Effects of Pilates, McKenzie and Heckscher training on disease activity, spinal motility and pulmonary function in patients with ankylosing spondylitis: a randomized controlled trial.

The optimal management of ankylosis spondylitis (AS) involves a combination of nonpharmacologic and pharmacologic treatment aiming to maximize health-related quality of life. The primary objective of our study was to demonstrate the benefits of an original multimodal exercise program combining Pilates, McKenzie and Heckscher techniques on pulmonary function in patients with AS, while secondary objectives were to demonstrate the benefits of the same program on function and disease activity. This is a randomized controlled study on ninety-six consecutive patients with AS (axial disease subset), assigned on a 1:1 rationale into two groups based on their participation in the Pilates, McKenzie and Heckscher (group I) or in the classical kinetic program (group II). The exercise program consisted of 50-min sessions performed 3 times weekly for 48 weeks. Standard assessments were done at week 0 and 48 and included pain, modified Schober test (mST) and finger-floor distance (FFD), chest expansion (CE) and vital capacity (VC), as well as disease activity Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), functional Bath Ankylosing Spondylitis Functional Index (BASFI) and metrology index Bath Ankylosing Spondylitis Metrology Index (BASMI). Groups were comparable at baseline; we demonstrated significant improvement between baseline and after 48 weeks of regular kinetic training for all AS-related parameters in both groups. However, significant improvement was found in pain, lumbar spine motility (mST, FFD), BASFI, BASDAI and BASMI in AS performing the specific multimodal exercise program at the end of study (p = 0.001). Although there were significant improvements in CE in both groups as compared to baseline (group I, p = 0.001; group II, p = 0.002), this parameter increased significantly only in group I (p = 0.001). VC measurements were not significantly changed at the end of the study (group I, p = 0.127; group II, p = 0.997), but we found significant differences within groups (p = 0.011). A multimodal training combining Pilates, McKenzie and Heckscher exercises performed regularly should be included in the routine management of patients with AS for better control of function, disease activity and pulmonary function.

Good practice recommendations on paediatric training programmes for health care professionals in the EU.

Part of the SWEET Project: EU (European Union), Better Control in Paediatric and Adolescent Diabetes: Working to Create Centres of Reference, was specifically to examine the training of health care professionals (HCPs) across the EU. Several types of information were collected during 2009, and these included a literature search, workshops of the SWEET members, examination of the data collected by the Hvidøre Study Group and the Diabetes Attitudes, Wishes, and Needs (DAWN) Youth initiative, and a questionnaire distributed to SWEET members and professional colleagues who cared for children and young people (CYP) with diabetes. It was clear from the information collected that there was no European or global consensus either on a curriculum for the training of the paediatric diabetes multidisciplinary team (MDT) or individual professions in paediatric diabetes. A minority of countries had well-established training but, for the majority, there was little standardisation or accreditation. Moreover, most countries did not have available courses for training the diabetes MDT and training was not mandatory. Of the courses that were available more were accredited for doctors and nurses but fewer for the other professions. As a consequence, the majority of HCP posts in paediatric diabetes do not demand prior experience in the specialty. Standardised accredited training and continuous professional development (CPD) opportunities are severely limited. The SWEET Project supports a standardised, accredited approach to training and CPD of the MDT and for individual professions. As a consequence, a curriculum for the training of the MDT was developed, and this is now ready for implementation.

Congenital hyperinsulinism-A case of mild hypoglycemia in an adult, detected by family testing.

Symptoms of mild hypoglycemia are easily overlooked especially when there are no complaints from the patients, but it could be a warning sign of an underlying genetic disease. Genetic testing for the entire family is a key step in neonatal hypoglycemia workup.

Severe osteoporosis as atypical presentation of hereditary hemochromatosis.

Besides important metabolic repercussions, iron overload is reported to be associated with deleterious effects on articulations and bones. We present the case of a male patient diagnosed with severe osteoporosis and vertebral fracture, in whom the evaluation for secondary osteoporosis revealed hereditary hemochromatosis.

Rare cause of a resistant hypertension in a middle-aged man: A case report.

Congenital adrenal hyperplasia associated to 11-beta-hydroxylase deficiency is a rare cause of secondary hypertension, usually discovered during childhood; however, a late diagnosis in adults has also been reported. Despite low cortisol levels, accumulated adrenal steroid precursors can activate the glucocorticoid receptor and thus protect the patient against adrenal crisis.

A Phase II Study to Prevent Radiation-induced Rectal Injury With Lovastatin.

PURPOSE: Physician reported symptomatic late rectal injury occurs in about 5% to 25% of patients treated with radiation therapy for prostate cancer, depending on the treatment technique. Patients, however, report clinically meaningful declines in bowel/rectal function regardless of the technique used. Lovastatin has been shown to protect mice from late radiation injury. This study was designed to determine if lovastatin might reduce the incidence of late rectal injury in patients receiving radiation therapy for prostate cancer. MATERIALS AND METHODS: Patients with adenocarcinoma of the prostate receiving radiotherapy with curative intent were eligible. A portion of the rectum had to receive at least 60 Gy. Gastrointestinal functioning was assessed using both physician-reported and patient-reported instruments at baseline and at prescribed intervals during and after treatment. Lovastatin (20 to 80 mg/d) was started on day 1 of radiation and continued for 12 months. Patients were followed for an additional 12 months. The primary endpoint was physician-reported rectal toxicity ≥grade 2 during the first 2 years after treatment. RESULTS: A total of 20/53 (38%) patients developed grade 2 or higher toxicity during the 2-year follow-up period. Seventeen patients had 1 or more unresolved gastrointestinal symptom at the end of 2 years, 3 (6%) of which were grade 2 and none were of higher grade. CONCLUSIONS: The primary endpoint of the study was not met. Lovastatin, as administered in this trial, did not reduce the incidence of grade 2 or higher rectal toxicity compared with historical controls.

The impact of breathing motion versus heterogeneity effects in lung cancer treatment planning.

The purpose of this study is to investigate the effects of tissue heterogeneity and breathing-induced motion/deformation on conformal treatment planning for pulmonary tumors and to compare the magnitude and the clinical importance of changes induced by these effects. Treatment planning scans were acquired at normal exhale/inhale breathing states for fifteen patients. The internal target volume (ITV) was defined as the union of exhale and inhale gross tumor volumes uniformly expanded by 5 mm. Anterior/posterior opposed beams (AP/PA) and three-dimensional (3D)-conformal plans were designed using the unit-density exhale ("static") dataset. These plans were further used to calculate (a) density-corrected ("heterogeneous") static dose and (b) heterogeneous cumulative dose, including breathing deformations. The DPM Monte Carlo code was used for dose computations. For larger than coin-sized tumors, relative to unit-density plans, tumor and lung doses increased in the heterogeneity-corrected plans. In comparing cumulative and static plans, larger normal tissue complication probability changes were observed for tumors with larger motion amplitudes and uncompensated breathing-induced hot/cold spots in lung. Accounting for tissue heterogeneity resulted in average increases of 9% and 7% in mean lung dose (MLD) for the 6 MV and 15 MV photon beams, respectively. Breathing-induced effects resulted in approximately 1% and 2% average decreases in MLD from the static value, for the 6 and 15 MV photon beams, respectively. The magnitude of these effects was not found to correlate with the treatment plan technique, i.e., AP/PA versus 3D-CRT. Given a properly designed ITV, tissue heterogeneity effects are likely to have a larger clinical significance on tumor and normal lung treatment evaluation metrics than four-dimensional respiratory-induced changes.

How extensive of a 4D dataset is needed to estimate cumulative dose distribution plan evaluation metrics in conformal lung therapy?

The purpose of this study was to investigate the number of intermediate states required to adequately approximate the clinically relevant cumulative dose to deforming/moving thoracic anatomy in four-dimensional (4D) conformal radiotherapy that uses 6 MV photons to target tumors. Four patients were involved in this study. For the first three patients, computed tomography images acquired at exhale and inhale were available; they were registered using B-spline deformation model and the computed transformation was further used to simulate intermediate states between exhale and inhale. For the fourth patient, 4D-acquired, phase-sorted datasets were available and each dataset was registered with the exhale dataset. The exhale-inhale transformation was also used to simulate intermediate states in order to compare the cumulative doses computed using the actual and the simulated datasets. Doses to each state were calculated using the Dose Planning Method (DPM) Monte Carlo code and dose was accumulated for scoring on the exhale anatomy via the transformation matrices for each state and time weighting factors. Cumulative doses were estimated using increasing numbers of intermediate states and compared to simpler scenarios such as a "2-state" model which used only the exhale and inhale datasets or the dose received during the average phase of the breathing cycle. Dose distributions for each modeled state as well as the cumulative doses were assessed using dose volume histograms and several treatment evaluation metrics such as mean lung dose, normal tissue complication probability, and generalized uniform dose. Although significant "point dose" differences can exist between each breathing state, the differences decrease when cumulative doses are considered, and can become less significant yet in terms of evaluation metrics depending upon the clinical end point. This study suggests that for certain "clinical" end points of importance for lung cancer, satisfactory predictions of accumulated total dose to be received by the distorting anatomy can be achieved by calculating the dose to but a few (or even simply the average) phases of the breathing cycle.

Effect of variations in atelectasis on tumor displacement during radiation therapy for locally advanced lung cancer.

PURPOSE: Atelectasis (AT), or collapsed lung, is frequently associated with central lung tumors. We investigated the variation of atelectasis volumes during radiation therapy and analyzed the effect of AT volume changes on the reproducibility of the primary tumor (PT) position. METHODS AND MATERIALS: Twelve patients with lung cancer who had AT and 10 patients without AT underwent repeated 4-dimensional fan beam computed tomography (CT) scans during radiation therapy per protocols that were approved by the institutional review board. Interfraction volume changes of AT and PT were correlated with PT displacements relative to bony anatomy using both a bounding box (BB) method and change in center of mass (COM). Linear regression modeling was used to determine whether PT and AT volume changes were independently associated with PT displacement. PT displacement was compared between patients with and without AT. RESULTS: The mean initial AT volume on the planning CT was 189 cm3 (37-513 cm3), and the mean PT volume was 93 cm3 (12-176 cm3). During radiation therapy, AT and PT volumes decreased on average 136.7 cm3 (20-369 cm3) for AT and 40 cm3 (-7 to 131 cm3) for PT. Eighty-three percent of patients with AT had at least one unidirectional PT shift that was greater than 0.5 cm outside of the initial BB during treatment. In patients with AT, the maximum PT COM shift was ≥0.5 cm in all patients and >1 cm in 58% of patients (0.5-2.4 cm). Changes in PT and AT volumes were independently associated with PT displacement (P < .01), and the correlation was smaller with COM (R2 = 0.58) compared with the BB method (R2 = 0.80). The median root mean squared PT displacement with the BB method was significantly less for patients without AT (0.45 cm) compared with those with AT (0.8cm, P = .002). CONCLUSIONS: Changes in AT and PT volumes during radiation treatment were significantly associated with PT displacements that often exceeded standard setup margins. Repeated 3-dimensional imaging is recommended in patients with AT to evaluate for PT displacements during treatment.

Reporting and analyzing statistical uncertainties in Monte Carlo-based treatment planning.

PURPOSE: To investigate methods of reporting and analyzing statistical uncertainties in doses to targets and normal tissues in Monte Carlo (MC)-based treatment planning. METHODS AND MATERIALS: Methods for quantifying statistical uncertainties in dose, such as uncertainty specification to specific dose points, or to volume-based regions, were analyzed in MC-based treatment planning for 5 lung cancer patients. The effect of statistical uncertainties on target and normal tissue dose indices was evaluated. The concept of uncertainty volume histograms for targets and organs at risk was examined, along with its utility, in conjunction with dose volume histograms, in assessing the acceptability of the statistical precision in dose distributions. The uncertainty evaluation tools were extended to four-dimensional planning for application on multiple instances of the patient geometry. All calculations were performed using the Dose Planning Method MC code. RESULTS: For targets, generalized equivalent uniform doses and mean target doses converged at 150 million simulated histories, corresponding to relative uncertainties of less than 2% in the mean target doses. For the normal lung tissue (a volume-effect organ), mean lung dose and normal tissue complication probability converged at 150 million histories despite the large range in the relative organ uncertainty volume histograms. For "serial" normal tissues such as the spinal cord, large fluctuations exist in point dose relative uncertainties. CONCLUSIONS: The tools presented here provide useful means for evaluating statistical precision in MC-based dose distributions. Tradeoffs between uncertainties in doses to targets, volume-effect organs, and "serial" normal tissues must be considered carefully in determining acceptable levels of statistical precision in MC-computed dose distributions.

Dose reconstruction in deforming lung anatomy: dose grid size effects and clinical implications.

In this study we investigated the accumulation of dose to a deforming anatomy (such as lung) based on voxel tracking and by using time weighting factors derived from a breathing probability distribution function (p.d.f.). A mutual information registration scheme (using thin-plate spline warping) provided a transformation that allows the tracking of points between exhale and inhale treatment planning datasets (and/or intermediate state scans). The dose distributions were computed at the same resolution on each dataset using the Dose Planning Method (DPM) Monte Carlo code. Two accumulation/interpolation approaches were assessed. The first maps exhale dose grid points onto the inhale scan, estimates the doses at the "tracked" locations by trilinear interpolation and scores the accumulated doses (via the p.d.f.) on the original exhale data set. In the second approach, the "volume" associated with each exhale dose grid point (exhale dose voxel) is first subdivided into octants, the center of each octant is mapped to locations on the inhale dose grid and doses are estimated by trilinear interpolation. The octant doses are then averaged to form the inhale voxel dose and scored at the original exhale dose grid point location. Differences between the interpolation schemes are voxel size and tissue density dependent, but in general appear primarily only in regions with steep dose gradients (e.g., penumbra). Their magnitude (small regions of few percent differences) is less than the alterations in dose due to positional and shape changes from breathing in the first place. Thus, for sufficiently small dose grid point spacing, and relative to organ motion and deformation, differences due solely to the interpolation are unlikely to result in clinically significant differences to volume-based evaluation metrics such as mean lung dose (MLD) and tumor equivalent uniform dose (gEUD). The overall effects of deformation vary among patients. They depend on the tumor location, field size, volume expansion, tissue heterogeneity, and direction of tumor displacement with respect to the beam, and are more likely to have an impact on serial organs (such as esophagus), rather than on large parallel organs (such as lung).

The influence of beam model differences in the comparison of dose calculation algorithms for lung cancer treatment planning.

In this study, we show that beam model differences play an important role in the comparison of does calculated with various algorithms for lung cancer treatment planning. These differences may impact the accurate correlation of dose with clinical outcome. To accomplish this, we modified the beam model penumbral parameters in an equivalent path length (EPL) algorithm and subsequently compared the EPL doses with those generated with Monte Carlo (MC). A single AP beam was used for beam fitting. Two different beam models were generated for EPL calculations: (1) initial beam model (init_fit) and (2) optimized beam model (best_fit) , with parameters optimized to produce the best agreement with MC calculated profiles at several depths in a water phantom. For the 6 MV, AP beam, EPL(init_fit) calculations were on average within 2%/2 mm (1.4 mm max.) agreement with MC; the agreement for EPL(best_fit) was 2%/1.0 mm (1.3 mm max.) for EPL(best_fit). Treatment planning was performed using a realistic lung phantom using 6 and 15 MV photons. In all homogeneous phantom plans, EPL(best_fit) calculations were in better agreement with MC. In the heterogeneous 6 MV plan, differences between EPL(best_fit and init_fit) and MC were significant for the tumour. The EPL(init_fit), unlike the EPL(best_fit) calculation, showed large differences in the lung relative to MC. For the 15 MV heterogeneous plan, clinically important differences were found between EPL(best_fit or init_fit) and MC for tumour and lung, suggesting that the algorithmic difference in inhomogeneous cases, differences between EPL(best_fit) and MC for lung tissues were smaller compared to those between EPL(init_fit) and MC. Although the extent to which beam model differences impact the dose comparisons will be dependent upon beam parameters (orientation, field size and energy), and the size and location of the tumour, this study shows that failing to correctly account for beam model differences will lead to biased comparisons between dose algorithms. This may ultimately hinder our ability to accurately correlate dose with clinical outcome.

Alterations in normal liver doses due to organ motion.

PURPOSE: To assess the clinical significance of differences between treatment planning calculations based on static computed tomography (CT) and more realistic predictions of the actual delivered dose to intrahepatic lesions by a geometric convolution approach that accounts for random setup variations and breathing-induced organ motion. MATERIALS AND METHODS: We recalculated target and normal liver doses for 40 patients previously treated on a conformal therapy dose escalation protocol to include the effect of setup uncertainties and liver motion due to patient breathing. Initial three-dimensional (3D) dose calculations based on pretreatment CT scans taken with voluntary breath-hold at normal exhalation were convolved with 3D anisotropic probability distribution functions reflecting population measurements of position setup variation. The convolution also included a distribution function (one-dimensional, inferior-superior direction only) representing the asymmetric temporal pattern (biased toward exhalation, based on population measurements) of a typical breathing cycle, scaled in amplitude for each patient. RESULTS: After convolution, the minimum clinical target volume (CTV) dose met or exceeded the minimum planning target volume (PTV) dose from the static plan in all but one case, indicating adequate PTV design. However, clinically relevant and statistically significant increases (decreases) in liver normal tissue complication probability (NTCP) from values computed for the static cases occurred for tumors located toward the bottom (top) of the liver, as predicted for these patients scanned at exhalation. The change in liver NTCP (from a nominal 20%) ranged from +12.0% to -11.7% (average magnitude change 3.9% [sigma = 3.3%]). Changes in prescription dose required to restore the original 20% NTCP ranged from -3.7 Gy to +7.9 Gy (average magnitude change 1.9 Gy [sigma = 1.9 Gy]). CONCLUSIONS: Although the PTV concept can ensure adequate CTV coverage, the doses to normal liver are incorrectly modeled without including patient-related geometric uncertainties.

Accounting for center-of-mass target motion using convolution methods in Monte Carlo-based dose calculations of the lung.

We have applied convolution methods to account for some of the effects of respiratory induced motion in clinical treatment planning of the lung. The 3-D displacement of the GTV center-of-mass (COM) as determined from breath-hold exhale and inhale CT scans was used to approximate the breathing induced motion. The time-course of the GTV-COM was estimated using a probability distribution function (PDF) previously derived from diaphragmatic motion [Med. Phys. 26, 715-720 (1990)] but also used by others for treatment planning in the lung [Int. J. Radiat. Oncol., Biol., Phys. 53, 822-834 (2002); Med. Phys. 30, 1086-1095 (2003)]. We have implemented fluence and dose convolution methods within a Monte Carlo based dose calculation system with the intent of comparing these approaches for planning in the lung. All treatment plans in this study have been calculated with Monte Carlo using the breath-hold exhale CT data sets. An analysis of treatment plans for 3 patients showed substantial differences (hot and cold spots consistently greater than +/- 15%) between the motion convolved and static treatment plans. As fluence convolution accounts for the spatial variance of the dose distribution in the presence of tissue inhomogeneities, the doses were approximately 5% greater than those calculated with dose convolution in the vicinity of the lung. DVH differences between the static, fluence and dose convolved distributions for the CTV were relatively small, however, larger differences were observed for the PTV. An investigation of the effect of the breathing PDF asymmetry on the motion convolved dose distributions showed that reducing the asymmetry resulted in increased hot and cold spots in the motion convolved distributions relative to the static cases. In particular, changing from an asymmetric breathing function to one that is symmetric results in an increase in the hot/cold spots of +/- 15% relative to the static plan. This increase is not unexpected considering that the target spends relatively more time at inhale as the asymmetry decreases (note that the treatment plans were generated using the exhale CT scans).

A fluence convolution method to account for respiratory motion in three-dimensional dose calculations of the liver: a Monte Carlo study.

We describe the implementation of a fluence convolution method to account for the influence of superior-inferior (SI) respiratory induced motion on a Monte Carlo-based dose calculation of a tumor located in the liver. This method involves convolving the static fluence map with a function describing the SI motion of the liver-the motion function has been previously derived from measurements of diaphragm movement observed under fluoroscopy. Significant differences are noted between fluence-convolved and static dose distributions in an example clinical treatment plan; hot and cold spots (on the order of 25%) are observed in the fluence-convolved plan at the superior and inferior borders of the liver, respectively. This study illustrates that the fluence convolution method can be incorporated into Monte Carlo dose calculation algorithms to account for some of the effects of patient breathing during radiotherapy treatment planning, thus leading to more accurate dose calculations.

An unusual etiology of viral hepatitis in three renal transplant recipients with normal graft function.

Liver impairment in renal transplant recipients is not a common complication and is associated, in most cases, with viral infections (HBV, HCV, HVD, HGV) or drug hepatotoxicity (Cyclosporin, Azathioprine, statins). Cytomegalovirus (CMV) infection is common, with 50 to 80% of the adult population being seropositive for CMV antibodies. In immunocompetent individuals, primary infection is usually asymptomatic or associated with minor illness. CMV remains latent after primary infection. In immunocompromised patients, as in renal transplant recipients or transplant recipients of other solid organ or bone marrow, the virus can cause serious disease. This could be the result of newly acquired infection or reactivation of the latent virus. One of the organs involved in CMV disease is the liver. The subjects of this report are renal transplant recipients with liver impairment due to CMV induced acute hepatitis.

Nonalcoholic fatty liver disease: a frequent condition in type 2 diabetic patients.

OBJECTIVE: Nonalcoholic fatty liver disease represents an excessive fat accumulation in the liver of patients with no other liver disease and no history of alcohol abuse. It is associated with insulin resistance, being more prevalent in obesity and type 2 diabetes. Our aim was to assess the prevalence of fatty liver and nonalcoholic steatohepatitis in patients with type 2 diabetes and to evaluate the influence of obesity on its prevalence. METHODS: We included 348 type 2 diabetes patients (age: 18-65 years), without a history of liver disease or alcohol abuse. We assessed demographical data, medical history, physical examination, blood tests, and abdominal ultrasonography. RESULTS: The prevalence of liver steatosis in our group was 87.1 %, with no significant differences between men and women. Patients with steatosis had higher abdominal circumference, body mass index (BMI; p = 0.001), and serum triglyceride (p < 0.0001), HbA1c (p < 0.001), and alaninaminotranspherase levels (ALT, p = 0.001). The value of BMI, abdominal circumference, and serum triglyceride levels independently influenced the prevalence of liver steatosis; the influence of HbA1c level was not significant. In 23.9 % of the patients with steatosis, we found elevated liver enzymes. CONCLUSION: We observed an elevated prevalence of nonalcoholic fatty liver disease (87.1 %) in type 2 diabetic patients. The factors influencing this prevalence are BMI, abdominal circumference,and serum triglyceride levels.

Advances in 4D radiation therapy for managing respiration: part I - 4D imaging.

Techniques for managing respiration during imaging and planning of radiation therapy are reviewed, concentrating on free-breathing (4D) approaches. First, we focus on detailing the historical development and basic operational principles of currently-available "first generation" 4D imaging modalities: 4D computed tomography, 4D cone beam computed tomography, 4D magnetic resonance imaging, and 4D positron emission tomography. Features and limitations of these first generation systems are described, including necessity of breathing surrogates for 4D image reconstruction, assumptions made in acquisition and reconstruction about the breathing pattern, and commonly-observed artifacts. Both established and developmental methods to deal with these limitations are detailed. Finally, strategies to construct 4D targets and images and, alternatively, to compress 4D information into static targets and images for radiation therapy planning are described.

Advances in 4D radiation therapy for managing respiration: part II - 4D treatment planning.

The development of 4D CT imaging technology made possible the creation of patient models that are reflective of respiration-induced anatomical changes by adding a temporal dimension to the conventional 3D, spatial-only, patient description. This had opened a new venue for treatment planning and radiation delivery, aimed at creating a comprehensive 4D radiation therapy process for moving targets. Unlike other breathing motion compensation strategies (e.g. breath-hold and gating techniques), 4D radiotherapy assumes treatment delivery over the entire respiratory cycle - an added bonus for both patient comfort and treatment time efficiency. The time-dependent positional and volumetric information holds the promise for optimal, highly conformal, radiotherapy for targets experiencing movements caused by respiration, with potentially elevated dose prescriptions and therefore higher cure rates, while avoiding the uninvolved nearby structures. In this paper, the current state of the 4D treatment planning is reviewed, from theory to the established practical routine. While the fundamental principles of 4D radiotherapy are well defined, the development of a complete, robust and clinically feasible process still remains a challenge, imposed by limitations in the available treatment planning and radiation delivery systems.