23 March 2017.

The Long-Term Outcome of Treatment for Graves' Hyperthyroidism.

Background: The treatment efficacy of antithyroid drug (ATD) therapy, radioactive iodine (131I), or surgery for Graves' hyperthyroidism is well described. However, there are a few reports on the long-term total outcome of each treatment modality regarding how many require levothyroxine supplementation, the need of thyroid ablation, or the individual patient's estimation of their recovery. Methods: We conducted a pragmatic trial to determine the effectiveness and adverse outcome in a patient cohort newly diagnosed with Graves' hyperthyroidism between 2003 and 2005 (n = 2430). The patients were invited to participate in a longitudinal study spanning 8 ± 0.9 years (mean ± standard deviation) after diagnosis. We were able to follow 1186 (60%) patients who had been treated with ATD, 131I, or surgery. We determined the mode of treatment, remission rate, recurrence, quality of life, demographic data, comorbidities, and lifestyle factors through questionnaires and a review of the individual's medical history records. Results: At follow-up, the remission rate after first-line treatment choice with ATD was 45.3% (351/774), with 131I therapy 81.5% (324/264), and with surgery 96.3% (52/54). Among those patients who had a second course of ATD, 29.4% achieved remission (vs. the 45.3% after the first course of ATD). The total number of patients who had undergone ablative treatment was 64.3% (763/1186), of whom 23% (278/1186) had received surgery, 43% (505/1186) had received 131I therapy, including 2% (20/1186) who had received both surgery and 131I. Patients who received ATD as first-line treatment and possibly additional ATD had 49.7% risk (385/774) of having undergone ablative treatment at follow-up. Levothyroxine replacement was needed in 23% (81/351) of the initially ATD treated in remission, in 77.3% (204/264) of the 131I treated, and in 96.2% (50/52) of the surgically treated patients. Taken together after 6-10 years, and all treatment considered, normal thyroid hormone status without thyroxine supplementation was only achieved in 35.7% (423/1186) of all patients and in only 40.3% of those initially treated with ATD. The proportion of patients that did not feel fully recovered at follow-up was 25.3%. Conclusion: A patient selecting ATD therapy as the initial approach in the treatment of Graves' hyperthyroidism should be informed that they have only a 50.3% chance of ultimately avoiding ablative treatment and only a 40% chance of eventually being euthyroid without thyroid medication. Surprisingly, 1 in 4 patients did not feel fully recovered after 6-10 years. The treatment for Graves' hyperthyroidism, thus, has unexpected long-term consequences for many patients.

Impaired Quality of Life After Radioiodine Therapy Compared to Antithyroid Drugs or Surgical Treatment for Graves' Hyperthyroidism: A Long-Term Follow-Up with the Thyroid-Related Patient-Reported Outcome Questionnaire and 36-Item Short Form Health Status Survey.

BACKGROUND: Hyperthyroidism is known to have a significant impact on quality of life (QoL), at least in the short term. The purpose of the present study was to assess QoL in patients 6-10 years after treatment for Graves' disease (GD) with radioiodine (RAI) compared to those treated with thyroidectomy or antithyroid drugs (ATD) as assessed with both thyroid-specific Thyroid-Related Patient-Reported Outcome (ThyPRO) questionnaire and general (36-item Short Form Health Status) QoL survey. METHODS: The study evaluated 1186 GD patients in a sub-cohort from an incidence study 2003-2005 who had been treated according to routine clinical practice at seven participating centers. Patients were included if they had returned the ThyPRO (n = 975) and/or the 36-item Short Form Health Status survey questionnaire (n = 964) and informed consent at follow-up. Scores from ThyPRO were compared to scores from a general population sample (n = 712) using multiple linear regression adjusting for age and sex as well as multiple testing. Treatment-related QoL outcome for ATD, RAI, and surgery were compared, including adjustment for the number of treatments received, sex, age, and comorbidity. RESULTS: Regardless of treatment modality, patients with GD had worse thyroid-related QoL 6-10 years after diagnosis compared to the general population. Patients treated with RAI had worse thyroid-related and general QoL than patients treated with ATD or thyroidectomy on the majority of QoL scales. Sensitivity analyses supported the relative negative comparative effects of RAI treatment on QoL in patients with hyperthyroidism. CONCLUSIONS: GD is associated with a lower QoL many years after treatment compared to the general population. In a previous small randomized controlled trial, no difference was found in patient satisfaction years after ATD, RAI, or surgery. Now, it is reported that in a large non-randomized cohort, patients who received RAI had adverse scores on ThyPRO and 36-item Short Form Health Status survey. These findings in a Swedish population are limited by comparison to normative data from Denmark, older age, and possibly a more prolonged course in those patients who received RAI, and a lack of information regarding thyroid status at the time of evaluation. The way RAI may adversely affect QoL is unknown, but since the results may be important for future considerations regarding treatment options for GD, they need to be substantiated in further studies.

Supporting sexuality and improving sexual function in transgender persons.

Sexuality is important for most cisgender as well as transgender persons and is an essential aspect of quality of life. For both the patient and their clinicians, managing gender dysphoria includes establishing a comfortable relationship with sexual health issues, which can evolve throughout the course of gender-affirming treatment. Gender-affirming endocrine treatment of transgender men and women has considerable effects on sex drive and sexual function. Gender-affirming surgery (GAS) can improve body satisfaction and ease gender dysphoria, but surgery itself can be associated with sexual sequelae associated with physical constraints of the new genitals or postsurgical pain, psychological difficulties with accepting the new body, or social aspects of having changed gender. In general, a positive body image is associated with better sexual function and satisfaction, but satisfaction with sexual function after GAS can be present despite dissatisfaction with the surgery and vice versa. Factors involved in the integrated experience of gender-affirming treatment and the way in which sexuality is perceived are complex, and supporting sexuality and improving sexual function in transgender patients is, correspondingly, multifaceted. As the transgender patient moves through their life before, during, and after gender-affirming treatment, sexuality and sexual function should be considered and maximized at all stages in order to improve quality of life.

Association between the reported intensity of an acute symptom at first prehospital assessment and the subsequent outcome: a study on patients with acute chest pain and presumed acute coronary syndrome.

BACKGROUND: To decrease the morbidity burden of cardiovascular disease and to avoid the development of potentially preventable complications, early assessment and treatment of acute coronary syndrome (ACS) are important. The aim of this study has therefore been to explore the possible association between patients' estimated intensity of chest pain when first seen by the ambulance crew in suspected ACS, and the subsequent outcome before and after arrival in hospital. METHODS: Data was collected both prospectively and retrospectively. The inclusion criteria were chest pain raising suspicion of ACS and a reported intensity of pain ≥4 on the visual analogue scale. RESULTS: All in all, 1603 patients were included in the study. Increased intensity of chest pain was related to: 1) more heart-related complications before hospital admission; 2) a higher proportion of heart failure, anxiety and chest pain after hospital admission; 3) a higher proportion of acute myocardial infarction and 4) a prolonged hospitalisation. However, there was no significant association with mortality neither in 30 days nor in three years. Adjustment for possible confounders including age, a history of smoking and heart failure showed similar results. CONCLUSION: The estimated intensity of chest pain reported by the patients on admission by the ambulance team was associated with the risk of complications prior to hospital admission, heart failure, anxiety and chest pain after hospital admission, the final diagnosis and the number of days in hospital. TRIAL REGISTRATION: ClinicalTrials.gov 151:2008/4564 Identifier: NCT00792181. Registred 17 November 2008 'retrospectively registered'.

Salvage radiation therapy following radical prostatectomy. A national Danish study.

BACKGROUND: The purpose of this observational cohort study was to evaluate the outcome and prognostic factors following salvage radiotherapy (SRT) in a consecutive national cohort. MATERIAL AND METHODS: Between 2006 and 2010, 259 patients received SRT in Denmark. Patient- and cancer-related characteristics were retrospectively retrieved from patient charts. The primary end point was biochemical progression-free survival (b-PFS). RESULTS: At the end of follow-up, 51% of the patients displayed a prostate-specific antigen (PSA) level <0.1 ng/ml. The three-year b-PFS rate for the total cohort was 57.0%. Nearly half of the patients (44%) received androgen deprivation therapy (ADT) in combination with SRT. Positive surgical tumour margins (p = 0.025) and ADT (p = 0.001) were the only markers independently correlated with b-PFS. In patients who received SRT without ADT, both a pre-SRT PSA level ≤0.5 ng/ml (p = 0.003) and pathological tumour stage T1-T2 (p = 0.036) independently correlated with b-PFS. Moreover, a duration between radical prostatectomy (RP) and SRT ≤29 months (p = 0.035) independently correlated with b-PFS in patients treated with ADT in combination with RT. CONCLUSIONS: In patients treated for biochemical failure after RP, positive surgical tumour margins and PSA levels ≤0.5 ng/mL at the time of SRT were associated with a favourable outcome. Despite less favourable tumour characteristics, patients receiving SRT and ADT demonstrated improved b-PFS, and in particular, patients with PSA levels >0.2 ng/ml benefitted from additional ADT.

Presurgical functional magnetic resonance imaging in patients with brain tumors.

BACKGROUND: Clinical functional magnetic resonance imaging (fMRI) is still an upcoming diagnostic tool because it is time-consuming to perform the post-scan calculations and interpretations. A standardized and easily used method for the clinical assessment of fMRI scans could decrease the workload and make fMRI more attractive for clinical use. PURPOSE: To evaluate a standardized clinical approach for distance measurement between benign brain tumors and eloquent cortex in terms of the ability to predict pre- and postoperative neurological deficits after intraoperative neuronavigation-assisted surgery. MATERIAL AND METHODS: A retrospective study of 34 patients. The fMRI data were reanalyzed using a standardized distance measurement procedure combining data from both fMRI and three-dimensional T1 MRI scans. The pre- and postoperative neurological status of each patient was obtained from hospital records. Data analysis was performed using logistic regression analysis to determine whether the distance measured between the tumor margin and fMRI activity could serve as a predictor for neurological deficits. RESULTS: An odds ratio of 0.89 mm(-1) (P = 0.03) was found between the risk of preoperative neurological motor deficits and the tumor-fMRI distance. An odds ratio of 0.82 mm(-1) (P = 0.04) was found between the risk of additional postoperative neurological motor deficits and the tumor-fMRI distance. The tumor was radically removed in 10 cases; five patients experienced additional postoperative motor deficits (tumor-fMRI distance <18 mm) and five did not (tumor-fMRI distance >18 mm) (P = 0.008). CONCLUSION: This study indicates that the distance measured between the tumor margin and fMRI activation could serve as a valuable predictor of neurological motor deficits.

Docetaxel rechallenge after an initial good response in patients with metastatic castration-resistant prostate cancer.

OBJECTIVE: To evaluate the benefit of docetaxel rechallenge in patients with metastatic castration-resistant prostate cancer (mCRPC) relapsing after an initial good response to first-line docetaxel. PATIENTS AND METHODS: We retrospectively reviewed the records of consecutive patients with mCRPC with a good response to first-line docetaxel [serum prostate specific antigen (PSA) decrease ≥50%; no clinical/radiological progression]. We analysed the impact of management at relapse (docetaxel rechallenge or non-taxane-based therapy) on PSA response, symptomatic response (performance status/pain/analgesic consumption), and overall survival (OS). We used multivariate stepwise logistic regression to analyse potential predictors of a favourable outcome. RESULTS: We identified 270 good responders to first-line docetaxel. The median progression-free interval (PFI) was 6 months from the last docetaxel dose. At relapse, 223 patients were rechallenged with docetaxel (82.5%) and 47 received non-taxane-based therapy. There was no significant difference in median OS {18.2 [95% confidence interval (CI) 16.1-22.00] and 16.8 [95%CI 13.4-21.5] months, respectively, P = 0.35}. However, good PSA response and symptom relief/stable disease were more frequent on docetaxel rechallenge (40.4% vs 10.6%, P < 0.001 for PSA). A PFI of >6 months and added estramustine predicted a good PSA response and symptomatic response on docetaxel rechallenge but only a PFI of >6 months predicted longer OS. Haemoglobin (<13 g/dL) and pain were associated with reduced OS. Docetaxel rechallenge increased the incidence of grade ≥3 sensory neuropathy, nail disorders and asthenia/fatigue. CONCLUSIONS: Docetaxel rechallenge is a management option for responders to docetaxel with a PFI of >6 months, but did not prolong survival. Potential benefits should be weighed against the risk of cumulative toxicity.

A comparison of morbidity following conformal versus intensity-modulated radiotherapy for urinary bladder cancer.

BACKGROUND: In radiotherapy (RT) of urinary bladder cancer, the use of intensity-modulated RT (IMRT) opens for sparing of considerable intestinal volumes. The purpose of the present study was to investigate the acute and late toxicities following either conformal RT (CRT) or IMRT for bladder cancer, and to correlate the toxicities to dose-volume parameters. MATERIAL AND METHODS: The study included 116 consecutively treated patients with muscle-invasive bladder cancer who received either CRT (n = 66) or IMRT (n = 50) during 2007-2010. Acute side effects were retrospectively collected whereas late effects were assessed by a cross-sectional evaluation by telephone interview of 44 recurrence-free patients. Acute and late toxicities were scored according to the Common Terminology Criteria for Adverse Event (CTCAE) version 3.0. RESULTS: Acute diarrhoea grade ≥ 2 was more frequent in patients treated by CRT (56%) compared to IMRT (30%) (p = 0.008). Logistic regression analysis showed a correlation between acute diarrhoea and bowel cavity dose-volume parameters in the 10-50 Gy range. Severe late toxicity (grade ≥ 3) was recorded in 10% of the total cohort, with no statistical difference between the IMRT and CRT groups. CONCLUSION: Patients treated with IMRT for bladder cancer had significantly less acute diarrhoea compared to those treated with CRT, but there was no significant difference in late morbidity between the groups. The risk of acute diarrhoea was related to the volume of bowel irradiated.

MRI target delineation may reduce long-term toxicity after prostate radiotherapy.

BACKGROUND AND PURPOSE: Aiming for minimal toxicity after radical prostate cancer (PC) radiotherapy (RT), magnetic resonance imaging (MRI) target delineation could be a possible benefit knowing that clinical target volumes (CTV) are up to 30% smaller, when CTV delineation on MRI is compared to standard computed tomography (CT). This study compares long-term toxicity using CT or MRI delineation before PC RT. MATERIAL AND METHODS: Urinary and rectal toxicity assessments 36 months after image-guided RT (78 Gy) using CTC-AE scores in two groups of PC patients. Peak symptom score values were registered. One group of patients (n=72) had standard CT target delineation and gold markers as fiducials. Another group of patients (n=73) had MRI target delineation and a nickel-titanium stent as fiducial. RESULTS: At 36 months no difference in overall survival (92% in both groups, p=0.29) or in PSA-relapse free survival was found between the groups (MRI=89% and CT=94%, p=0.67). A significantly smaller CTV was found in the MRI group (p=0.02). Urinary retention and frequency were significantly reduced in the MRI group (p=0.03 in the matter of both). The overall urinary and rectal toxicity did not differ between the two groups. CONCLUSION: MRI delineation leads to a significantly reduced CTV. Significantly lower urinary frequency and urinary retention toxicity scores were observed following MRI delineation. The study did not find significant differences in overall urinary or rectal toxicity between the two groups. PSA-relapse survival did not differ between the two groups at 36 months.

Differences in supratentorial white matter diffusion after radiotherapy--new biomarker of normal brain tissue damage?

INTRODUCTION: Therapy-induced injury to normal brain tissue is a concern in the treatment of all types of brain tumours. The purpose of this study was to investigate if magnetic resonance diffusion tensor imaging (DTI) could serve as a potential biomarker for the assessment of radiation-induced long-term white matter injury. MATERIAL AND METHODS: DTI- and T1-weighted images of the brain were obtained in 19 former radiotherapy patients [nine men and 10 women diagnosed with astrocytoma (4), pituitary adenoma (6), meningioma (8) and craniopharyngioma (1), average age 57.8 (range 35-71) years]. Average time from radiotherapy to DTI scan was 4.6 (range 2.0-7.1) years. NordicICE software (NIC) was used to calculate apparent diffusion coefficient maps (ADC-maps). The co-registration between T1 images and ADC-maps were done using the auto function in NIC. The co-registration between the T1 images and the patient dose plans were done using the auto function in the treatment planning system Eclipse from Varian. Regions of interest were drawn on the T1-weighted images in NIC based on isocurves from Eclipse. Data was analysed by t-test. Estimates are given with 95% CI. RESULTS: A mean ADC difference of 4.6(0.3;8.9)× 10(-5) mm(2)/s, p = 0.03 was found between paired white matter structures with a mean dose difference of 31.4 Gy. Comparing the ADC-values of the areas with highest dose from the paired data (dose > 33 Gy) with normal white matter (dose < 5 Gy) resulted in a mean dose difference of 44.1 Gy and a mean ADC difference of 7.87(3.15;12.60)× 10(-5) mm(2)/s, p = 0.003. Following results were obtained when looking at differences between white matter mean ADC in average dose levels from 5 to 55 Gy in steps of 10 Gy with normal white matter mean ADC: 5 Gy; 1.91(-1.76;5.58)× 10(-5) mm(2)/s, p = 0.29; 15 Gy; 5.81(1.53;10.11)× 10(-5) mm(2)/s, p = 0.01; 25 Gy; 5.80(2.43;9.18)× 10(-5) mm(2)/s, p = 0.002; 35 Gy; 5.93(2.89;8.97)× 10(-5) mm(2)/s, p = 0.0007; 45 Gy; 4.32(-0.24;8.89)× 10(-5) mm(2)/s, p = 0.06; 55 Gy; -4.04(-14.96;6.89)× 10(-5) mm(2)/s, p = 0.39. CONCLUSION: The results indicate that the structural integrity of white matter, assessed by ADC-values based on DTI, undergoes changes after radiation therapy starting as early as total dose levels between 5 and 15 Gy.

A phase II trial with bevacizumab and irinotecan for patients with primary brain tumors and progression after standard therapy.

UNLABELLED: The combination of irinotecan and bevacizumab has shown efficacy in the treatment of recurrent glioblastoma multiforme (GBM). A prospective, phase II study of 85 patients with various recurrent brain tumors was carried out. Primary endpoints were progression free survival (PFS) and response rate. MATERIAL AND METHODS: Patients with recurrent primary brain tumors with performance status 0-2 were eligible. Intravenous bevacizumab 10 mg/kg and irinotecan 125/340 mg/m(2) were administered every 14 days. Evaluation was carried out every eight weeks using MRI and Macdonald response criteria. Treatment was continued until progression. RESULTS: In total 85 patients were included with the following histologies: GBM (n = 32), glioma WHO gr. III (n = 33), glioma WHO gr. II (n = 12) and others (n = 8). Patients received a median of four cycles. ORR (overall response rate) for glioblastoma was 25% and 59% achieved stable disease (SD). Median PFS was 5.2 months. For grade III gliomas ORR was 21% and 45% had SD. Median PFS was 3.7 months. No objective responses occurred in grade II gliomas. In the non-glioma population, one PR as well as several long PFS times were observed. DISCUSSION AND CONCLUSION: The combination of bevacizumab and irinotecan is well tolerated and moderately efficacious in glioblastoma and glioma WHO gr. III. A majority of patients achieve at least disease stabilization. Prolonged progression-free survival in non-glioma patients warrants further research.

Clinical results from first use of prostate stent as fiducial for radiotherapy of prostate cancer.

PURPOSE: A clinical feasibility study using a removable prostate stent as fiducial for image-guided radiotherapy (IGRT) of localized prostate cancer (PC). MATERIAL AND METHODS: The study included patients with local or locally advanced PC. The clinical target volume (CTV) was outlined on magnetic resonance (MR) images co-registered to planning computer tomography (CT) images. Daily online IGRT was delivered using the stent as fiducial. Risk of migration was estimated using multiple MR. Acute urinary toxicity was scored using the international prostate symptom score (IPSS). Late gastro-intestinal (GI) and genito-urinary (GU) toxicity was scored using the Radio Therapy Oncology Group (RTOG) score, biochemical failure (BF) was defined as an elevation of prostate specific antigen (PSA) above nadir plus 2 ng/ml after radiotherapy. RESULTS: One hundred men were enrolled in the study. Ninety completed radiotherapy with the stent as fiducial. No migration of the stent was seen, but three cases of dislocation of the stent to the bladder were observed. Acute urinary toxicity based on IPSS was comparable to toxicity in patients who had gold markers (GM) as fiducials. Removal of the stent was associated with a high frequency of urinary retention. Late GI and GU toxicity and BF were comparable to those of other studies, but longer observation time is needed. CONCLUSIONS: This study reports the first clinical results of using a prostate stent as fiducial. No migration of the stent observed. Dislocation of the stent to the urinary bladder was observed in three cases, requiring removal of the stent and insertion of a new fiducial. Acute toxicity during radiotherapy evaluated from IPSS was comparable to toxicity in patients with GM. Removal of the stent was associated with a high frequency of post procedural urinary retention. Late toxicity and BF were comparable to those of other studies, though longer observation time is needed.

Identification of MOAG-4/SERF as a regulator of age-related proteotoxicity.

Fibrillar protein aggregates are the major pathological hallmark of several incurable, age-related, neurodegenerative disorders. These aggregates typically contain aggregation-prone pathogenic proteins, such as amyloid-beta in Alzheimer's disease and alpha-synuclein in Parkinson's disease. It is, however, poorly understood how these aggregates are formed during cellular aging. Here we identify an evolutionarily highly conserved modifier of aggregation, MOAG-4, as a positive regulator of aggregate formation in C. elegans models for polyglutamine diseases. Inactivation of MOAG-4 suppresses the formation of compact polyglutamine aggregation intermediates that are required for aggregate formation. The role of MOAG-4 in driving aggregation extends to amyloid-beta and alpha-synuclein and is evolutionarily conserved in its human orthologs SERF1A and SERF2. MOAG-4/SERF appears to act independently from HSF-1-induced molecular chaperones, proteasomal degradation, and autophagy. Our results suggest that MOAG-4/SERF regulates age-related proteotoxicity through a previously unexplored pathway, which will open up new avenues for research on age-related, neurodegenerative diseases.

Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: a phase II trial.

The aim of this clinical trial was to investigate safety and efficacy when combining cetuximab with bevacizumab and irinotecan in patients with recurrent primary glioblastoma multiforme (GBM). Patients were included with recurrent primary GBM and progression within 6 months of ending standard treatment (radiotherapy and temozolomide). Bevacizumab and irinotecan were administered IV every 2 weeks. The first 10 patients received bevacizumab 5 mg/kg, but this was increased to 10 mg/kg after interim safety analysis. Irinotecan dose was based on whether patients were taking enzyme-inducing antiepileptic drugs or not: 340 and 125 mg/m(2), respectively. Cetuximab 400 mg/m(2) as loading dose followed by 250 mg/m(2) weekly was administered IV. Forty-three patients were enrolled in the trial, of which 32 were available for response. Radiographic responses were noted in 34%, of which 2 patients had complete responses and 9 patients had partial responses. The 6-month progression-free survival probability was 30% and median overall survival was 29 weeks (95% CI: 23-37 weeks). One patient had lacunar infarction, 1 patient had multiple pulmonary embolisms, and 3 patients had grade 3 skin toxicity, for which 1 patient needed plastic surgery. One patient was excluded due to suspicion of interstitial lung disease. Three patients had deep-vein thrombosis; all continued on study after adequate treatment. Cetuximab in combination with bevacizumab and irinotecan in recurrent GBM is well tolerated except for skin toxicity, with an encouraging response rate. However, the efficacy data do not seem to be superior compared with results with bevacizumab and irinotecan alone.