Monsoonal wet season influences the migration tendency of a catadromous fish (barramundi Lates calcarifer).

Many animals exhibit partial migration, which occurs when populations contain coexisting contingents of migratory and resident individuals. This individual-level variation in migration behaviour may drive differences in growth, age at maturity and survival. Therefore, partial migration is widely considered to play a key role in shaping population demography. Otolith chemistry and microstructural analysis were used to identify the environmental- and individual-specific factors that influence migratory behaviour in the facultatively catadromous barramundi (Lates calcarifer) at two distinct life history stages: firstly, as juveniles migrating upstream into fresh water; and secondly, as adults or sub-adults returning to the estuarine/marine spawning habitat. Monsoonal climate played an important role in determining the migration propensity of juveniles: individuals born in the driest year examined (weak monsoon) were more than twice as likely to undergo migration to freshwater than those born in the wettest (strong monsoon) year. In contrast, the ontogenetic timing of return migrations to the estuary by adults and sub-adults was highly variable and not strongly associated with the environmental parameters examined. We propose that scarce resources within saline natal habitats during lower rainfall years may provide an ecological incentive for juveniles to migrate upstream, whereas more abundant resources in higher rainfall years may promote resident life histories within estuaries. We conclude that inter-annual climatic variation, here evidenced by monsoonal strength, likely plays an important role in driving the persistence of diversified life histories within wild barramundi populations.

Influence of life history variation and habitat on mercury bioaccumulation in a high-order predatory fish in tropical Australia.

Mercury distribution and bioaccumulation in aquatic ecosystems of tropical Australia is poorly characterised. Barramundi (Lates calcarifer), a widespread high-order predator in both fresh and coastal marine waters of the region, fulfils requirements for a bio-indicator of mercury contamination. In a study of the Mary River system of the Northern Territory, total mercury in the muscle tissue of 300 specimens gathered over four years (2013-2017, across both wet and dry seasons) was determined by direct combustion-atomic absorption spectrometry. Source of nutrition and trophic position of barramundi in the food web was also estimated via carbon and nitrogen isotopes (δ13C and δ15N), respectively, in tissue by stable isotope mass spectrometry, and determination of strontium isotopes (87Sr/86Sr) in otoliths by laser ablation-ICPMS differentiated between freshwater and saltwater residence. Results showed that fish moving into freshwater floodplain wetlands concentrated mercury in muscle tissue at approximately twice the level of those that remained in saline habitats. Resolving life histories through otolith analyses demonstrated diversity in mercury bioaccumulation for individual fish of the same migratory contingent on the floodplains. Although trophic level (δ15N), capture location, source of nutrition (δ13C), and age or size partly predicted mercury concentrations in barramundi, our results suggest that individual variability in diets, migration patterns and potentially metabolism are also influential. Using a migratory fish as a bio-indicator, and tracking its life history and use of resources, proved valuable as a tool to discern hot spots in a coastal waterway for a contaminant, such as mercury.

Environmental drivers of recruitment in a tropical fishery: Monsoonal effects and vulnerability to water abstraction.

Fisheries and natural water resources across the world are under increasing pressure from human activity, including fishing and irrigated agriculture. There is an urgent need for information on the climatic/hydrologic drivers of fishery productivity that can be readily applied to management. We use a generalized linear mixed model framework of catch curve regression to resolve the key climatic/hydrological drivers of recruitment in Barramundi Lates calcarifer using biochronological (otolith aging) data collected from four river-estuary systems in the Northern Territory, Australia. These models were then used to generate estimates of the year class strength (YCS) outcomes of different water abstraction scenarios (ranging from 10% to 40% abstraction per season/annum) for two of the rivers in low, moderate, and high discharge years. Barramundi YCS displayed strong interannual variation and was positively correlated with regional monsoon activity in all four rivers. River-specific analyses identified strong relationships between YCS and several river-specific hydrology variables, including wet and dry season discharge and flow duration. Water abstraction scenario models based on YCS-hydrology relationships predicted reductions of >30% in YCS in several cases, suggesting that increased water resource development in the future may pose risks for Barramundi recruitment and fishery productivity. Our study demonstrates the importance of the tropical monsoon as a driver of Barramundi recruitment and the potential for detrimental impacts of increased water abstraction on fishery productivity. The biochronological and statistical approaches we used have the potential to be broadly applied to inform policy and management of water resource and fisheries.

Faster juvenile growth promotes earlier sex change in a protandrous hermaphrodite (barramundi Lates calcarifer).

The relationship between growth and sexual maturation is central to understanding the dynamics of animal populations which exhibit indeterminate growth. In sequential hermaphrodites, which undergo post-maturation sex change, the size and age at which sex change occurs directly affects reproductive output and hence population productivity. However, these traits are often labile, and may be strongly influenced by heterogenous growth and mortality rates. We analysed otolith microstructure of a protandrous (i.e., male-to-female) fish (barramundi Lates calcarifer) to examine growth in relation to individual variation in the timing of sex change. Growth trajectories of individuals with contrasting life histories were examined to elucidate the direction and extent to which growth rate influences the size and age individuals change sex. Then, the relationships between growth rate, maturation schedules and asymptotic maximum size were explored to identify potential trade-offs between age at female maturity and growth potential. Rapid growth was strongly associated with decreased age at sex change, but this was not accompanied by a decrease in size at sex change. Individuals that were caught as large females grew faster than those caught as males, suggesting that fast-growing individuals ultimately obtain higher fitness and therefore make a disproportionate contribution to population fecundity. These results indicate that individual-level variation in maturation schedules is not reflective of trade-offs between growth and reproduction. Rather, we suggest that conditions experienced during the juvenile phase are likely to be a key determinant of post-maturation fitness. These findings highlight the vulnerability of sex-changing species to future environmental change and harvest.

Safety of thoracic radiotherapy in patients with prior immune-related adverse events from immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) and thoracic radiotherapy are increasingly used to treat advanced cancers. Despite data indicating exaggerated radiation toxicities in patients with autoimmune disease, the safety of thoracic radiotherapy in patients with prior ICI-associated immune-related adverse events (irAEs) is undefined. PATIENTS AND METHODS: Patients treated from 2014 to 2020 with ICIs were queried for receipt of corticosteroids and radiotherapy. Patients who received thoracic radiation after symptomatic irAEs were assessed for ≥grade 2 radiation pneumonitis (RP). Characteristics predictive of RP were assessed using logistic regression and response relationships were modeled. RESULTS: Among 496 assessed patients, 41 with irAE history subsequently treated with thoracic radiotherapy were analyzed. Most irAEs were grade 2 (n = 21) and 3 (n = 19). Median time from irAE onset to radiotherapy was 8.1 months. Most patients received stereotactic body radiation therapy (n = 20) or hypofractionated radiotherapy (n = 18). In total, 25 patients (61%) developed ≥grade 2 RP at a median of 4 months from radiotherapy and 11 months from onset of irAEs. Three months from RP onset, 16 of 24 (67%) assessable patients had persistent symptoms. Among patients with prior ICI pneumonitis (n = 6), five patients (83%) developed ≥grade 2 RP (grade 2, n = 3; grade ≥3, n = 2). The mean lung radiation dose (MLD) predicted for RP (odds ratio: 1.60, P = 0.00002). The relationship between MLD and RP was strong (area under the receiver-operating characteristic curve: 0.85) and showed an exaggerated dose-response. Among patients with an MLD >5 Gy (n = 26), 21 patients (81%) developed ≥grade 2 RP. CONCLUSION: This is the first study assessing the toxicity of radiotherapy among patients with prior irAEs from ICIs. Patients with prior irAEs were found to be at very high risk for clinically significant and persistent RP from thoracic radiotherapy. Careful consideration should be given to the possibility of an increased risk of RP, and close monitoring is recommended in these patients.

Does combination therapy work in chronic thromboembolic pulmonary hypertension?

OBJECTIVE: The current experience with combination therapy in chronic thromboembolic pulmonary hypertension (CTEPH) is limited. We present the first survival results up to 5 years for dual combination therapy versus monotherapy in CTEPH. METHODS: All consecutive, non-operated CTEPH or residual PH after pulmonary endarterectomy patients treated with PH-specific medical therapy between January 2002 and November 2019 were included. We report and compare survival between monotherapy and (upfront or sequential) dual combination therapy until five years after medication initiation. RESULTS: In total, 183 patients (mean age 65 ± 14 years, 60% female, 66% WHO FC III/IV, 86% non-operated) were included, of which 83 patients received monotherapy and 100 patients received dual combination therapy. At baseline, patients receiving combination therapy had a higher NT-proBNP (p = 0.02) mean pulmonary artery pressure (p = 0.0001) and pulmonary vascular resistance (p = 0.02), while cardiac index was lower (p = 0.03). Total follow-up duration was 3.3 ± 1.8 years, during which 31 (17%) patients died. Estimated 1-, 3- and 5-year survival for monotherapy were 99%, 92% and 79%, respectively. For combination therapy percentages were 98%, 89% and 70%, respectively. Survival did not significantly differ between both groups (p = 0.22). CONCLUSION: Survival up to 5 years for patients treated with combination therapy, regardless of the combination strategy, was similar as patients with monotherapy, despite worse clinical and haemodynamic baseline characteristics.

Long-term real world clinical outcomes of macitentan therapy in chronic thromboembolic pulmonary hypertension.

BACKGROUND: Macitentan treatment for chronic thromboembolic pulmonary hypertension (CTEPH) in the routine clinical setting is increasing. However, 'real world' macitentan experience is scarce and is needed to differentiate from controlled clinical trial settings. OBJECTIVE: We describe our outcomes and clinical 'real world' experience of macitentan mono- and combination therapy with riociguat or sildenafil in CTEPH. METHODS: We included all consecutive CTEPH patients, either non-operated or with residual PH after pulmonary endarterectomy (PEA), treated with macitentan in the St. Antonius hospital in Nieuwegein, the Netherlands, between 01-2014 and 11-2019. We describe clinical outcomes and adverse events (AEs) until 2 years after macitentan initiation. RESULTS: In total 73 CTEPH patients on macitentan were included, of which 18 patients were clinically inoperable (n = 7 declined PEA, n = 11 nonacceptable risk-benefit) and 55 had technically inoperable CTEPH (n = 48)/residual PH (n = 7). Clinically inoperable patients (mean age 72.4 ± 10.2 years, 61% female, 28% macitentan monotherapy, observation period 2.0 (1.9-2.0) years) had a survival of 100% and clinical worsening (CW)-free survival of 88% at 2-year follow-up respectively, with a significant increased 6-min walking distance (6MWD). Technically inoperable/residual PH patients (mean age 62.1 ± 14.1 years, 60% female, 27% macitentan monotherapy, observation period 2.0 (1.0-2.0) years) had a 2-year survival and CW-free survival of 86% and 68% respectively, with significant improved 6MWD and NT-proBNP. Nonsevere AEs were reported in 30% of all patients. CONCLUSION: Macitentan mono- and combination therapy in non-operated CTEPH and residual PH is safe and improves clinical outcomes till 2-year follow-up.

Safety and efficacy of balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension in the Netherlands.

BACKGROUND: Balloon pulmonary angioplasty (BPA) is an emerging treatment in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and chronic thromboembolic disease (CTED). We describe the first safety and efficacy results of BPA in the Netherlands. METHODS: We selected all consecutive patients with inoperable CTEPH and CTED accepted for BPA treatment who had a six-month follow-up in the St. Antonius Hospital in Nieuwegein and the Amsterdam University Medical Center (UMC) in Amsterdam. Functional class (FC), N­terminal pro-brain natriuretic peptide (NT-proBNP), 6­minute walking test distance (6MWD) and right-sided heart catheterisation were performed at baseline and six months after last BPA. Complications for each BPA procedure were noted. RESULTS: A hundred and seventy-two BPA procedures were performed in 38 patients (61% female, mean age 65 ± 15 years). Significant improvements six months after BPA treatment were observed for functional class (63% FC I/II to 90% FC I/II, p = 0.014), mean pulmonary artery pressure (-8.9 mm Hg, p = 0.0001), pulmonary vascular resistance (-2.8 Woods Units (WU), p = 0.0001), right atrial pressure (-2.0 mm Hg, p = 0.006), stroke volume index (+5.7 ml/m2, p = 0.009) and 6MWD (+48m, p = 0.007). Non-severe complications occurred in 20 (12%) procedures. CONCLUSIONS: BPA performed in a CTEPH expert centre is an effective and safe treatment in patients with inoperable CTEPH.

Tracking the resource pulse: Movement responses of fish to dynamic floodplain habitat in a tropical river.

Natural river floodplains are among the Earth's most biologically diverse and productive ecosystems but face a range of critical threats due to human disturbance. Understanding the ecological processes that support biodiversity and productivity in floodplain rivers is essential for their future protection and rehabilitation. Fish assemblage structure on tropical river floodplains is widely considered to be driven by dispersal limitation during the wet season and by environmental filtering and interspecific interactions during the dry season. However, the individual-level movement behaviours (e.g. site attachment, nomadism, homing) that regulate dispersal of fish on floodplains are poorly understood. We combined radiotelemetry and remote sensing to examine the movement behaviour of two large-bodied fishes (barramundi Lates calcarifer, forktail catfish Neoarius leptaspis) over the flood cycle in a tropical river-floodplain system in northern Australia to: (a) quantify movement responses in relation to dynamic habitat resources at a landscape scale; and (b) determine the extent of spatial 'reshuffling' of individual fish following the wet season. Both species altered their behaviour rapidly in response to changes in the availability and distribution of aquatic habitat, with most individuals undertaking extensive movements (up to ~27 km from the tagging location) on the inundated floodplain during the wet season. Although there was considerable individual variation in movement patterns, overall barramundi distributions closely tracked the extent of floodplain primary productivity, whereas catfish distributions were most closely associated with the extent of flooded area. Most individuals of both species exhibited homing back to previously occupied dry season refugia during the wet-to-dry transition, even though other potential refugia were available in closer proximity to wet season activity areas. We postulate that homing behaviour modulates temporal variation in fish assemblage composition and abundance and limits the transfer of aquatic-derived energy and nutrients into terrestrial food webs by reducing fish mortality on drying floodplains. Our study demonstrates the importance of quantifying individual-level behaviour across the three stages of dispersal (emigration, inter-patch movement, immigration) for our understanding of how animal movement influences energetic subsidies and other large-scale ecosystem processes.

Does a bigger mouth make you fatter? Linking intraspecific gape variability to body condition of a tropical predatory fish.

In gape-limited predators, gape size restricts the maximum prey size a predator is capable to ingest. However, studies investigating the energetic consequences of this relationship remain scarce. In this study, we tested the hypothesis that gape-size variability influences individual body condition (a common proxy for fitness) in one of the largest freshwater teleost predators, the barramundi. We found that individual barramundi with larger gapes relative to body size had higher body condition values compared to conspecifics with smaller gapes. Body condition was highest soon after the wet season, a period of high feeding activity on productive inundated floodplains, and body condition decreased as the dry season progressed when fish were restricted to dry season remnant habitats. The increased condition obtained during the wet season apparently offsets weight loss through the dry season, as individuals with large gapes were still in better condition than fish with small gapes in the late-dry season. Elucidation of the links between intraspecific variability in traits and performance is a critical challenge in functional ecology. This study emphasizes that even small intraspecific variability in morphological trait values can potentially affect individual fitness within a species' distribution.

Bosentan or Macitentan Therapy in Chronic Thromboembolic Pulmonary Hypertension?

OBJECTIVE: Research comparing bosentan and macitentan in chronic thromboembolic pulmonary hypertension (CTEPH) is scarce, although macitentan might have superior pharmacologic properties. We present the first real-world, 2-year follow-up results and compare clinical outcomes of both drugs in CTEPH. METHODS: All consecutive, technical inoperable or residual CTEPH patients receiving bosentan or macitentan, diagnosed in our multidisciplinary team between January 2003 and January 2019, were included. We report and compare survival, clinical worsening (CW), adverse events, WHO FC, NT-proBNP and 6-min walking test (6MWT) until 2 years after medication initiation. RESULTS: In total, 112 patients receiving bosentan or macitentan (58% female, mean age 62 ± 14 years, 68% WHO FC III/IV, 51% bosentan) could be included. Mean treatment duration was 1.9 ± 0.4 years for bosentan and 1.2 ± 0.6 years for macitentan. Two-year survival rate was 91% for bosentan and 80% for macitentan (HR mortality macitentan 1.85 [0.56-6.10], p = 0.31). Two-year CW-free survival was 81% and 58%, respectively (HR CW macitentan 2.16 [0.962-4.87], p = 0.06). Right atrial pressure, cardiac output (for mortality alone) and 6MWT lowest saturation were multivariate predictors at baseline. Overall adverse event rates were comparable and WHO FC, NT-proBNP and 6MWT distance improved similar for both drugs till 2-year follow-up. CONCLUSION: CTEPH patients receiving bosentan or macitentan have improved clinical outcomes till 2-year follow-up, without significant differences in outcomes between both therapies.

Migration to freshwater increases growth rates in a facultatively catadromous tropical fish.

Diadromy is a form of migration where aquatic organisms undergo regular movements between fresh and marine waters for the purposes of feeding and reproduction. Despite having arisen in independent lineages of fish, gastropod molluscs and crustaceans, the evolutionary drivers of diadromous migration remain contentious. We test a key aspect of the 'productivity hypothesis', which proposes that diadromy arises in response to primary productivity differentials between marine and freshwater habitats. Otolith chemistry and biochronology data are analysed in a facultatively catadromous tropical fish (barramundi, Lates calcarifer) to determine the effect of freshwater residence on growth rates. Individuals that accessed freshwater grew ~ 25% faster on average than estuarine residents in the year following migration, suggesting that catadromy provides a potential fitness advantage over non-catadromous (marine/estuarine) life histories, as predicted by the productivity hypothesis. Although diadromous barramundi exhibited faster growth than non-diadromous fish, we suggest that the relative reproductive success of diadromous and non-diadromous contingents is likely to be strongly influenced by local environmental variability such as temporal differences in river discharge, and that this may facilitate the persistence of diverse life history strategies within populations.

Toward personalized dose-prescription in locally advanced non-small cell lung cancer: Validation of published normal tissue complication probability models.

PURPOSE: To identify published normal tissue complication probability (NTCP) models suitable for patient-specific dose-prescription in locally advanced non-small cell lung cancer (LA-NSCLC) through in-house validation. MATERIAL AND METHODS: From eight previously published candidate NTCP models (≥grade 2 acute esophagitis and radiation pneumonitis; AE2, RP2), patient-specific dose-responses were calculated using model variables and fractionation-corrected doses for 241 LA-NSCLC patients treated with chemo-IMRT to 50-80 Gy@1.8-2.0 Gy between 2004 and 2014 (AE2/RP2 rate: 50%/12%). A model was judged final if it significantly predicted AE2 or RP2 (p ≤ 0.05), was discriminative and well calibrated (AUC > 0.60; Hosmer-Lemeshow test pHL > 0.05), which were assessed as the median over 1000 bootstrap samples. RESULTS: Models for AE2 had superior discrimination to RP2 models (AUC = 0.63-0.65 vs. 0.51-0.65). The final AE2 model included mean esophageal dose and concurrent chemotherapy (AUC = 0.65; p < 0.0001). The final RP2 model was a slightly adjusted version of the RP2 model with the best discrimination, and included age, mean lung dose, and pulmonary comorbidity (AUC = 0.73; p < 0.0001). CONCLUSION: Of the eight investigated and published NTCP models, one model successfully described AE2 and one slightly adjusted model successfully described RP2 in the independent cohort. Estimates from these two NTCP models will, therefore, be considered internally when prescribing patient-specific doses in LA-NSCLC patients.

Long-term clinical value and outcome of riociguat in chronic thromboembolic pulmonary hypertension.

BACKGROUND: To improve clinical outcome, patients with inoperable and residual chronic thromboembolic pulmonary hypertension (CTEPH) can be treated with riociguat. The aim of this study is to explore long-term outcomes and to compare our 'real world' data with previous research. METHODS: We included all consecutive patients with technical inoperable and residual CTEPH, in whom riociguat therapy was initiated from January 2014 onwards, with patients followed till January 2019. Survival, clinical worsening (CW), functional class (FC), N-terminal pro brain natriuretic peptide (NT-proBNP) and 6-minute walking distance (6MWD) were described yearly after riociguat initiation. RESULTS: Thirty-six patients (50% female, mean age 64.9 ±â€¯12.1 years, 54% WHO FC III/IV and 6MWD 337 ±â€¯138 m could be included, with a mean follow-up of 2.3 ±â€¯1.2 years. Survival and CW-free survival three years after initiation of riociguat were 94% and 78%, respectively. The 6MWD per 10 m at baseline was a significant predictor (HR 0.90 [0.83-0.97], p = 0.009) for CW. At three years follow-up the WHO FC and 6MWD improved and NT-proBNP decreased compared to baseline. CONCLUSION: Our study confirms that riociguat is an effective treatment in patients with technical inoperable and residual CTEPH at long-term follow-up. Although our results are consistent with previous studies, more 'real world' research is necessary to confirm long-term results.

Treatment data and technical process challenges for practical big data efforts in radiation oncology.

The term Big Data has come to encompass a number of concepts and uses within medicine. This paper lays out the relevance and application of large collections of data in the radiation oncology community. We describe the potential importance and uses in clinical practice. The important concepts are then described and how they have been or could be implemented are discussed. Impediments to progress in the collection and use of sufficient quantities of data are also described. Finally, recommendations for how the community can move forward to achieve the potential of big data in radiation oncology are provided.

Temporal patterns of patient-reported trismus and associated mouth-opening distances in radiotherapy for head and neck cancer: A prospective cohort study.

OBJECTIVES: To identify temporal patterns of patient-reported trismus during the first year post-radiotherapy, and to study their associations with maximal interincisal opening distances (MIOs). DESIGN: Single institution case series. SETTING: University hospital ENT clinic. PARTICIPANTS: One hundred and ninety-six subjects who received radiotherapy (RT) for head and neck cancer (HNC) with or without chemotherapy in 2007-2012 to a total dose of 64.6/68 Gy in 38/34 fractions, respectively. All subjects were prospectively assessed for mouth-opening ability (Gothenburg Trismus Questionnaire (GTQ), European Organization for Research and Treatment of Cancer quality of life Questionnaire (EORTC QLQ-H&N35), and MIO) pre-RT and at 3, 6 and 12 months after RT. MAIN OUTCOME MEASURES: Correlations between temporally robust GTQ symptoms and MIO as given by Pearson's correlation coefficients (Pr ); temporally robust GTQ-symptom domains as given by factor analysis; rates of trismus with respect to baseline by risk ratios (RRs). RESULTS: Four temporally robust domains were identified: Eating (3-7 symptoms), Jaw (3-7), Pain (2-5) and Quality of Life (QoL, 2-5), and included 2-3 persistent symptoms across all post-RT assessments. The median RR for a moderate/severe (>2/>3) cut-off was the highest for Jaw (3.7/3.6) and QoL (3.2/2.9). The median Pr between temporally robust symptoms and MIO post-radiotherapy was 0.25-0.35/0.34-0.43/0.24-0.31/0.34-0.50 for Eating/Jaw/Pain/QoL, respectively. CONCLUSIONS: Mouth-opening distances in patients with HNC post-RT can be understood in terms of associated patient-reported outcomes on trismus-related difficulties. Our data suggest that a reduction in MIO can be expected as patients communicate their mouth-opening status to interfere with private/social life, a clinical warning signal for emerging or worsening trismus as patients are being followed after RT.

Characterization, development and multiplexing of microsatellite markers in three commercially exploited reef fish and their application for stock identification.

Thirty-four microsatellite loci were isolated from three reef fish species; golden snapper Lutjanus johnii, blackspotted croaker Protonibea diacanthus and grass emperor Lethrinus laticaudis using a next generation sequencing approach. Both IonTorrent single reads and Illumina MiSeq paired-end reads were used, with the latter demonstrating a higher quality of reads than the IonTorrent. From the 1-1.5 million raw reads per species, we successfully obtained 10-13 polymorphic loci for each species, which satisfied stringent design criteria. We developed multiplex panels for the amplification of the golden snapper and the blackspotted croaker loci, as well as post-amplification pooling panels for the grass emperor loci. The microsatellites characterized in this work were tested across three locations of northern Australia. The microsatellites we developed can detect population differentiation across northern Australia and may be used for genetic structure studies and stock identification.

Influence of image slice thickness on rectal dose-response relationships following radiotherapy of prostate cancer.

When pooling retrospective data from different cohorts, slice thicknesses of acquired computed tomography (CT) images used for treatment planning may vary between cohorts. It is, however, not known if varying slice thickness influences derived dose-response relationships. We investigated this for rectal bleeding using dose-volume histograms (DVHs) of the rectum and rectal wall for dose distributions superimposed on images with varying CT slice thicknesses. We used dose and endpoint data from two prostate cancer cohorts treated with three-dimensional conformal radiotherapy to either 74 Gy (N = 159) or 78 Gy (N = 159) at 2 Gy per fraction. The rectum was defined as the whole organ with content, and the morbidity cut-off was Grade ≥2 late rectal bleeding. Rectal walls were defined as 3 mm inner margins added to the rectum. DVHs for simulated slice thicknesses from 3 to 13 mm were compared to DVHs for the originally acquired slice thicknesses at 3 and 5 mm. Volumes, mean, and maximum doses were assessed from the DVHs, and generalized equivalent uniform dose (gEUD) values were calculated. For each organ and each of the simulated slice thicknesses, we performed predictive modeling of late rectal bleeding using the Lyman-Kutcher-Burman (LKB) model. For the most coarse slice thickness, rectal volumes increased (≤18%), whereas maximum and mean doses decreased (≤0.8 and ≤4.2 Gy, respectively). For all a values, the gEUD for the simulated DVHs were ≤1.9 Gy different than the gEUD for the original DVHs. The best-fitting LKB model parameter values with 95% CIs were consistent between all DVHs. In conclusion, we found that the investigated slice thickness variations had minimal impact on rectal dose-response estimations. From the perspective of predictive modeling, our results suggest that variations within 10 mm in slice thickness between cohorts are unlikely to be a limiting factor when pooling multi-institutional rectal dose data that include slice thickness variations within this range.

Bladder dose accumulation based on a biomechanical deformable image registration algorithm in volumetric modulated arc therapy for prostate cancer.

Variations in bladder position, shape and volume cause uncertainties in the doses delivered to this organ during a course of radiotherapy for pelvic tumors. The purpose of this study was to evaluate the potential of dose accumulation based on repeat imaging and deformable image registration (DIR) to improve the accuracy of bladder dose assessment. For each of nine prostate cancer patients, the initial treatment plan was re-calculated on eight to nine repeat computed tomography (CT) scans. The planned bladder dose-volume histogram (DVH) parameters were compared to corresponding parameters derived from DIR-based accumulations as well as DVH summation based on dose re-calculations. It was found that the deviations between the DIR-based accumulations and the planned treatment were substantial and ranged (-0.5-2.3) Gy and (-9.4-13.5) Gy for D(2%) and D(mean), respectively, whereas the deviations between DIR-based accumulations and DVH summation were small and well within 1 Gy. For the investigated treatment scenario, DIR-based bladder dose accumulation did not result in substantial improvement of dose estimation as compared to the straightforward DVH summation. Large variations were found in individual patients between the doses from the initial treatment plan and the accumulated bladder doses. Hence, the use of repeat imaging has a potential for improved accuracy in treatment dose reporting.

Allosteric interaction of the neuromuscular blockers vecuronium and pancuronium with recombinant human muscarinic M2 receptors.

Neuromuscular blocking drugs produce muscle weakness by interaction with nicotinic-acetylcholine receptors. Cardiovascular side effects have been reported. In this study the neuromuscular blocking drug vecuronium and the controls gallamine and pancuronium slowed the rate of atropine induced [(3)H]N-methylscopolamine dissociation from Chinese hamster ovary cells expressing recombinant human muscarinic M2 receptors K(off) values min(-1); vecuronium (125 nM), atropine 0.45+/-0.07+blocker 0.04+/-0.02; gallamine (21 nM), atropine 0.42+/-0.05+blocker 0.15+/-0.04; pancuronium(21 nM), atropine 0.36+/-0.03+blocker 0.03+/-0.01). These data indicate that vecuronium, gallamine and pancuronium interact with an allosteric site on the muscarinic M2 receptor (located on the heart) and this may explain some of their cardiac side effects.