The impact of radiotherapy on the hypothalamo-pituitary axis: old vs new radiotherapy techniques

Multimodality cancer therapy has led to remarkable improvements in survival of childhood and young adult cancer, with survival rates exceeding 85%. Such remission rates come with their own adverse sequelea or ‘late effects’. Although the cause of these late effects is multi-factorial, radiation-related adverse effects are one of the most prevalent. Hypopituitarism is a recognised complication of irradiation of brain tumours distant to the hypothalamo-pituitary (HP) axis when the axis is included within the exposed field. Much of the data concerning the development of hypopituitarism, however, relate to early forms of photon-based radiotherapy. In this narrative review, we discuss advances in individual radiotherapy techniques currently used in treating brain tumours and their theoretical benefits based primarily on dosimetric studies. Increasingly precise radiation techniques, including advances in the delivery of photons (i.e. intensity-modulated radiotherapy) and proton beam therapy, are now available options. The premise behind these newer techniques is to reduce the dose and volume of normal tissue irradiated whilst maintaining an effective radiation dose to target tissue. When treating brain tumours distant to the HP axis the expectation, based upon dosimetric studies, is that newer forms of radiotherapy will less frequently involve the HP axis in the exposed field, and where incorporated within the field it will be exposed to a lower radiotherapy dosage. Intuitively the dosimetric studies should translate into significant reductions in the prevalence of HP dysfunction. These data are promising; however, to date there are minimal robust clinical data to determine if the theoretical benefits of these newer techniques on HP dysfunction is to be realised

Exploring the morbidity and mortality in acromegaly

Introduction: Acromegaly is a rare clinical condition characterized by chronic growth hormone (GH) excess, resulting into body disfigurement and systemic complications. Despite the therapeutic advancements in the management of patients with acromegaly, there still remains significant morbidity and mortality. Of the different complications associated with acromegaly, arthropathy has the highest prevalence and is one of the main determinants of quality of life in these patients, while cardiovascular disease remains one of the leading causes of mortality in acromegaly patients. Aims: The aim of this thesis is to explore further the unresolved issues of impaired quality of life, arthropathy and cardiovascular mortality associated with acromegaly and in particular to: i) establish whether quality of life (QoL) changes over time in patients previously treated for acromegaly and who have biochemically stable or improved disease and identify positive and negative predictors of quality of life in patients with acromegaly; ii) characterise the joint alterations in patients with acromegaly, by evaluating subchonadral knee bone shape (a surrogate marker of osteoarthritis) using a novel imaging technique based on automated segmentation of MR images of knee bones and calculation of bone area using active appearance models and identify factors, which may be associated with altered bone shape in patients with acromegaly; and iii) explore whether acromegaly is associated with increased thrombotic potential, by evaluating the effects of GH/IGF-1 excess on clot formation and lysis, as a potential mechanism for the increased cardiovascular mortality observed in patients with acromegaly. Results: For the QoL evaluation a two-arm study was conducted, consisting of a cross-sectional arm to compare QoL between patients with treated and controlled acromegaly and healthy controls; and a longitudinal arm to assess QoL changes in patients with biochemically stable disease during 5.7±0.6 years of follow-up. Fifty eight (58) patients and 116 matched controls were recruited for the cross-sectional arm; 28 patients completed the longitudinal arm. Three generic questionnaires [Psychological General Well-Being Schedule (PGWBS), 36-item Short-Form (SF-36), EuroQoL (EQ-5D)] and the disease-specific acromegaly QoL questionnaire (AcroQoL) were applied for QoL evaluation. QoL assessment was performed 11.6±8.2 years following diagnosis and treatment of acromegaly. Patients with treated acromegaly had lower QoL scores compared with controls in all questionnaires with the exception of the PGWBS “Anxiety” subscale. The “Appearance” subscale of the AcroQoL and the “physical function” subscales of the remaining questionnaires were the most underscored domains. No difference in the total and subscale scores of all questionnaires was observed between baseline and follow-up assessment, with the exception of the SF-36 “Physical Function”, where a decline was found between baseline and follow-up (58.5±24.7% vs. 43.1±31.1%; p=0.002). Duration of IGF-1/GH control was positively correlated with QoL scores in most questionnaires at baseline, whereas use of GH lowering therapy at the time of QoL assessment was a negative predictive factor of QoL. For the characterisation of the the arthropathy in acromegaly, a two-arm study was conducted. In the cross-sectional arm, 60 patients with acromegaly (29 males, mean age 54.8±12.9yrs) were compared with 300 age/gender-matched controls from the publicly available Osteoarthritis Initiative (OAI) database via propensity score matching. An additional control group of 886 individuals without any evidence of knee osteoarthritis on serial MRI scans, also referred as non-OA group, was selected from the OAI. In the longitudinal arm, bone shape data from 42 patients with acromegaly were compared at baseline and after at least 12 months of follow-up. Acromegaly patients attended for bilateral knee MRI scan at baseline and after at least 12 months of follow-up. Knee bone shape, joint space width (JSW) and cartilage thickness were measured based on automated segmentation of MR images of knee bones and calculation of bone area using active appearance models. Acromegaly patients had increased medial JSW compared with controls [6.21mm (95% CI 6.03-6.40) vs. 5.78mm (95% CI 5.70-5.87) respectively, p<0.001] and increased lateral and medial femorotibial cartilage thickness. Patella and medial tibia bone areas were also increased in acromegaly patients. B-score (a biomarker associated with severity and risk of progression of OA) was significantly higher in patients compared with controls [1.7 (95% CI 1.32-2.08) vs. 1.01 (0.84-1.18) respectively, p=0.001]. Thirty-five percent (n=21) of acromegaly patients had B-score ≥2, which is indicative of OA. These patient had higher GH levels at the time of diagnosis of acromegaly and required a higher number of therapeutic interventions during the disease management compared with patients with B-score <2 (n=39). Additionally, patients with B-score ≥2 had significantly larger femoral, tibial and patella bone areas, increased medial JSW and lateral and medial femorotibial cartilage thickness compared with the remaining patients. However, when patients with B-score <2 (within the B-score reference range) were compared with the non-OA control group, acromegaly patients still demonstrated differences in bone shape, with increased bone area at the lateral patella, medial patella and medial tibia; increased B-score [patients:0.69 (95% CI 0.36-1.02), non-OA controls: 0.018 (95% CI -0.05 – 0.08), p<0.001]; and increased lateral and medial femorotibial cartilage thickness. Comparison between baseline and follow-up scans for the 42 patients who completed the longitudinal arm of the study did not show any change in the bone size area, B-score or JSW. For the assessment of potential cardiovascular risk factors and clot dynamics in patients with acromegaly, a cross-sectional study with 40 patients with acromegaly (21 males, age 53±13yrs) and 40 age/gender-matched controls was conducted. Clot structure was analysed using a validated turbidimetric assay and fibrin networks were visualised by laser scanning confocal microscopy (LSCM). Metabolic profile parameters, body composition, plasma fibrinogen and PAI-1 were also assessed. Twenty-two patients had active acromegaly and 18 were in remission. There was no difference in qualitative patient characteristics between the two groups. Both groups had less favourable body composition and cardiovascular risk profile compared with controls. Despite no difference in clot formation and lysis parameters between the two patient groups, active disease patients had higher fibrinogen and clot maximum absorbance compared with controls, after adjusting for BMI (3.8±0.2 vs. 2.6±0.2mg/ml, p<0.001; and 0.39±0.02 vs. 0.33±0.01 arbitrary units, p=0.03, respectively). Patients in remission had higher fibrinogen compared with controls following adjustment for BMI (3.3±0.2 vs. 2.6±0.2mg/ml, p=0.02) but not clot maximum absorbance (0.35±0.03 vs. 0.33±0.02 arbitrary units, p=0.6). LSCM showed increased fibrin network density only in active disease patients, consistent with turbidimetric analysis. In addition to active disease, BMI, fat mass and skinfold thickness were associated with higher clot density and longer lysis time. Conclusions: Patients with biochemically controlled acromegaly demonstrate impaired quality of life, which persists despite long-term disease control, is primarily consisted of impaired physical function and secondly of impaired psycho-social well-being. Duration of biochemical disease control and current use of GH lowering therapy were the predominant factors determining patients’ QoL. Acromegaly patients despite higher B-score (a biomarker of osteoarthritis) and larger bone area particularly of the patella and medial tibia bones have preserved and/or increased joint space due to increased cartilage thickness, which distinguishes acromegalic arthropathy from osteoarthritis. The higher pre-treatment GH values and the higher number of therapeutic interventions seen in patients with B-score ≥2, indicate that overall exposure of peripheral tissues to excessive GH levels is a risk factor for more pronounced changes to the knee bone shape and potentially more severe arthropathy. Clot structure was analysed using a validated turbidimetric assay and fibrin networks were visualised by laser scanning confocal microscopy (LSCM). Metabolic profile parameters, body composition, plasma fibrinogen and PAI-1 were also assessed

A Hybrid Clustered Ant Colony Optimization Approach for the Hierarchical Multi-Switch Multi-Echelon Vehicle Routing Problem with Service Times

In this paper, the Hierarchical Multi Switch Multi Echelon Vehicle Routing Problem with Service Times (HMSME-VRP-ST) is presented. This novel problem considers distribution applications in which goods are delivered either directly from a central depot or through intermediate facilities called switch points. Commodities are loaded into interchangeable containers called swap bodies at the central depot, and can be transferred from one vehicle to another at the switch points. The goal is to minimize fixed and variable costs of the vehicle fleet and swap-bodies while serving a predetermined set of customers. The routes are constrained by time and swap bodies by loading capacity. A mathematical model of the HMSME-VRP-ST is presented, and a Hybrid Clustered Ant Colony Optimization (HCACO) algorithm is proposed to address the complexity of the problem. The approach utilizes the ant-based clustering algorithm, combining the density and connectivity properties of clustering for creating promising neighborhoods with the solution construction methodology and pheromone-based memory of the Ant Colony Optimization framework. Additionally, two local search schemes based on Variable Neighborhood Descent are incorporated to further improve the generated solutions. The behavior of each HCACO variant is analyzed, and their results are compared to a Greedy Randomized Adaptive Search Procedure metaheuristic in 36 newly generated benchmarks comprising of clustered, uniformly random, and mixed clustered-random instances.Validerad;2024;Nivå 2;2024-03-18 (joosat);CC BY Full text license;This article has previously appeared as a manuscript in a thesis.</p

Modeling and algorithmic solution of the vehicle routing problem with drones

Modem supply chains are inclined to redesign their operations in order to accommodate the environmental goals that many countries have set for the future. In urban and suburban transportation in particular, the transition to electric means of transportation is expected to significantly improve the life quality of populations. A type of electric vehicle which has the potential to vastly change urban transportation is the Unmanned Aerial Vehicles (UAV), commonly known as the drone.This thesis approaches the use of UAVs in routing problems, in both humanitarian and commercial applications. In particular, two problems are modeled, which utilize UAVs for search and rescue operations, and two problems which utilize UAVs for parcel deliveries in urban logistics. The first problem presented is the Cumulative Unmanned Aerial Vehicle Routing Problem which addresses search and rescue operations. These operations can be considered as problems which aim at minimizing the time required to cover the area of interest. The proposed approach transforms the underlying coverage problem to a vehicle routing problem using UAVs, incorporating the objective of the search and the limitations regarding the UAVs’ range. The second problem, addressing search and rescue operations is the Moving Peak Drone Search Problem. In this problem, the movement of the victims are taken in consideration, thus it is a dynamic optimization problem. The goal is to maximize the value of the locations which are covered by the UAVs, during the operation. The next problem presented is the Electric Vehicle Routing Problem with Drones, which applies to commercial applications, having the two vehicle types cooperating, in order to overcome their limitations and offer their individual benefits. The goal is to minimize the total energy consumption required for completing the parcel delivery operation. The second problem in this category is the Energy Minimizing Drone Routing Problem with Pickups and Deliveries, which addresses courier operations, such as those used in online trading between individuals. The goal is to minimize the energy required to complete the transportation of the parcels.Οι σύγχρονες εφοδιαστικές αλυσίδες καλούνται να ανασχεδιάσουν τις διαδικασίες τους προκειμένου αυτές να εναρμονιστούν με τους περιβαλλοντικούς στόχους που πολλές χώρες έχουν θέσει για το εγγύς μέλλον. Ειδικότερα, στον τομέα των αστικών και περιαστικών μεταφορών, η μετάβαση στην ηλεκτροκίνηση αναμένεται να αναβαθμίσει σημαντικά την ποιότητα ζωής των κατοίκων των πόλεων. Ένας τύπος ηλεκτρικού οχήματος που έχει τη δυνατότητα να αλλάξει άρδην τις αστικές μεταφορές είναι τα Μη Στελεχωμένα Εναέρια Οχήματα (Unmanned Aerial Vehicles - UAV ), γνωστά ως «drones».Η παρούσα διδακτορική διατριβή πραγματεύεται τη χρήση των UAV σε προβλήματα δρομολόγησης οχημάτων που αφορούν ανθρωπιστικές και εμπορικές εφαρμογές. Συγκεκριμένα, μοντελοποιεί και επιλύει δύο προβλήματα όπου τα UAV χρησιμοποιούνται σε αποστολές έρευνας και διάσωσης, και δύο προβλήματα που αφορούν τη χρήση τους για τη μεταφορά εμπορευμάτων στον αστικό ιστό πόλεων. Αρχικά παρουσιάζεται το Συσσωρευτικό Πρόβλημα Δρομολόγησης UAV που έχειεφαρμογή σε αποστολές έρευνας και διάσωσης. Οι αποστολές αυτές αποτελούν προβλήματα ελαχιστοποίησης του χρόνου που απαιτείται για την κάλυψη μιας περιοχής ενδιαφέροντος. Η προτεινόμενη μεθοδολογία μετατρέπει το πρόβλημα κάλυψης σε ένα πρόβλημα δρομολόγησης UAV, ενσωματώνοντας σε αυτό τον αντικειμενικό στόχο της αποστολής και τους περιορισμούς που διέπουν την αυτονομία των UAV. Το δεύτερο πρόβλημα που προτείνεται για τη μοντελοποίηση σεναρίων έρευνας, είναι το Πρόβλημα Αναζήτησης Κινούμενων Κορυφών με UAV. Σε αυτό λαμβάνεται υπόψη η κίνηση των αγνοουμένων εντός της περιοχής ενδιαφέροντος, επομένως αποτελεί ένα δυναμικό πρόβλημα βελτιστοποίησης. Στόχος του προβλήματος είναι η μεγιστοποίηση της αξίας των σημείων που καλύπτουν UAV, για το σύνολο του χρόνου που διαρκεί η έρευνα. Στη συνέχεια παρουσιάζεται το Πρόβλημα Δρομολόγησης συνδυασμού Ηλεκτρικών Οχημάτων Δρόμου και UAV, όπου αφορά εμπορικές εφαρμογές, με τους δύο τύπους ηλεκτρικών οχημάτων να λειτουργούν συνεργατικά προκειμένου να παρακάμψουν τις αδυναμίες τους και να προσφέρουν τα πλεονεκτήματά τους. Στόχος του προβλήματος είναι η ελαχιστοποίηση της συνολικά καταναλισκόμενης ενέργειας που απαιτείται για την παράδοση δεμάτων. Το δεύτερο πρόβλημα που προτείνεται σε αυτή την κατηγορία είναι το Πρόβλημα Ελαχιστοποίησης Ενέργειας Δρομολόγησης UAV με Παραλαβές και Παραδόσεις. Σε αυτό μοντελοποιούνται υπηρεσίες ταχυμεταφορών με χρήση UAV μεταξύ ιδιωτών και έχει εφαρμογή σε αγοραπωλησίες μέσω των μέσων κοινωνικής δικτύωσης. Στόχος είναι η ελαχιστοποίηση της ενέργειας που απαιτείται για την εκτέλεση του μεταφορικού έργου

Dataset for the cumulative unmanned aerial vehicle routing problem

The Cumulative Unmanned Aerial Vehicle Routing Problem applies to area covering operations using UAVs. It is defined on a graph, the nodes of which, ensure the complete coverage of the underlying area of interest. The data generation process takes into account the characteristics of such operations, in particular, the viewing window of the UAVs’ sensor, their maximum range, the size of the UAV fleet and the unknown locations of the targets within the area of interest. Instances are created simulating different scenarios, using different values for those UAV characteristics, as well as the different locations where the search targets might be positioned in the area of interest

Self-adaptive ACO approach for the CCVRP

Περίληψη: Στα πλαίσια της μεταπτυχιακής εργασίας, μελετάμε το Συσσωρευτικό πρόβλημα δρομολόγησης οχημάτων, το οποίο επιλύουμε με 5 παραλλαγές του αλγορίθμου της αποικίας μυρμηγκιών

Modeling and algorithmic solution of the vehicle routing rroblem with drones

Περίληψη: Οι σύγχρονες εφοδιαστικές αλυσίδες καλούνται να ανασχεδιάσουν τις διαδικασίες τους προκειμένου αυτές να εναρμονιστούν με τους περιβαλλοντικούς στόχους που πολλές χώρες έχουν θέσει για το εγγύς μέλλον. Ειδικότερα, στον τομέα των αστικών και περιαστικών μεταφορών, η μετάβαση στην ηλεκτροκίνηση αναμένεται να αναβαθμίσει σημαντικά την ποιότητα ζωής των κατοίκων των πόλεων. Ένας τύπος ηλεκτρικού οχήματος που έχει τη δυνατότητα να αλλάξει άρδην τις αστικές μεταφορές είναι τα Μη Στελεχωμένα Εναέρια Οχήματα (Unmanned Aerial Vehicles - UAV ), γνωστά ως «drones». Η παρούσα διδακτορική διατριβή πραγματεύεται τη χρήση των UAV σε προβλήματα δρομολόγησης οχημάτων που αφορούν ανθρωπιστικές και εμπορικές εφαρμογές. Συγκεκριμένα, μοντελοποιεί και επιλύει δύο προβλήματα όπου τα UAV χρησιμοποιούνται σε αποστολές έρευνας και διάσωσης, και δύο προβλήματα που αφορούν τη χρήση τους για τη μεταφορά εμπορευμάτων στον αστικό ιστό πόλεων. Αρχικά παρουσιάζεται το Συσσωρευτικό Πρόβλημα Δρομολόγησης UAV που έχει εφαρμογή σε αποστολές έρευνας και διάσωσης. Οι αποστολές αυτές αποτελούν προβλήματα ελαχιστοποίησης του χρόνου που απαιτείται για την κάλυψη μιας περιοχής ενδιαφέροντος. Η προτεινόμενη μεθοδολογία μετατρέπει το πρόβλημα κάλυψης σε ένα πρόβλημα δρομολόγησης UAV, ενσωματώνοντας σε αυτό τον αντικειμενικό στόχο της αποστολής και τους περιορισμούς που διέπουν την αυτονομία των UAV. Το δεύτερο πρόβλημα που προτείνεται για τη μοντελοποίηση σεναρίων έρευνας, είναι το Πρόβλημα Αναζήτησης Κινούμενων Κορυφών με UAV. Σε αυτό λαμβάνεται υπόψη η κίνηση των αγνοουμένων εντός της περιοχής ενδιαφέροντος, επομένως αποτελεί ένα δυναμικό πρόβλημα βελτιστοποίησης. Στόχος του προβλήματος είναι η μεγιστοποίηση της αξίας των σημείων που καλύπτουν UAV, για το σύνολο του χρόνου που διαρκεί η έρευνα. Στη συνέχεια παρουσιάζεται το Πρόβλημα Δρομολόγησης συνδυασμού Ηλεκτρικών Οχημάτων Δρόμου και UAV, όπου αφορά εμπορικές εφαρμογές, με τους δύο τύπους ηλεκτρικών οχημάτων να λειτουργούν συνεργατικά προκειμένου να παρακάμψουν τις αδυναμίες τους και να προσφέρουν τα πλεονεκτήματά τους. Στόχος του προβλήματος είναι η ελαχιστοποίηση της συνολικά καταναλισκόμενης ενέργειας που απαιτείται για την παράδοση δεμάτων. Το δεύτερο πρόβλημα που προτείνεται σε αυτή την κατηγορία είναι το Πρόβλημα Ελαχιστοποίησης Ενέργειας Δρομολόγησης UAV με Παραλαβές και Παραδόσεις. Σε αυτό μοντελοποιούνται υπηρεσίες ταχυμεταφορών με χρήση UAV μεταξύ ιδιωτών και έχει εφαρμογή σε αγοραπωλησίες μέσω των μέσων κοινωνικής δικτύωσης. Στόχος είναι η ελαχιστοποίηση της ενέργειας που απαιτείται για την εκτέλεση του μεταφορικού έργου