Statistical Analysis of Gastric Cancer Cells Response to Broadband Terahertz Radiation with and without Contrast Nanoparticles.

The paper describes the statistical analysis of the response of gastric cancer cells and normal cells to broadband terahertz radiation up to 4 THz, both with and without the use of nanostructured contrast agents. The THz spectroscopy analysis was comparatively performed under the ATR procedure and transmission measurement procedure. The statistical analysis was conducted towards multiple pairwise comparisons, including a support medium (without cells) versus a support medium with nanoparticles, normal cells versus normal cells with nanoparticles, and, respectively, tumor cells versus tumor cells with nanoparticles. When generally comparing the ATR procedure and transmission measurement procedure for a broader frequency domain, the differentiation between normal and tumor cells in the presence of contrast agents is superior when using the ATR procedure. THz contrast enhancement by using contrast agents derived from MRI-related contrast agents leads to only limited benefits and only for narrow THz frequency ranges, a disadvantage for THz medical imaging.

The impact of palliative care on the frailty-stroke continuum: from theoretical concepts to practical aspects.

With a constant increase in prevalence and incidence worldwide, stroke remains a public health issue in the 21st century. Additionally, population aging inevitably leads to increased vulnerability in the general population, a clinical state known as frailty. While there are adequate guidelines on the treatment of stroke in the acute setting, there are a lot of gaps regarding the chronic management of stroke patients, particularly the frail ones. From the therapeutic point of view, palliative care could be the key to offering complex and individualized treatment to these frail chronic stroke patients. In the context of the heterogeneous data and incomplete therapeutic guidelines, this article provides a new and original perspective on the topic, aiming to increase awareness and understanding and improve palliative care management in stroke patients. Based on current knowledge, the authors describe a new concept called the frailty-stroke continuum and offer a detailed explanation of the intricate stroke-frailty connection in the first part. After understanding the role of palliative care in managing this kind of patients, the authors discuss the most relevant practical aspects aiming to offer an individualized framework for daily clinical practice. The novel approach consists of developing a four-step scale for characterizing frail stroke patients, with the final aim of providing personalized treatment and correctly evaluating prognosis. By pointing out the limitations of current guidelines and the challenges of new research directions, this article opens the pathway for the better evaluation of frail stroke patients, offering a better perception of patients' prognosis.

Iron chelators as a therapeutic option for Alzheimer's disease-A mini-review.

Neurodegenerative disorders, particularly Alzheimer's disease (AD), remain a great challenge regarding the finding of effective treatment, one main reason being the incomplete understanding of their etiology. With many intensely debated hypotheses, a newer approach based on the impact of iron imbalance in sustaining neurodegeneration in the central nervous system becomes increasingly popular. Altered iron homeostasis leads to increased iron accumulation in specific brain areas, explaining the clinical picture of AD patients. Moreover, growing evidence sustains the significant impact of iron metabolism in relationship to other pathological processes encountered in the AD-affected brain, such as the amyloidogenic pathway, chronic inflammation, or oxidative stress. In this context, this mini-review aims to summarize the novel data from the continuously expanding literature on this topic in a didactic manner. Thus, in the first part, the authors briefly highlight the most relevant aspects related to iron absorption, transport, regulation, and elimination at the cerebral level, focusing on the role of the blood-brain barrier and the newer concept of ferroptosis. Subsequently, currently available iron chelation therapies are discussed, including an overview of the most relevant clinical trials on this topic. In the final part, based on the latest results from in vitro and in vivo studies, new research directions are suggested to enhance the development of effective antidementia therapies.

Efficient removal of antibodies to adeno-associated viruses by immunoadsorption.

BACKGROUND: Gene therapies based on adeno-associated viruses (AAV) are a therapeutic option to successfully treat monogenetic diseases. However, the influence of pre-existing immunity to AAV can compromise the application of AAV gene therapy, most notably by the presence of neutralizing antibodies (NAb) to AAV. METHODS: In the following study, we investigated to what extent the treatment by immunoadsorption (IA) would reduce the levels of human anti-AAV antibodies to AAV2 and AAV5. To that end, we screened blood sera from 40 patients receiving IA treatment because of underlying autoimmune disease or transplant rejection, with detectable AAV-antibodies in 23 patients (22 by NAb detection, and 1 additionally by anti-AAV5 ELISA analysis). RESULTS: Our results show that IA efficiently depleted anti-AAV2 NAb with a mean reduction of 3.92 ± 1.09 log2 titer steps (93.4%) after three to five single IA treatments, 45% of seropositive subjects had an anti-AAV2 titer below the threshold titer of 1:5 after the IA treatment series. Anti-AAV5 NAb were reduced to below the threshold titer of 1:5 in all but one of five seropositive subjects. Analysis of total anti-AAV5 antibodies by ELISA demonstrated an anti-AAV5 antibody reduction over the IA treatment series of 2.67 ± 1.16 log2 titer steps (84.3%). CONCLUSION: In summary, IA may represent a safe strategy to precondition patients with pre-existing anti-AAV antibodies to make this population eligible for an effective AAV-based gene therapy.

The ENIGI (European Network for the Investigation of Gender Incongruence) Study: Overview of Acquired Endocrine Knowledge and Future Perspectives.

Literature on the efficacy and safety of gender-affirming hormonal treatment (GAHT) in transgender people is limited. For this reason, in 2010 the European Network for the Investigation of Gender Incongruence (ENIGI) study was born. The aim of this review is to summarize evidence emerging from this prospective multicentric study and to identify future perspectives. GAHT was effective in inducing desired body changes in both trans AMAB and AFAB people (assigned male and female at birth, respectively). Evidence from the ENIGI study confirmed the overall safety of GAHT in the short/mid-term. In trans AMAB people, an increase in prolactin levels was demonstrated, whereas the most common side effects in trans AFAB people were acne development, erythrocytosis, and unfavorable changes in lipid profile. The main future perspectives should include the evaluation of the efficacy and safety of non-standardized hormonal treatment in non-binary trans people. Furthermore, long-term safety data on mortality rates, oncological risk, and cardiovascular, cerebrovascular and thromboembolic events are lacking. With this aim, we decided to extend the observation of the ENIGI study to 10 years in order to study all these aspects in depth and to answer these questions.

Dielectrophoretic and Electrical Impedance Differentiation of Cancerous Cells Based on Biophysical Phenotype.

Here, we reported a study on the detection and electrical characterization of both cancer cell line and primary tumor cells. Dielectrophoresis (DEP) and electrical impedance spectroscopy (EIS) were jointly employed to enable the rapid and label-free differentiation of various cancer cells from normal ones. The primary tumor cells that were collected from two colorectal cancer patients, cancer cell lines (SW-403, Jurkat, and THP-1), and healthy peripheral blood mononuclear cells (PBMCs) were trapped first at the level of interdigitated microelectrodes with the help of dielectrophoresis. Correlation of the cells dielectric characteristics that was obtained via electrical impedance spectroscopy (EIS) allowed evident differentiation of the various types of cell. The differentiations were assigned to a "dielectric phenotype" based on their crossover frequencies. Finally, Randles equivalent circuit model was employed for highlighting the differences with regard to a series group of charge transport resistance and constant phase element for cancerous and normal cells.

Is there a need for liver enzyme monitoring in people using gender-affirming hormone therapy?

CONTEXT: Individuals with gender dysphoria can receive gender-affirming hormone therapy. Different guidelines mention a severe risk of liver injury within the first months after the start of treatment with anabolic androgenic steroids, anti-androgens, and oral contraceptives, which is potentially fatal. OBJECTIVE: The incidence of liver injury in a transgender population using gender-affirming hormone therapy. DESIGN: Multicentre prospective study with 1933 transgender individuals, who started with hormone therapy between 2010 and 2020. METHODS: The following parameters were analysed before hormone therapy, after 3 months, and after 12 months of hormone therapy: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT). Both male and female reference values were considered. Liver injury was defined as either an elevation of 2× upper limit of normal (ULN) of ALP, 3× ULN of ALT, or 3× ULN of AST. RESULTS: 889 transgender women and 1044 transgender men were included in the analysis. The incidence of liver injury within 12 months after the start of hormone therapy, without attribution to alcohol abuse, medical history, or comedication was 0.1 and 0.0%. in transgender women according to female and male reference intervals respectively, and 0.6 and 0.4% in transgender men (female and male reference intervals). CONCLUSION: The incidence of liver injury is found to be very low. We, therefore, conclude that liver enzyme monitoring within the frame of the risk of liver injury due to hormone therapy is not necessary for a transgender population.

Lower Serum Estradiol Levels in Assigned Female at Birth Transgender People with Initiation of Testosterone Therapy: Results from the European Network for the Investigation of Gender Incongruence.

Purpose: Concerns have been raised about undesired estrogenic effects in assigned female at birth (AFAB) transgender people on testosterone therapy. How serum estradiol levels change after initiation of testosterone therapy and if these levels should be monitored remain unclear. Methods: This prospective cohort study was part of the European Network for the Investigation of Gender Incongruence. Serum levels of sex steroids were assessed in 746 AFAB transgender people during a 3-year follow-up period, starting at the initiation of hormone treatment. Results: Estradiol levels decreased from median [P25-P75] 45.6 [24.0-102.2] pg/mL to 36.5 [25.0-46.2] pg/mL over 3 years (p < 0.001); a change was already noticeable during the first 3 months (mean -17.1 pg/mL, 95% confidence interval -23.8 to -10.6, p < 0.001). Serum estradiol levels were lower in people without endogenous estradiol production from ovarian source (contraceptive users or post hystero-oophorectomy) at baseline and after 3 months, compared with people with endogenous estradiol production. Using long-acting testosterone undecanoate injections resulted in a more prominent decrease in serum estradiol values over 12 months, compared with short-acting mixed testosterone esters (p < 0.001) or testosterone gel (p = 0.001). Changes in serum estradiol were positively correlated to changes in luteinizing hormone (ρ = 0.107, p < 0.001) and negatively correlated to changes in follicle-stimulating hormone levels (ρ = -0.167, p < 0.001) and body mass index (ρ = -0.082, p < 0.001). Conclusion: Testosterone administration in AFAB transgender people resulted in decreasing serum estradiol levels. Our results suggest that testosterone therapy leads to central suppression of estradiol production, with partial restitution due to aromatization.

Union of light ion therapy centers in Europe (ULICE EC FP7) - Objectives and achievements of joint research activities.

Under the umbrella of the European Network for Light Ion Therapy (ENLIGHT), the project on Union of Light Ion Centers in Europe (ULICE), which was funded by the European Commission (EC/FP7), was carried out from 2009 to 2014. Besides the two pillars on Transnational Access (TNA) and Networking Activities (NA), six work packages formed the pillar on Joint Research Activities (JRA). The current manuscript focuses on the objectives and results achieved within these research work packages: "Clinical Research Infrastructure", "Biologically Based Expert System for Individualized Patient Allocation", "Ion Therapy for Intra-Fractional Moving Targets", "Adaptive Treatment Planning for Ion Radiotherapy", "Carbon Ion Gantry", "Common Database and Grid Infrastructures for Improving Access to Research Infrastructures". The objectives and main achievements are summarized. References to either publications or open access deliverables from the five year project work are given. Overall, carbon ion radiotherapy is still not as mature as photon or proton radiotherapy. Achieved results and open questions are reflected and discussed in the context of the current status of carbon ion therapy and particle and photon beam therapy. Most research topics covered in the ULICE JRA pillar are topical. Future research activities can build upon these ULICE results. Together with the continuous increase in the number of particle therapy centers in the last years ULICE results and proposals may contribute to the further growth of the overall particle therapy field as foreseen with ENLIGHT and new joint initiatives such as the European Particle Therapy Network (EPTN) within the overall radiotherapy community.

Bone Mineral Density Increases in Trans Persons After 1 Year of Hormonal Treatment: A Multicenter Prospective Observational Study.

Sex steroids are important determinants of bone acquisition and bone homeostasis. Cross-sex hormonal treatment (CHT) in transgender persons can affect bone mineral density (BMD). The aim of this study was to investigate in a prospective observational multicenter study the first-year effects of CHT on BMD in transgender persons. A total of 231 transwomen and 199 transmen were included who completed the first year of CHT. Transwomen were treated with cyproterone acetate and oral or transdermal estradiol; transmen received transdermal or intramuscular testosterone. A dual-energy X-ray absorptiometry (DXA) was performed to measure lumbar spine (LS), total hip (TH), and femoral neck (FN) BMD before and after 1 year of CHT. In transwomen, an increase in LS (+3.67%, 95% confidence interval [CI] 3.20 to 4.13%, p < 0.001), TH (+0.97%, 95% CI 0.62 to 1.31%, p < 0.001), and FN (+1.86%, 95% CI 1.41 to 2.31%, p < 0.001) BMD was found. In transmen, TH BMD increased after 1 year of CHT (+1.04%, 95% CI 0.64 to 1.44%, p < 0.001). No changes were observed in FN BMD (-0.46%, 95% CI -1.07 to 0.16%, p = 0.144). The increase in LS BMD was larger in transmen aged ≥50 years (+4.32%, 95% CI 2.28 to 6.36%, p = 0.001) compared with transmen aged <50 years (+0.68%, 95% CI 0.19 to 1.17%, p = 0.007). In conclusion, BMD increased in transgender persons after 1 year of CHT. In transmen of postmenopausal age, the LS BMD increased more than in younger transmen, which may lead to the hypothesis that the increase in BMD in transmen is the result of the aromatization of testosterone to estradiol. © 2017 American Society for Bone and Mineral Research.

Implementation of spot scanning dose optimization and dose calculation for helium ions in Hyperion.

PURPOSE: Helium ions ((4)He) may supplement current particle beam therapy strategies as they possess advantages in physical dose distribution over protons. To assess potential clinical advantages, a dose calculation module accounting for relative biological effectiveness (RBE) was developed and integrated into the treatment planning system Hyperion. METHODS: Current knowledge on RBE of (4)He together with linear energy transfer considerations motivated an empirical depth-dependent "zonal" RBE model. In the plateau region, a RBE of 1.0 was assumed, followed by an increasing RBE up to 2.8 at the Bragg-peak region, which was then kept constant over the fragmentation tail. To account for a variable proton RBE, the same model concept was also applied to protons with a maximum RBE of 1.6. Both RBE models were added to a previously developed pencil beam algorithm for physical dose calculation and included into the treatment planning system Hyperion. The implementation was validated against Monte Carlo simulations within a water phantom using γ-index evaluation. The potential benefits of (4)He based treatment plans were explored in a preliminary treatment planning comparison (against protons) for four treatment sites, i.e., a prostate, a base-of-skull, a pediatric, and a head-and-neck tumor case. Separate treatment plans taking into account physical dose calculation only or using biological modeling were created for protons and (4)He. RESULTS: Comparison of Monte Carlo and Hyperion calculated doses resulted in a γ mean of 0.3, with 3.4% of the values above 1 and γ 1% of 1.5 and better. Treatment plan evaluation showed comparable planning target volume coverage for both particles, with slightly increased coverage for (4)He. Organ at risk (OAR) doses were generally reduced using (4)He, some by more than to 30%. Improvements of (4)He over protons were more pronounced for treatment plans taking biological effects into account. All OAR doses were within tolerances specified in the QUANTEC report. CONCLUSIONS: The biological (4)He model proposed above is a first approach matching biological data published so far. The advantage of (4)He seems to lie in the reduction of dose to surrounding tissue and to OARs. Nevertheless, additional biological experiments and treatment planning studies with larger patient numbers and more tumor indications are necessary to study the possible benefits of helium ion beam therapy in detail.

Chronic fatigue is prevalent and associated with hormonal dysfunction in long-term non-Hodgkin lymphoma survivors treated with radiotherapy to the head and neck region.

The purposes of this study were to assess the prevalence of chronic fatigue (CF) in irradiated survivors of non-Hodgkin lymphoma, analyze for associations between hormonal dysfunction and CF, and to investigate the associations between CF and functioning. Invited survivors were all treated with radiation to the head and neck region, with or without additional chemotherapy. The participants (n=98) responded to questionnaires measuring CF, mental distress (HADS), and functioning (SF-36), and had blood drawn for analyses of four hormonal axes. Hormonal status was categorized as normal, hormone dysfunction in one or more axes, or hormone replacement therapy. A total of 29% of the survivors had CF. In multivariate analyses there was an increased risk of CF among survivors with untreated hormone dysfunction (OR 3.87, 95% CI: 1.20-12.51, p=0.02). Survivors on hormone substitution did not have increased risk for CF compared to survivors with normal hormonal status. CF was significantly associated with reduced functioning.

Hormonal dysfunction is frequent in cancer survivors treated with radiotherapy to the head and neck region.

PURPOSE: Cancer treatment may lead to hormonal dysfunction. Therefore, we assessed the prevalence of dysfunction in four hormonal axes among long-term cancer survivors who received radiotherapy to the head and neck region and analyzed associations between hormonal status and clinical variables. METHODS: We included 140 cancer survivors who received radiotherapy to the head and neck region, either locally or through total body irradiation after a diagnosis of lymphoma, plasmacytoma/multiple myeloma, or carcinoma of the epipharynx. Radiation doses to the pituitary gland and thyroid gland were estimated, and blood samples were collected to analyze hormonal levels. RESULTS: At a median of 16 years after their cancer diagnosis, 46% of cancer survivors showed dysfunction in one hormonal axis, 24% had dysfunction in two axes, and 3% had dysfunction in three axes. Twenty cancer survivors (14%) had hormone levels consistent with pituitary dysfunction. Cancer survivors who had received an estimated 30 Gray (Gy) or more to the pituitary gland had an increased risk for pituitary dysfunction in one of the hormonal axes (odds ratio [OR] 3.16, confidence interval [CI] 1.02-9.87, p = 0.047) and for growth hormone dysfunction alone (OR 2.96, CI 1.02-8.55, p = 0.045). CONCLUSIONS: Abnormal hormone values are frequent after radiotherapy to the head and neck region. IMPLICATIONS FOR CANCER SURVIVORS: Screening for hormonal dysfunction during follow-up might be indicated.

Cross-sex hormone therapy in trans persons is safe and effective at short-time follow-up: results from the European network for the investigation of gender incongruence.

INTRODUCTION: Data on the effects of cross-sex hormone therapy (CHT) are limited due to the low prevalence of gender dysphoria, small number of subjects treated at each center, lack of prospective studies, and wide variations in treatment modalities. AIM: The aim of this study is to report the short-term effects of CHT on hormonal and clinical changes, side effects, and adverse events in trans men (female-to-male gender dysphoric persons) and trans women (male-to-female gender dysphoric persons). METHODS: This was a multicenter 1-year prospective study in 53 trans men and 53 trans women. Trans men received injections of testosterone undecanoate every 3 months. Trans women younger than 45 years received 50 mg cyproterone acetate (CA) and 4 mg estradiol valerate daily, whereas those older than 45 years received 50 mg CA daily together with 100 µg/24 hours transdermal 17-ß estradiol. MAIN OUTCOME MEASURES: Sex steroids, prolactin, liver enzymes, lipids, hematocrit, blood pressure, anthropometrics, Ferriman and Gallwey score, and global acne grading scale were measured. Side effects, adverse events, and desired clinical changes were examined. RESULTS: No deaths or severe adverse events were observed. Two trans men developed erythrocytosis, and two had transient elevation of the liver enzymes. Trans men reported an increase in sexual desire, voice instability, and clitoral pain (all P ≤ 0.01). Testosterone therapy increased acne scores, facial and body hair, and prevalence of androgenetic alopecia. Waist-hip ratio, muscle mass, triglycerides, total cholesterol (C), and LDL-C increased, whereas total body fat mass and HDL-C decreased. Three trans women experienced transient elevation of liver enzymes. A significant increase in breast tenderness, hot flashes, emotionality, and low sex drive was observed (all P ≤ 0.02). Fasting insulin, total body fat mass, and prolactin levels increased, and waist-hip ratio, lean mass, total C, and LDL-C decreased. CONCLUSIONS: Current treatment modalities were effective and carried a low risk for side effects and adverse events at short-time follow-up.

Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC-PGL syndromes: a clinicopathological and molecular analysis.

OBJECTIVE: Although the succinate dehydrogenase (SDH)-related tumor spectrum has been recently expanded, there are only rare reports of non-pheochromocytoma/paraganglioma tumors in SDHx-mutated patients. Therefore, questions still remain unresolved concerning the aforementioned tumors with regard to their pathogenesis, clinicopathological phenotype, and even causal relatedness to SDHx mutations. Absence of SDHB expression in tumors derived from tissues susceptible to SDH deficiency is not fully elucidated. DESIGN AND METHODS: Three unrelated SDHD patients, two with pituitary adenoma (PA) and one with papillary thyroid carcinoma (PTC), and three SDHB patients affected by renal cell carcinomas (RCCs) were identified from four European centers. SDHA/SDHB immunohistochemistry (IHC), SDHx mutation analysis, and loss of heterozygosity analysis of the involved SDHx gene were performed on all tumors. A cohort of 348 tumors of unknown SDHx mutational status, including renal tumors, PTCs, PAs, neuroblastic tumors, seminomas, and adenomatoid tumors, was investigated by SDHB IHC. RESULTS: Of the six index patients, all RCCs and one PA displayed SDHB immunonegativity in contrast to the other PA and PTC. All immunonegative tumors demonstrated loss of the WT allele, indicating bi-allelic inactivation of the germline mutated gene. Of 348 tumors, one clear cell RCC exhibited partial loss of SDHB expression. CONCLUSIONS: These findings strengthen the etiological association of SDHx genes with pituitary neoplasia and provide evidence against a link between PTC and SDHx mutations. Somatic deletions seem to constitute the second hit in SDHB-related renal neoplasia, while SDHx alterations do not appear to be primary drivers in sporadic tumorigenesis from tissues affected by SDH deficiency.

A pencil beam algorithm for helium ion beam therapy.

PURPOSE: To develop a flexible pencil beam algorithm for helium ion beam therapy. Dose distributions were calculated using the newly developed pencil beam algorithm and validated using Monte Carlo (MC) methods. METHODS: The algorithm was based on the established theory of fluence weighted elemental pencil beam (PB) kernels. Using a new real-time splitting approach, a minimization routine selects the optimal shape for each sub-beam. Dose depositions along the beam path were determined using a look-up table (LUT). Data for LUT generation were derived from MC simulations in water using GATE 6.1. For materials other than water, dose depositions were calculated by the algorithm using water-equivalent depth scaling. Lateral beam spreading caused by multiple scattering has been accounted for by implementing a non-local scattering formula developed by Gottschalk. A new nuclear correction was modelled using a Voigt function and implemented by a LUT approach. Validation simulations have been performed using a phantom filled with homogeneous materials or heterogeneous slabs of up to 3 cm. The beams were incident perpendicular to the phantoms surface with initial particle energies ranging from 50 to 250 MeV/A with a total number of 10(7) ions per beam. For comparison a special evaluation software was developed calculating the gamma indices for dose distributions. RESULTS: In homogeneous phantoms, maximum range deviations between PB and MC of less than 1.1% and differences in the width of the distal energy fall off of the Bragg-Peak from 80% to 20% of less than 0.1 mm were found. Heterogeneous phantoms using layered slabs satisfied a γ-index criterion of 2%/2mm of the local value except for some single voxels. For more complex phantoms using laterally arranged bone-air slabs, the γ-index criterion was exceeded in some areas giving a maximum γ-index of 1.75 and 4.9% of the voxels showed γ-index values larger than one. The calculation precision of the presented algorithm was considered to be sufficient for clinical practice. Although only data for helium beams was presented, the performance of the pencil beam algorithm for proton beams was comparable. CONCLUSIONS: The pencil beam algorithm developed for helium ions presents a suitable tool for dose calculations. Its calculation speed was evaluated to be similar to other published pencil beam algorithms. The flexible design allows easy customization of measured depth-dose distributions and use of varying beam profiles, thus making it a promising candidate for integration into future treatment planning systems. Current work in progress deals with RBE effects of helium ions to complete the model.

Comparison of basic features of proton and helium ion pencil beams in water using GATE.

PURPOSE: The aim of this study was to investigate the basic features of helium ions for their possible application in advanced radiotherapy and to benchmark them against protons, the current particle of choice in the low linear energy transfer (LET) range. MATERIAL AND METHODS: Geant4 Application for Emission Tomography (GATE) simulations were performed with beams of 1x10(7) monodirectional particles traversing a water phantom. Initial energies ranged from 50 to 250 MeV per nucleon (MeV/A). The following parameters were evaluated: particle range at the distal 80% of maximum energy deposition (E(max)), width of the Bragg peak (BP) at 60% of E(max), and dose fall-off width between 80% and 20% of E(max) for longitudinal spectra. In addition the fragmentation tail was quantified in terms of length, percental energy deposition, and contributing particles. For each energy lateral profiles were registered along the beam axis and the FWHM at four different depths was extracted. Besides the comparison of parameters between the two particle types, results were also compared to data in the literature. RESULTS: As expected, the position of the BP as a function of initial kinetic energy showed similar values for protons and helium ions, with deviations smaller than 1.3%. The quantitative results of the Monte Carlo (MC) study showed less range straggling effects and smaller lateral deflections for helium ions compared to protons for the investigated energy range. On average, an about 56% reduction of the width of the BP and a 48% reduction of the dose fall-off was observed for helium ions compared to protons. Both the width of the BP and the dose fall-off width as a function of particle range or energy showed an almost linear increase with increasing energy. The tail length increased from 55.9 mm to 592.7 mm and the deposited energy increased from 0.5% to 7.3% for energies between 90 and 250 MeV/A. Lateral profiles of helium ions were about 52% narrower than those of protons. CONCLUSIONS: Due to their mass and charge helium ions distinguish themselves from protons in reduced range straggling effects, smaller lateral deflections, and a fragmentation tail. The MC based comprehensive data set for 21 clinically relevant energies can be used to create look-up tables for semi-analytical pencil beam model for helium ions.

Growth hormone treatment in adults with Prader-Willi syndrome: the Scandinavian study.

Prader-Willi syndrome (PWS) is characterized by short stature, muscular hypotonia, cognitive dysfunction, and hyperphagia usually leading to severe obesity. Patients with PWS share similarities with growth hormone deficiency (GHD). Few studies have dealt with growth hormone (GH) treatment in PWS adults. The purpose of the Scandinavian study was to evaluate the effects of GH on body composition, lipid and glucose metabolism, physical performance and safety parameters in adults with PWS. Twenty-five women and 21 men with PWS were randomized to treatment with GH or placebo during 1 year followed by 2 years of open labeled GH treatment. At baseline 1/3 had normal BMI, six patients severe GHD, ten impaired glucose tolerance and seven diabetes. At 1 year insulin-like growth factor I (IGF-I) SDS had increased by 1.51 (P < 0.001) and body composition improved in the GH treated group. Visceral fat decreased by 22.9 ml (P = 0.004), abdominal subcutaneous fat by 70.9 ml (P = 0.003) and thigh fat by 21.3 ml (P = 0.013), whereas thigh muscle increased 6.0 ml (P = 0.005). Lean body mass increased 2.25 kg (P = 0.005), and total fat mass decreased 4.20 kg (P < 0.001). The positive effects on body composition were maintained after 2 years of GH treatment. Peak expiratory flow increased by 12% (P < 0.001) at 2 years of GH treatment. Lipid and glucose metabolism were unchanged, however, three patients developed diabetes at 2 years of GH treatment. In conclusion GH treatment had beneficial effects on the abnormal body composition without serious adverse events making it a logic treatment option in adults with PWS.

Intra-operative MRI facilitates tumour resection during trans-sphenoidal surgery for pituitary adenomas.

BACKGROUND: During trans-sphenoidal microsurgical resection of pituitary adenomas, the extent of resection may be difficult to assess, especially when extensive suprasellar and parasellar growth has occurred. In this prospective study, we investigated whether intra-operative magnetic resonance imaging (iMRI) can facilitate tumour resection. METHODS: Twenty patients with macroadenomas, (16 non-functioning, three growth-hormone secreting and one pharmaco-resistant prolactinoma) were selected for surgery in the iMRI. The mean tumour diameter was 27 mm (range 11-41). The mean parasellar grade, according to the Knosp classification, was 2.3. Pre-operative coronal and sagittal T1-weighted and T2-weighted images were obtained. The trans-sphenoidal tumour resection was performed at the edge of the tunnel of a Signa SP 0.5-Tesla MRI. The surgeon aimed at a radical tumour resection that was followed by a peri-operative MRI scan. When a residual tumour was visualised and deemed resectable, an extended resection was performed, followed by another MRI scan. This procedure was repeated until the imaging results were satisfactory. In all patients, we were able to obtain images to assess the extent of resection and to classify the resection as either total or subtotal. RESULTS: After primary resection, eight out of 20 cases were classified as total resections. A second resection was performed in 11 of 12 cases classified as subtotal resections, and in four of these, total resection was achieved. A third resection was performed in three of the remaining seven cases with subtotal resections, but we did not achieve total resection in any of these cases. Therefore, the use of iMRI increased the number of patients with total resection from 8/20 (40%) to 12/20 (60%). The only observed complication was a transient spinal fluid leakage. CONCLUSION: Intra-operative MRI during trans-sphenoidal microsurgery is useful in selected patients for a safe and more complete resection.

Six-month preoperative octreotide treatment in unselected, de novo patients with acromegaly: effect on biochemistry, tumour volume, and postoperative cure.

OBJECTIVE: Treatment with somatostatin analogues is the primary medical treatment of acromegaly. Controversies still exist whether acute octreotide effect predicts long-term biochemical effects, tumour regression or surgical cure. This prospective study investigates effect of 6-month treatment with octreotide long-acting repeatable (LAR) on insulin-like growth factor-1 (IGF-1) and growth hormone (GH) levels, pituitary function, tumour regression and postoperative cure in de novo acromegalic patients. DESIGN AND METHODS: After a baseline evaluation including fasting hormone levels, MRI scan and an acute 50 µg octreotide test, 32 patients were treated with octreotide LAR 20 mg every 28th day for 6 months before surgery. Treatment effects on IGF-1 and GH levels, serum hormone levels and tumour volume were monitored. Surgical cure was evaluated 3 months postoperatively. RESULTS: Mean tumour volume reduction was 35%, in one-third of the patients more than 50%, while approximately one-third achieved biochemical remission evaluated by normalized IGF-1 levels. The GH reduction following an acute octreotide test was 81 ± 19% and associated with long-term GH reduction (r = 0·78, P < 0·0005). However, neither acute (r = 0·29, P = 0·12) nor the long-term octreotide effect (r = 0·11, P = 0·58) on GH levels was associated with tumour volume reduction and did not predict subsequent surgical cure. CONCLUSION: Six months of long-acting octreotide using a fixed dose, 1/3 of the patients came in biochemical remission, while 2/3 had significant tumour reduction. Moreover, an acute effect of octreotide seemed to be a prerequisite for long-term effect.