Interim 18F-FDG-PET based response-adaptive dose escalation of proton therapy for head and neck cancer: a treatment planning feasibility study.

BACKGROUND: Image-driven dose escalation to tumor subvolumes has been proposed to improve treatment outcome in head and neck cancer (HNC). We used 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) acquired at baseline and into treatment (interim) to identify biologic target volumes (BTVs). We assessed the feasibility of interim dose escalation to the BTV with proton therapy by simulating the effects to organs at risk (OARs). METHODS: We used the semiautomated just-enough-interaction (JEI) method to identify BTVs in 18F-FDG-PET images from nine HNC patients. Between baseline and interim FDG-PET, patients received photon radiotherapy. BTV was identified assuming that high standardized uptake value (SUV) at interim reflected tumor radioresistance. Using Eclipse (Varian Medical Systems), we simulated a 10% (6.8 Gy(RBE1.1)) and 20% (13.6 Gy(RBE1.1)) dose escalation to the BTV with protons and compared results with proton plans without dose escalation. RESULTS: At interim 18F-FDG-PET, radiotherapy resulted in reduced SUV compared to baseline. However, spatial overlap between high-SUV regions at baseline and interim allowed for BTV identification. Proton therapy planning demonstrated that dose escalation to the BTV was feasible, and except for some 20% dose escalation plans, OAR doses did not significantly increase. CONCLUSION: Our in silico analysis demonstrated the potential for interim 18F-FDG-PET response-adaptive dose escalation to the BTV with proton therapy. This approach may give more efficient treatment to HNC with radioresistant tumor subvolumes without increasing normal tissue toxicity. Studies in larger cohorts are required to determine the full potential for interim 18F-FDG-PET-guided dose escalation of proton therapy in HNC.

Evaluation of Radiation Therapy Treatment Plans in a Randomized Phase 2 Trial Comparing 2 Schedules of Twice-Daily Thoracic Radiation Therapy in Limited Stage Small Cell Lung Cancer.

PURPOSE: There is limited clinical data for recommendations on how to deliver thoracic radiation therapy (TRT) concurrently with chemotherapy in limited-stage small cell lung cancer. We reviewed radiation therapy treatment plans in a randomized phase 2 trial comparing high-dose with standard-dose twice-daily TRT to assess treatment planning techniques, dose-volume data for target volumes and organs at risk (OARs), evaluate compliance with the protocol, associations with radiation-induced toxicity, and whether an imbalance in treatment planning parameters might be a reason for the large survival benefit of the higher dose (median overall survival 43.6 vs 22.6 months). METHODS AND MATERIALS: In the study, 170 patients were to receive 4 courses of platinum/etoposide and were randomized to receive twice-daily TRT of 60 Gy/40 fractions (fx) or 45 Gy/30 fx. TRT treatment plans for those who received 1 or more fx of TRT (n = 166) were analyzed. RESULTS: The most common treatment planning technique was 3-dimensional conformal radiation therapy (67%). The 75th percentile of the reported dose-volume parameters for the OARs were within the protocol-recommended limits for both groups. Mean doses to the esophagus of 25.5 Gy (IQR, 20.2-31.3; 60 Gy/40 fx) and 24.3 Gy (IQR, 20.3-27.5; 45 Gy/30 fx) were associated with 21% and 18% ≥ grade 3 acute esophagitis, respectively. In the 60 Gy/40 fx group, a mean dose to the lungs of 16.5 Gy (IQR, 15.8-16.9), V20 Gy of 29.5% (IQR, 28.8-30.4), and V5 Gy of 65.6% (IQR, 61.5-68.7) led to ≥ grade 3 pneumonitis in 4% of the patients. There was no ≥ grade 3 pneumonitis in the 45 Gy/30 fx group. The treatment planning techniques, the percentage change in volumes between original and redelineated OARs, planning target volumes, relative doses, and laterality were well balanced between the randomly assigned groups. CONCLUSIONS: Considering the incidences of severe radiation-induced toxicities were within the range of other recent trials, the reported doses to the OARs appear to be safe. Treatment planning parameters were well balanced between the randomly assigned groups, supporting that the survival benefit of the twice-daily 60 Gy/40 fx TRT schedule was due to the higher dose.

Patient-Reported Experiences and Associated Factors in a Norwegian Radiotherapy Setting: An Explorative Cross-Sectional Study.

Introduction: Radiotherapy is the main treatment modality in cancer. There is sparse knowledge on how patients with cancer experience their radiotherapy trajectory, and which factors might be associated with patients' experiences. Objectives: The aim of the present study was to explore how adults with cancer receiving radiotherapy evaluate the quality of their care, utilizing a patient-reported experience measure, and how patient- and service-related characteristics are associated with their evaluation. Methods: An explorative cross-sectional study using a self-completed questionnaire to assess patients' radiotherapy experiences was performed. Participants were recruited consecutively, within their last week of treatment, from two different hospitals in Norway from January 2021 to January 2022. Four hundred and eighty paper questionnaires were distributed to recruited patients, 240 at each hospital. Questionnaires were self-completed at home and returned by mail. The instrument person-centered coordinated care experience questionnaire (P3CEQ) was used. In addition to this, participants completed the European Organization of Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) and The Sense of Coherence 13 scale (SOC-13). Data were analyzed using descriptive statistics, parametric tests, and unadjusted/adjusted linear regression models were estimated. Results: The study included 373 patients. Patients evaluated quality of care in terms of P3CEQ scores, with a mean score of 19.5 (standard deviation = 5.4). Lowest scores were identified in areas concerning person-centeredness and service coordination. There were no significant differences in P3CEQ scores between the younger and older groups. Having a partner and better SOC-13 scores were independently associated with the overall patient-reported experience score, whereas age was not. Conclusion: Patient-reported experience scores indicate that improvements are needed in some areas, such as informing and involving patients in the planning and coordination of their care. Findings suggest paying special attention to patients without a partner to offer patients the best possible care.

Psychometric properties of the person-centred coordinated care experience questionnaire (P3CEQ) in a Norwegian radiotherapy setting.

BACKGROUND: The number of older adults with cancer is increasing. Radiotherapy is an important treatment modality for cancer and may cause side effects and distress. Patient-reported experience measures aim to measure patients' experiences with health care. This can help healthcare services to improve in line with patients' needs. To assess how Norwegian patients receiving radiotherapy experience their care, a valid and reliable tool is required. We selected the person-centred coordinated care experience questionnaire as a tool. OBJECTIVE: The aim of the study is to validate the Norwegian version of the person-centred coordinated care experience questionnaire in a radiotherapy setting. METHODS: A feasibility study of the person-centred coordinated care experience questionnaire and a cross-sectional study-testing psychometric properties of the questionnaire in a Norwegian radiotherapy setting-were conducted. Participants were recruited from two different hospitals in Norway. Patient characteristics and item scores are described using descriptive statistics. We performed an exploratory factor analysis and applied principal component analysis with a varimax rotation. Cronbach's α was used to assess internal consistency. RESULTS: In total, 24 patients participated in the feasibility test, and 176 were included in the cross-sectional study where we explored the psychometric properties of the person-centred coordinated care experience questionnaire. Three factors were identified. Internal consistency was established for the 10-item scale, with Cronbach's α = 0.698. CONCLUSIONS: Conclusions must consider the Norwegian setting and healthcare context. We found that the Norwegian version of the person-centred coordinated care experience questionnaire is a relevant, valid and reliable tool to provide insight into different areas of patients' experiences upon receiving radiotherapy. However, further testing on a larger sample is necessitated.

Body condition score, morphometric measurements and estimation of body weight in mature Icelandic horses in Denmark.

BACKGROUND: Obesity is related to the development of several diseases like insulin resistance and laminitis in horses. The prevalence of obesity among mature Icelandic horses in Denmark has not been investigated previously. This study aimed to find the prevalence of obesity, to compare body condition score (BCS) based on owner perception with that of an experienced person and to correlate the BCS to body weight (BW) and morphometric measures in a group of mature Icelandic horses in Denmark. A total of 254 Icelandic horses (≥4 years; 140 geldings, 105 mares, 9 stallions) from 46 different farms were included. All horses were assigned a BCS on a scale from 1 to 9 (1 is poor, 5 is moderate and 9 is extremely fat) by their owner and by an experienced person. Two weight tapes were used to assess BW. Girth circumference (GC), neck circumference (NC) and height at withers (HW) were measured, and the GC:HW and NC:HW ratios were calculated. RESULTS: Categorising the horses into four groups, 5.9 % were underweight (BCS 3-4), 70.1 % were optimal (BCS 5-6), 13.8 % were overweight (BCS 7) and 10.2 % were obese (BCS 8-9). The GC:HW and NC:HW ratios increased with increasing BCS, as did the BW estimated with the weight tapes. A GC:HW ratio >1.21 might indicate overweight or obesity in Icelandic horses. Horse owners underestimated the BCS of their horses compared to an experienced person. CONCLUSIONS: The results from this study show that 24.0 % of mature Icelandic horses in Denmark are overweight or obese, and that owners tend to underestimate the BCS of their Icelandic horses. The GC:HW ratio might indicate overweight or obesity, however, the ratio for Icelandic horses is different than reported for horses and ponies of other breeds.

A new diagnosis of asthma or COPD is linked to smoking cessation - the Tromsø study.

BACKGROUND: Patients with COPD have had a lower tendency to quit smoking compared to patients with coronary heart disease (CHD). We wanted to investigate if this is still true in a Norwegian population. METHODS: Our data came from the fifth and sixth Tromsø surveys, which took place in 2001-2002 and 2007-2008. The predictors of smoking cessation were evaluated in a cohort of 4,497 participants who had stated their smoking status in both surveys. RESULTS: Of the 4,497 subjects in the cohort, 1,150 (25.6%) reported daily smoking in Tromsø 5. In Tromsø 6, 428 had quit (37.2%). A new diagnosis of obstructive lung disease (asthma or COPD) and CHD were both associated with increased quitting rates, 50.6% (P=0.01) and 52.1% (P=0.02), respectively. In multivariable logistic regression analysis with smoking cessation as outcome, the odds ratios (ORs) of a new diagnosis of obstructive lung disease and of CHD were 1.7 (1.1-2.7) and 1.7 (1.0-2.9), respectively. Male sex had an OR of 1.4 (1.1-1.8) compared to women in the multivariable model, whereas the ORs of an educational length of 13-16 years and ≥17 years compared to shorter education were 1.6 (1.1-2.2) and 2.5 (1.5-4.1), respectively. CONCLUSION: The general trend of smoking cessation in the population was confirmed. Increased rates of smoking cessation were associated with a new diagnosis of heart or lung disease, and obstructive lung disease was just as strongly linked to smoking cessation as was CHD. This should encourage the pursuit of early diagnosis of COPD.

Radiobiological treatment planning evaluation of inverse planning simulated annealing for cervical cancer high-dose-rate brachytherapy.

AIM: To compare five inverse treatment plans with one conventional manually-optimized plan for cervical cancer brachytherapy (BT) using radiobiological parameters combined with dosimetric and volumetric parameters. MATERIALS AND METHODS: Five inverse treatment plans were calculated using an inverse planning simulated annealing (IPSA) algorithm for each of four fractions for 12 cervical cancer patients treated with high-dose-rate (HDR) brachytherapy. The inverse treatment plans were compared to a manually-optimized plan used for the actual treatment of the patients. The comparison of the plans was performed with respect to the probability of cure without complication (P+). RESULTS: Overall, the manually optimized plan scored the best results; however, the probability of cure without complication is within an acceptable clinical range for all the plans. CONCLUSION: Although there are still considerable uncertainties in the radiobiological parameters, the radiobiological plan evaluation method presents itself as a potential complement to physical dosimetric methods.

Dosimetric evaluation of manually and inversely optimized treatment planning for high dose rate brachytherapy of cervical cancer.

BACKGROUND: To compare five inverse treatment planning methods with the conventional manually optimized planning approach for brachytherapy of cervical cancer with respect to dosimetric parameters. MATERIAL AND METHODS: Eighteen cervical cancer patients treated with magnetic resonance imaging (MRI)-guided high dose rate (HDR) brachytherapy were included in this study. Six plans were created for each of the 4 HDR brachytherapy fractions for each patient: 1 manually optimized and 5 inversely planned. Three of these were based on inverse planning simulated annealing (IPSA) with and without extra constraints on maximum doses of the target volume, and different constraints on doses to the organs at risk (OARs). In addition there were two plans based on dose to target surface points. The resulting dose-volume histograms were analyzed and compared from the dosimetric point of view by quantifying specific dosimetric parameters, such as clinical target volume (CTV) D90, CTV D100, conformal index (COIN), and D2cm3 for rectum, bladder and the sigmoid colon. RESULTS: Manual optimization led to a mean target coverage of 78.3% compared to 87.5%, 91.7% and 82.5% with the three IPSA approaches (p < 0.001). Similar COIN values for manual and inverse optimization were found. The manual optimization led to better results with respect to the dose to the OARs expressed as D2cm3. Overall, the best results were obtained with manual optimization and IPSA plans with volumetric constraints including maximum doses to the target volume. CONCLUSIONS: Dosimetric evaluation of manual and inverse optimization approaches is indicating the potential of IPSA for brachytherapy of cervical cancer. IPSA with constraints of maximum doses to the target volume is closer related to manual optimization than plans with constraints only to minimum dose to the target volume and maximum doses to OARs. IPSA plans with proper constraints performed better than those based on dose to target surface points and manually optimized plans.

Adaptive brachytherapy of cervical cancer, comparison of conventional point A and CT based individual treatment planning.

BACKGROUND: Locally advanced cervical cancer is commonly treated with external radiation therapy combined with local brachytherapy. The brachytherapy is traditionally given based on standard dose planning with prescription of dose to point A. Dosimetric aspects when changing from former standard treatment to individualized treatment plans based on computed tomography (CT) images are here investigated. MATERIAL AND METHODS: Brachytherapy data from 19 patients with a total of 72 individual treatment fractions were retrospectively reviewed. Standard library plans were analyzed with respect to doses to organs at risk (OARs), and the result was compared to corresponding delivered individualized plans. The theoretical potential of further optimization based on prescription to target volumes was investigated. The treatments were performed with a Fletcher applicator. RESULTS: For standard treatment planning, the tolerance dose limits were exceeded in the bladder, rectum and sigmoid in 26%, 4% and 15% of the plans, respectively. This was observed most often for the smallest target volumes. The individualized planning of the delivered treatment gave the possibility of controlling the dose to critical organs to below certain limits. The dose was still prescribed to point A. An increase in target dose coverage was achieved when additional individual optimization was performed, while still keeping the dose to the OARs below predefined limits. Relatively low average target coverage, especially for the largest volumes was however seen. CONCLUSION: The individualized delivered treatment plans ensured that doses to OARs were within acceptable limits. This was not the case in 42% of the corresponding standard plans. Further optimized treatment plans were found to give an overall better dose coverage. In lack of MR capacity, it may be favorable to use CT for planning due to possible protection of OARs. The CT based target volumes were, however, not equivalent to the volumes described in magnetic resonance imaging (MRI) based recommendations. Prescription and assessment of dose, when introducing such target volumes, should be evaluated and preferably compared to well known treatment regimens.

Relative biological effectiveness of photon energies used in brachytherapy and intraoperative radiotherapy techniques for two breast cancer cell lines.

BACKGROUND: Partial breast irradiation (IORT or brachytherapy) differ from external radiation of whole breast in terms of irradiated volumes, fractionation, radiation energy and dose rate; all factors influencing the treatment outcome in a complex manner. Theoretically obtained RBE values comparing effects of radiation used in IORT and external therapy are published, but experimental studies are required to confirm these data. The aim of this study is to establish such RBE values for two breast cancer cell lines. MATERIALS AND METHODS: Colony formation of breast cancer cell lines (MCF-7 and T-47D) were studied after photon irradiation with qualities and dose rates used in IORT, brachytherapy and external radiation. RBE values from survival data were used to compare effects. RESULTS: Increasing the photon energy (dose rate 0.2 Gy/min) from 50 kV (Intrabeam) to 380 keV (¹9²Ir source) and 6 MV (linear accelerator) yielded an increase in the cell survival, whereas increasing the dose rate to 6 Gy/min had minor effect. Average RBE values for 50 kV with 6 MV as reference radiation varied from about 1.4 (for doses < 5 Gy) to > 1.9 (for doses < 0.02 Gy) for MCF-7 cells and from about 1.4 to > 3.1 for T-47D cells for the same dose levels. Corresponding RBE values for 380 keV radiation were about 1.4 for MCF-7 cells and 1.3-2.3 for T-47D cells. CONCLUSION: RBE data for breast cancer cells exposed to radiation used in IORT, brachytherapy or external radiation differ among the cell lines tested. The values are in agreement with published theoretical and experimental work.

The influence of charge density of chitosan in the compaction of the polyanions DNA and xanthan.

In this study the relative importance of valence and charge density of the polycation chitosan on the compaction process of DNA and xanthan is investigated. Chitosans with approximately equal valence but differing in their charge density were employed to form polyelectrolyte complexes with the two polyanions. The resulting structures (toroids, rods, and globules) have been visualized by AFM. For DNA-chitosan the complexation process was additionally studied by utilizing the fluorescent probe ethidium bromide. The results show that not only the total charge per chitosan molecule (valence), but also the charge density is important in determining the association with polyanions such as DNA and xanthan. Furthermore, it is demonstrated that the pH at which the complexation takes place is an important parameter in the complexation process, influencing the structures formed.

Influence of chitosan structure on the formation and stability of DNA-chitosan polyelectrolyte complexes.

The interactions between DNA and chitosans varying in fractional content of acetylated units (FA), degree of polymerization (DP), and degree of ionization were investigated by several techniques, including an ethidium bromide (EtBr) fluorescence assay, gel retardation, atomic force microscopy, and dynamic and electrophoretic light scattering. The charge density of the chitosan and the number of charges per chain were found to be the dominating factors for the structure and stability of DNA-chitosan complexes. All high molecular weight chitosans condensed DNA into physically stable polyplexes; however, the properties of the complexes were strongly dependent on FA, and thereby the charge density of chitosan. By employing fully charged oligomers of constant charge density, it was shown that the complexation of DNA and stability of the polyplexes is governed by the number of cationic residues per chain. A minimum of 6-9 positive charges appeared necessary to provide interaction strength comparable to that of polycations. In contrast, further increase in the number of charges above 9 did not increase the apparent binding affinity as judged from the EtBr displacement assay. The chitosan oligomers exhibited a pH-dependent interaction with DNA, reflecting the number of ionized amino groups. The complexation of DNA and the stability of oligomer-based polyplexes became reduced above pH 7.4. Such pH-dependent dissociation of polyplexes around the physiological pH is highly relevant in gene delivery applications and might be one of the reasons for the high transfection activity of oligomer-based polyplexes observed.

Glycosaminoglycan destabilization of DNA-chitosan polyplexes for gene delivery depends on chitosan chain length and GAG properties.

Chitosan-based gene delivery systems are promising candidates for non-viral gene therapy. A wide range of chitosans has been studied to optimize the properties of the DNA-chitosan complexes to yield high transfection efficiencies. An important parameter to control is the polyplex stability to allow transport towards the cells, subsequent internalization and release of DNA intracellularly. The stability of the DNA-chitosan complexes was here studied after exposure to heparin and hyaluronic acid (HA) using atomic force microscopy (AFM) and ethidium bromide (EtBr) fluorescence assay. To study the effect of polycation chain length on the polyplex stability, chitosans with a degree of polymerization (DP) varying from approximately 10 to approximately 1000 were employed for DNA compaction. Whereas HA was unable to dissociate the complexes, the degree of dissociation caused by heparin depended on both the chitosan chain length and the amount of chitosan used for complexation. When increasing the chitosan concentration, larger heparin concentrations were required for polyplex dissociation. Furthermore, increasing the chitosan chain length yielded more stable complexes. Varying the chitosan chain length thus provides a tool for controlling the ability of the polyplex to deliver therapeutic gene vectors to cells.

DNA-polycation complexation and polyplex stability in the presence of competing polyanions.

Polyelectrolyte complex (polyplex) formation was studied by employing tapping mode atomic force microscopy (AFM) and an ethidium bromide fluorescence assay. The polycations chitosan and poly-L-lysine were used to compact DNA and the stability of the polyplexes was evaluated upon exposure to competing polyanions (alginate and xanthan). Furthermore, the relative preference of these polycations for DNA and the competing polyanion was investigated. The results showed that neither poly-L-lysine nor chitosan displayed any selectivity in binding to DNA relative to the competing polyanions, demonstrating the importance of electrostatics in the binding of a polycation to a polyanion. However, the ability of the polyanions to destabilize the DNA-polycation complexes depended on both the polyanion and the polycation employed, indicating that polymer-specific properties are also important for the complexation behavior and polyplex stability. Destabilization experiments further showed that annealing yielded complexes that were less prone to disruption upon subsequent exposure to alginate. Annealing experiments of plasmid DNA-chitosan complexes showed an increased fraction of rods following temperature treatment, indicating that the rods most likely are the more stable morphology for this system.

Structural analysis of chitosan mediated DNA condensation by AFM: influence of chitosan molecular parameters.

Chitosan is a nontoxic and biodegradable polysaccharide that has recently emerged as a promising candidate for gene delivery. Here the ability of various chitosans, differing in the fractional content of acetylated units (F(A)) and the degree of polymerization (DP), to compact DNA was studied. Polyplexes made from mixing plasmid DNA with chitosan yielded a blend of toroids and rods, as observed by AFM. The ratios between the fractions of toroids and rods were observed to decrease with increasing F(A) of the chitosan, indicating that the charge density of chitosan, proportional to (1 - F(A)), is important in determining the shape of the compacted DNA. The amount of chitosan required to fully compact DNA into well-defined toroidal and rodlike structures were found to be strongly dependent on the chitosan molecular weight, and thus its total charge. A higher charge ratio (+/-) was needed for the shorter chitosans, showing that an increased concentration of the low DP chitosan could compensate for the reduced interaction strength of the individual ligands with DNA. Employing chitosans with different molecular parameters offers the possibility of designing DNA-chitosan polyplexes with various geometries, reflecting various chitosan-DNA interaction strengths, which is necessary for the evaluation of efficient gene delivery vehicles.

Force spectroscopy of collagen fibers to investigate their mechanical properties and structural organization.

Tendons are composed of collagen and other molecules in a highly organized hierarchical assembly, leading to extraordinary mechanical properties. To probe the cross-links on the lower level of organization, we used a cantilever to pull substructures out of the assembly. Advanced force probe technology, using small cantilevers (length <20 microm), improved the force resolution into the sub-10 pN range. In the force versus extension curves, we found an exponential increase in force and two different periodic rupture events, one with strong bonds (jumps in force of several hundred pN) with a periodicity of 78 nm and one with weak bonds (jumps in force of <7 pN) with a periodicity of 22 nm. We demonstrate a good correlation between the measured mechanical behavior of collagen fibers and their appearance in the micrographs taken with the atomic force microscope.