Adoption by clinicians of electronic order communications in NHS secondary care: a descriptive account.

BACKGROUND: Due to the rapid advancement in information technology, changes to communication modalities are increasingly implemented in healthcare. One such modality is Computerised Provider Order Entry (CPOE) systems which replace paper, verbal or telephone orders with electronic booking of requests. We aimed to understand the uptake, and user acceptability, of CPOE in a large National Health Service hospital system. METHODS: This retrospective single-centre study investigates the longitudinal uptake of communications through the Prescribing, Information and Communication System (PICS). The development and configuration of PICS are led by the doctors, nurses and allied health professionals that use it and requests for CPOE driven by clinical need have been described.Records of every request (imaging, specialty review, procedure, laboratory) made through PICS were collected between October 2008 and July 2019 and resulting counts were presented. An estimate of the proportion of completed requests made through the system has been provided for three example requests. User surveys were completed. RESULTS: In the first 6 months of implementation, a total of 832 new request types (imaging types and specialty referrals) were added to the system. Subsequently, an average of 6.6 new request types were added monthly. In total, 8 035 132 orders were requested through PICS. In three example request types (imaging, endoscopy and full blood count), increases in the proportion of requests being made via PICS were seen. User feedback at 6 months reported improved communications using the electronic system. CONCLUSION: CPOE was popular, rapidly adopted and diversified across specialties encompassing wide-ranging requests.

Summary of the Centers for Disease Control and Prevention/National Institute of Allergy and Infectious Diseases Joint Workshop on Genital Herpes: 3-4 November 2022.

Genital herpes is caused by infection with herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) and currently has no cure. The disease is the second-most common sexually transmitted infection in the United States, with an estimated 18.6 million prevalent genital infections caused by HSV-2 alone. Genital herpes diagnostics and treatments are not optimal, and no vaccine is currently available. The Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases convened a workshop entitled "CDC/NIAID Joint Workshop on Genital Herpes." This report summarizes 8 sessions on the epidemiology of genital herpes, neonatal HSV, HSV diagnostics, vaccines, treatments, cures, prevention, and patient advocacy perspective intended to identify opportunities in herpes research and foster the development of strategies to diagnose, treat, cure, and prevent genital herpes.

KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape.

PURPOSE: Imatinib resistance in GI stromal tumors (GISTs) is primarily caused by secondary KIT mutations, and clonal heterogeneity of these secondary mutations represents a major treatment obstacle. KIT inhibitors used after imatinib have clinical activity, albeit with limited benefit. Ripretinib is a potent inhibitor of secondary KIT mutations in the activation loop (AL). However, clinical benefit in fourth line remains limited and the molecular mechanisms of ripretinib resistance are largely unknown. PATIENTS AND METHODS: Progressing lesions of 25 patients with GISTs refractory to ripretinib were sequenced for KIT resistance mutations. Resistant genotypes were validated and characterized using novel cell line models and in silico modeling. RESULTS: GISTs progressing on ripretinib were enriched for secondary mutations in the ATP-binding pocket (AP), which frequently occur in cis with preexisting AL mutations, resulting in highly resistant AP/AL genotypes. AP/AL mutations were rarely observed in a cohort of progressing GIST samples from the preripretinib era but represented 50% of secondary KIT mutations in patients with tumors resistant to ripretinib. In GIST cell lines harboring secondary KIT AL mutations, the sole genomic escape mechanisms during ripretinib drug selection were AP/AL mutations. Ripretinib and sunitinib synergize against mixed clones with secondary AP or AL mutants but do not suppress clones with AP/AL genotypes. CONCLUSION: Our findings underscore that KIT remains the central oncogenic driver even in late lines of GIST therapy. KIT-inhibitor combinations may suppress resistance because of secondary KIT mutations. However, the emergence of KIT AP/AL mutations after ripretinib treatment calls for new strategies in the development of next-generation KIT inhibitors.

Developing and centralising a nurse-led local anaesthetic transperineal biopsy service during COVID.

Introduction: Transperineal (TP) biopsy has recently replaced the transrectal ultrasound (TRUS) approach as the ideal method of biopsy in the United Kingdom with growing trends to adopt. To minimise transmission of COVID-19 during the first wave of the pandemic, the British Association of Urological Surgeons Section of Oncology issued guidelines reducing general anaesthesia (GA) procedures and initiate COVID-secure 'green' site diagnostics. As a result of these guidelines and reduction in clinical diagnostics trust-wide, we ceased all TRUS diagnostics and implemented a centralised, nurse-led LA TP biopsy service. Materials and methods: A waiting list was developed for those awaiting prostate cancer diagnostics across the network. A COVID-secure 'green' site was quickly identified with TP biopsies starting soon after. Quality improvement methodology was utilised and a run chart was used to show if changes were sustainable. Results: Successful implementation and centralisation of a TP biopsy service occurred with TRUS guided biopsies ceasing across all sites on 12 May 2020. The procedures were carried out by urology advanced nurse practitioners under local anaesthesia with a select few occurring under GA. Centralising the service in a COVID-secure manner freed up dedicated theatre sessions and personal leading to increased efficiency elsewhere. The service was robust and was maintained upon lifting of COVID restrictions. Conclusions: A centralised, nurse led LA TP biopsy service in a procedural unit was implemented successfully. The service has remained resilient upon lifting of restrictions and return to business as usual. This led to improved performance across trust by freeing up valuable resources and staff to undertake more duties. The service remains highly valued trust-wide.

Hypnotic treatment reverses NREM sleep disruption and EEG desynchronization in a mouse model of Fragile X syndrome to rescue memory consolidation deficits.

Fragile X syndrome (FXS) is a highly-prevalent genetic cause of intellectual disability, associated with disrupted cognition and sleep abnormalities. Sleep loss itself negatively impacts cognitive function, yet the contribution of sleep loss to impaired cognition in FXS is vastly understudied. One untested possibility is that disrupted cognition in FXS is exacerbated by abnormal sleep. We hypothesized that restoration of sleep-dependent mechanisms could improve functions such as memory consolidation in FXS. We examined whether administration of ML297, a hypnotic drug acting on G-protein-activated inward-rectifying potassium channels, could restore sleep phenotypes and improve disrupted memory consolidation in Fmr1 -/y mice. Using 24-h polysomnographic recordings, we found that Fmr1 -/y mice exhibit reduced non-rapid eye movement (NREM) sleep and fragmented NREM sleep architecture, alterations in NREM EEG spectral power (including reductions in sleep spindles), and reduced EEG coherence between cortical areas. These alterations were reversed in the hours following ML297 administration. Hypnotic treatment following contextual fear or spatial learning also ameliorated disrupted memory consolidation in Fmr1 -/y mice. Hippocampal activation patterns during memory recall was altered in Fmr1 -/y mice, reflecting an altered balance of activity among principal neurons vs. parvalbumin-expressing (PV+) interneurons. This phenotype was partially reversed by post-learning ML297 administration. These studies suggest that sleep disruption could have a major impact on neurophysiological and behavioral phenotypes in FXS, and that hypnotic therapy may significantly improve disrupted cognition in this disorder.

Enriched binocular experience followed by sleep optimally restores binocular visual cortical responses in a mouse model of amblyopia.

Studies of primary visual cortex have furthered our understanding of amblyopia, long-lasting visual impairment caused by imbalanced input from the two eyes during childhood, which is commonly treated by patching the dominant eye. However, the relative impacts of monocular vs. binocular visual experiences on recovery from amblyopia are unclear. Moreover, while sleep promotes visual cortex plasticity following loss of input from one eye, its role in recovering binocular visual function is unknown. Using monocular deprivation in juvenile male mice to model amblyopia, we compared recovery of cortical neurons' visual responses after identical-duration, identical-quality binocular or monocular visual experiences. We demonstrate that binocular experience is quantitatively superior in restoring binocular responses in visual cortex neurons. However, this recovery was seen only in freely-sleeping mice; post-experience sleep deprivation prevented functional recovery. Thus, both binocular visual experience and subsequent sleep help to optimally renormalize bV1 responses in a mouse model of amblyopia.

Machine intelligence for radiation science: summary of the Radiation Research Society 67th annual meeting symposium.

The era of high-throughput techniques created big data in the medical field and research disciplines. Machine intelligence (MI) approaches can overcome critical limitations on how those large-scale data sets are processed, analyzed, and interpreted. The 67th Annual Meeting of the Radiation Research Society featured a symposium on MI approaches to highlight recent advancements in the radiation sciences and their clinical applications. This article summarizes three of those presentations regarding recent developments for metadata processing and ontological formalization, data mining for radiation outcomes in pediatric oncology, and imaging in lung cancer.

Orally Ingested Probiotic, Prebiotic, and Synbiotic Interventions as Countermeasures for Gastrointestinal Tract Infections in Nonelderly Adults: A Systematic Review and Meta-Analysis.

Meta-analyses have not examined the prophylactic use of orally ingested probiotics, prebiotics, and synbiotics for preventing gastrointestinal tract infections (GTIs) of various etiologies in adult populations, despite evidence that these gut microbiota-targeted interventions can be effective in treating certain GTIs. This systematic review and meta-analysis aimed to estimate the effects of prophylactic use of orally ingested probiotics, prebiotics, and synbiotics on GTI incidence, duration, and severity in nonelderly, nonhospitalized adults. CENTRAL, PubMed, Scopus, and Web of Science were searched through January 2022. English-language, peer-reviewed publications of randomized, placebo-controlled studies testing an orally ingested probiotic, prebiotic, or synbiotic intervention of any dose for ≥1 wk in adults who were not hospitalized, immunosuppressed, or taking antibiotics were included. Results were analyzed using random-effects meta-analyses of intention-to-treat (ITT) and complete case (CC) cohorts. Heterogeneity was explored by subgroup meta-analysis and meta-regression. The risk of bias was assessed using the Cochrane risk-of-bias 2 tool. Seventeen publications reporting 20 studies of probiotics (n = 16), prebiotics (n = 3), and synbiotics (n = 1) were identified (n > 6994 subjects). In CC and ITT analyses, risk of experiencing ≥1 GTI was reduced with probiotics (CC analysis-risk ratio: 0.86; 95% CI: 0.73, 1.01) and prebiotics (risk ratio: 0.80; 95% CI: 0.66, 0.98). No effects on GTI duration or severity were observed. Sources of heterogeneity included the study population and number of probiotic strains administered but were often unexplained, and a high risk of bias was observed for most studies. The specific effects of individual probiotic strains and prebiotic types could not be assessed owing to a lack of confirmatory studies. Findings indicated that both orally ingested probiotics and prebiotics, relative to placebo, demonstrated modest benefit for reducing GTI risk in nonelderly adults. However, results should be interpreted cautiously owing to the low number of studies, high risk of bias, and unexplained heterogeneity that may include probiotic strain-specific or prebiotic-specific effects. This review was registered at PROSPERO as CRD42020200670.

Safety and efficacy of tuberculosis vaccine candidates in low- and middle-income countries: a systematic review of randomised controlled clinical trials.

BACKGROUND: Tuberculosis (TB) remains a leading cause of death worldwide, with 98% of cases occurring in low- and middle-income countries (LMICs). The only vaccine licenced for the prevention of TB has limited protection for adolescents, adults and vulnerable populations. A safe and effective vaccine for all populations at risk is imperative to achieve global elimination of TB. We aimed to systematically review the efficacy and safety of TB vaccine candidates in late-phase clinical trials conducted in LMICs. METHODS: Medline, Embase, CENTRAL, PubMed, Clinicaltrials.gov and Greylit.org were searched in June 2021 to identify phase 2 or later clinical randomised controlled trials that report the efficacy or safety (adverse events) of TB vaccine candidates with participants of any age living in an LMIC. TB vaccine candidates listed in the 2020 WHO Global TB Report were eligible for inclusion aside from BCG revaccination. Trials were excluded if all participants had active TB at baseline. Two reviewers independently assessed papers for eligibility, and for bias and quality using the Risk of Bias 2 tool and GRADE guidelines, respectively. We report efficacy rates and frequencies of adverse events from each included trial where available and qualitatively synthesise the findings. RESULTS: Thirteen papers representing eleven trials met our inclusion criteria. Seven vaccine candidates were reviewed across seven countries: M72/AS01, RUTI, VPM1002, H56:IC31, MTBVAC, DAR-901 and ID93 + GLA-SE. Two trials reported on efficacy: an efficacy rate of 54% (95% CI 11.5, 76.2) was reported for M72/AS01 in adults with latent TB and 3% (95% CI -13.9, 17.7) for DAR-901 in healthy adolescents. However, the latter trial was underpowered. All vaccine candidates had comparable occurrences of adverse events between treatment arms and demonstrated acceptable safety profiles; though, RUTI resulted in one serious complication in a person living with HIV. M72/AS01 was the only vaccine considered safe across a diverse group of people including people living with HIV or latent TB and healthy infants and adolescents. CONCLUSION: Further efficacy trials for M72/AS01 are warranted to include additional populations at risk where safety has been demonstrated. Further safety trials are needed for the remaining vaccine candidates to confirm safety in vulnerable populations.

Atypical hypnotic compound ML297 restores sleep architecture immediately following emotionally valenced learning, to promote memory consolidation and hippocampal network activation during recall.

Sleep plays a critical role in consolidating many forms of hippocampus-dependent memory. While various classes of hypnotic drugs have been developed in recent years, it remains unknown whether, or how, some of them affect sleep-dependent memory consolidation mechanisms. We find that ML297, a recently developed candidate hypnotic agent targeting a new mechanism (activating GIRK1/2-subunit containing G-protein coupled inwardly rectifying potassium [GIRK] channels), alters sleep architecture in mice over the first 6 hr following a single-trial learning event. Following contextual fear conditioning (CFC), ML297 reversed post-CFC reductions in NREM sleep spindle power and REM sleep amounts and architecture, renormalizing sleep features to what was observed at baseline, prior to CFC. Renormalization of post-CFC REM sleep latency, REM sleep amounts, and NREM spindle power were all associated with improved contextual fear memory (CFM) consolidation. We find that improvements in CFM consolidation due to ML297 are sleep-dependent, and are associated with increased numbers of highly activated dentate gyrus (DG), CA1, and CA3 neurons during CFM recall. Together our findings suggest that GIRK1/2 channel activation restores normal sleep architecture- including REM sleep, which is normally suppressed following CFC-and increases the number of hippocampal neurons incorporated into the CFM engram during memory consolidation.

Treatment-planning approaches to intensity modulated proton therapy and the impact on dose-weighted linear energy transfer.

PURPOSE: We quantified the effect of various forward-based treatment-planning strategies in proton therapy on dose-weighted linear energy transfer (LETd). By maintaining the dosimetric quality at a clinically acceptable level, we aimed to evaluate the differences in LETd among various treatment-planning approaches and their practicality in minimizing biologic uncertainties associated with LETd. METHOD: Eight treatment-planning strategies that are achievable in commercial treatment-planning systems were applied on a cylindrical water phantom and four pediatric brain tumor cases. Each planning strategy was compared to either an opposed lateral plan (phantom study) or original clinical plan (patient study). Deviations in mean and maximum LETd from clinically acceptable dose distributions were compared. RESULTS: In the phantom study, using a range shifter and altering the robust scenarios during optimization had the largest effect on the mean clinical target volume LETd, which was reduced from 4.5 to 3.9 keV/µm in both cases. Variations in the intersection angle between beams had the largest effect on LETd in a ring defined 3 to 5 mm outside the target. When beam intersection angles were reduced from opposed laterals (180°) to 120°, 90°, and 60°, corresponding maximum LETd increased from 7.9 to 8.9, 10.9, and 12.2 keV/µm, respectively. A clear trend in mean and maximum LETd variations in the clinical cases could not be established, though spatial distribution of LETd suggested a strong dependence on patient anatomy and treatment geometry. CONCLUSION: Changes in LETd from treatment-plan setup follow intuitive trends in a controlled phantom experiment. Anatomical and other patient-specific considerations, however, can preclude generalizable strategies in clinical cases. For pediatric cranial radiation therapy, we recommend using opposed lateral treatment fields to treat midline targets.

Three-dimensional dose and LETD prediction in proton therapy using artificial neural networks.

PURPOSE: Challenges in proton therapy include identifying patients most likely to benefit; ensuring consistent, high-quality plans as its adoption becomes more widespread; and recognizing biological uncertainties that may be related to increased relative biologic effectiveness driven by linear energy transfer (LET). Knowledge-based planning (KBP) is a domain that may help to address all three. METHODS: Artificial neural networks were trained using 117 unique treatment plans and associated dose and dose-weighted LET (LETD ) distributions. The data set was split into training (n = 82), validation (n = 17), and test (n = 18) sets. Model performance was evaluated on the test set using dose- and LETD -volume metrics in the clinical target volume (CTV) and nearby organs at risk and Dice similarity coefficients (DSC) comparing predicted and planned isodose lines at 50%, 75%, and 95% of the prescription dose. RESULTS: Dose-volume metrics significantly differed (α = 0.05) between predicted and planned dose distributions in only one dose-volume metric, D2% to the CTV. The maximum observed root mean square (RMS) difference between corresponding metrics was 4.3 GyRBE (8% of prescription) for D1cc to optic chiasm. DSC were 0.90, 0.93, and 0.88 for the 50%, 75%, and 95% isodose lines, respectively. LETD -volume metrics significantly differed in all but one metric, L0.1cc of the brainstem. The maximum observed difference in RMS differences for LETD metrics was 1.0 keV/µm for L0.1cc to brainstem. CONCLUSIONS: We have devised the first three-dimensional dose and LETD -prediction model for cranial proton radiation therapy has been developed. Dose accuracy compared favorably with that of previously published models in other treatment sites. The agreement in LETD supports future investigations with biological doses in mind to enable the full potential of KBP in proton therapy.

Image-based data mining applies to data collected from children.

PURPOSE: Image-based data mining (IBDM) is a novel voxel-based method for analyzing radiation dose responses that has been successfully applied in adult data. Because anatomic variability and side effects of interest differ for children compared to adults, we investigated the feasibility of IBDM for pediatric analyses. METHODS: We tested IBDM with CT images and dose distributions collected from 167 children (aged 10 months to 20 years) who received proton radiotherapy for primary brain tumors. We used data from four reference patients to assess IBDM sensitivity to reference selection. We quantified spatial-normalization accuracy via contour distances and deviations of the centers-of-mass of brain substructures. We performed dose comparisons with simplified and modified clinical dose distributions with a simulated effect, assessing their accuracy via sensitivity, positive predictive value (PPV) and Dice similarity coefficient (DSC). RESULTS: Spatial normalizations and dose comparisons were insensitive to reference selection. Normalization discrepancies were small (average contour distance < 2.5 mm, average center-of-mass deviation < 6 mm). Dose comparisons identified differences (p < 0.01) in 81% of simplified and all modified clinical dose distributions. The DSCs for simplified doses were high (peak frequency magnitudes of 0.9-1.0). However, the PPVs and DSCs were low (maximum 0.3 and 0.4, respectively) in the modified clinical tests. CONCLUSIONS: IBDM is feasible for childhood late-effects research. Our findings may inform cohort selection in future studies of pediatric radiotherapy dose responses and facilitate treatment planning to reduce treatment-related toxicities and improve quality of life among childhood cancer survivors.

Pre- and Posttherapy Risk Factors for Vasculopathy in Pediatric Patients With Craniopharyngioma Treated With Surgery and Proton Radiation Therapy.

PURPOSE: Vasculopathy (VAS) is a significant complication associated with radiation therapy in patients treated for brain tumors. We studied the type, location, severity, timing, and resolution of VAS in children with craniopharyngioma treated with proton radiation therapy (PRT) and evaluated predictors of stenosis (STN) using a novel patient and imaging-based modeling approach. METHODS AND MATERIALS: Children with craniopharyngioma (n = 94) were treated with 54 Gy relative biological effectiveness PRT in a clinical trial, NCT01419067. We evaluated VAS type, location, severity, and resolution. VAS events were segmented and related to their location, operative corridor, PRT dose, and vascular territory to facilitate mixed effect logistic regression modeling of spatial predictors of STN events. RESULTS: Forty-five (47.9%) patients had 111 instances of confirmed VAS (pre-PRT n = 37, 33.3%). The median time to post-PRT VAS was 3.41 years (95% confidence interval, 1.86-6.11). STN events were observed post-PRT in 23.4% (n = 22) of patients. Post-PRT VAS was detected by cerebral angiogram in 9.6% (n = 9), severe in 4.3% (n = 4), and compensated on perfusion in 2.1% (n = 2). Revascularization was required for 5 (5.3%) patients. Postsurgical, pre-PRT VAS, and PRT dose to unperturbed vessels were predictive of STN. The effect of PRT on STN was negligible within the surgical corridor. CONCLUSIONS: VAS often precedes PRT and was the strongest predictor of post-PRT STN. The adverse effect of PRT on STN was only apparent in unperturbed vasculature beyond the operative corridor.

Acknowledging and overcoming barriers to entry into radiation science for women.

PURPOSE: Radiation science is a unique field that brings together various disciplines to understand nature, develop new technologies, and cure diseases. Our field is a prime example of advancement through a diverse pool of competencies. Similarly, studies show that the power of diversity requires proportionate representation of sex and gender, minorities, or other groups. Nevertheless, women are still underrepresented in the radiation sciences, although disparities and underlying mechanisms were first described decades ago. This review summarizes barriers to entry and retention and suggests strategies for overcoming disparities in our field. We also highlight a concerted effort by young professionals to promote the underrepresented and underserved within the radiation science community. CONCLUSION: The radiation science community should avoid losing diverse perspectives among its ranks due to sex bias or gender disparity among others. Through targeted efforts, we can cultivate change and harness the talent of researchers, practitioners, and other professionals for the benefit of scientific progress, health-care improvement, and societal advancement overall.

Association Between Brain Substructure Dose and Cognitive Outcomes in Children With Medulloblastoma Treated on SJMB03: A Step Toward Substructure-Informed Planning.

PURPOSE: To characterize the association between neurocognitive outcomes (memory and processing speed) and radiation (RT) dose to the hippocampus, corpus callosum (CC), and frontal white matter (WM) in children with medulloblastoma treated on a prospective study, SJMB03. PATIENTS AND METHODS: Patients age 3-21 years with medulloblastoma were treated at a single institution on a phase III study. The craniospinal RT dose was 23.4 Gy for average-risk patients and 36-39.6 Gy for high-risk patients. The boost dose was 55.8 Gy to the tumor bed. Patients underwent cognitive testing at baseline and once yearly for 5 years. Performance on tests of memory (associative memory and working memory) and processing speed (composite processing speed and perceptual speed) was analyzed. Mixed-effects models were used to estimate longitudinal trends in neurocognitive outcomes. Reliable change index and logistic regression were used to define clinically meaningful neurocognitive decline and identify variables associated with decline. RESULTS: One hundred and twenty-four patients were eligible for inclusion, with a median neurocognitive follow-up of 5 years. Mean right and left hippocampal doses were significantly associated with decline in associative memory in patients without posterior fossa syndrome (all P < .05). Mean CC and frontal WM doses were significantly associated with decline in both measures of processing speed (all P < .05). Median brain substructure dose-volume histograms were shifted to the right for patients with a decline in associative memory or processing speed. The odds of decline in associative memory and composite processing speed increased by 23%-26% and by 10%-15% for every 1-Gy increase in mean hippocampal dose and mean CC or frontal WM dose, respectively. CONCLUSION: Increasing RT dose to the CC or frontal WM and hippocampus is associated with worse performance on tests of processing speed and associative memory, respectively. Brain substructure-informed RT planning may mitigate neurocognitive impairment.

Proton therapy delivery method affects dose-averaged linear energy transfer in patients.

The dosimetric advantages of proton therapy have led to its rapid proliferation in recent decades. This has been accompanied by a shift in technology from older units that deliver protons by passive scattering (PS) to newer units that increasingly use pencil-beam scanning (PBS). The biologic effectiveness of proton physical dose purportedly rises with increasing dose-weighted average linear energy transfer (LETD). The objective of this study was to determine the extent to which proton delivery methods affect LETD. We calculated LETDfrom simple, dosimetrically matched, and clinical treatment plans with TOPAS Monte-Carlo transport code. Simple treatment plans comprised single fields of PS and PBS protons in a water phantom. We performed simulations of matched and clinical treatment plans by using the treatment and anatomic data obtained from a cohort of children with craniopharyngioma who previously received PS or PBS proton therapy. We compared the distributions of LETDfrom PS and PBS delivery methods in clinically relevant ROIs. Wilcoxon signed-rank tests comparing single fields in water revealed that the LETDvalues from PBS were significantly greater than those from PS inside and outside the targeted volume (p < 0.01). Statistical tests comparing LETD-volume histograms from matched and clinical treatment plans showed that LETDwas generally greater for PBS treatment plans than for PS treatment plans (p < 0.05). In conclusion, the proton delivery method affects LETDboth inside and outside of the target volume. These findings suggest that PBS is more biologically effective than PS. Given the rapid expansion of PBS proton therapy, future studies are needed to confirm the applicability of treatment evaluation methods developed for PS proton therapy to those for modern PBS treatments to ensure their safety and effectiveness for the growing population of patients receiving proton therapy. This study uses data from two clinical trials: NCT01419067 and NCT02792582.

Generalized approach for radiotherapy treatment planning by optimizing projected health outcome: preliminary results for prostate radiotherapy patients.

Research in cancer care increasingly focuses on survivorship issues, e.g. managing disease- and treatment-related morbidity and mortality occurring during and after treatment. This necessitates innovative approaches that consider treatment side effects in addition to tumor cure. Current treatment-planning methods rely on constrained iterative optimization of dose distributions as a surrogate for health outcomes. The goal of this study was to develop a generally applicable method to directly optimize projected health outcomes. We developed an outcome-based objective function to guide selection of the number, angle, and relative fluence weight of photon and proton radiotherapy beams in a sample of ten prostate-cancer patients by optimizing the projected health outcome. We tested whether outcome-optimized radiotherapy (OORT) improved the projected longitudinal outcome compared to dose-optimized radiotherapy (DORT) first for a statistically significant majority of patients, then for each individual patient. We assessed whether the results were influenced by the selection of treatment modality, late-risk model, or host factors. The results of this study revealed that OORT was superior to DORT. Namely, OORT maintained or improved the projected health outcome of photon- and proton-therapy treatment plans for all ten patients compared to DORT. Furthermore, the results were qualitatively similar across three treatment modalities, six late-risk models, and 10 patients. The major finding of this work was that it is feasible to directly optimize the longitudinal (i.e. long- and short-term) health outcomes associated with the total (i.e. therapeutic and stray) absorbed dose in all of the tissues (i.e. healthy and diseased) in individual patients. This approach enables consideration of arbitrary treatment factors, host factors, health endpoints, and times of relevance to cancer survivorship. It also provides a simpler, more direct approach to realizing the full beneficial potential of cancer radiotherapy.