Travel-Time Disparities in Access to Proton Beam Therapy for Cancer Treatment.

Importance: Proton beam therapy is an emerging radiotherapy treatment for patients with cancer that may produce similar outcomes as traditional photon-based therapy for many cancers while delivering lower amounts of toxic radiation to surrounding tissue. Geographic proximity to a proton facility is a critical component of ensuring equitable access both for indicated diagnoses and ongoing clinical trials. Objective: To characterize the distribution of proton facilities in the US, quantify drive-time access for the population, and investigate the likelihood of long commutes for certain population subgroups. Design, Setting, and Participants: This population-based cross-sectional study analyzed travel times to proton facilities in the US. Census tract variables in the contiguous US were measured between January 1, 2017, and December 31, 2021. Statistical analysis was performed from September to November 2023. Exposures: Drive time in minutes to nearest proton facility. Population totals and prevalence of specific factors measured from the American Community Survey: age; race and ethnicity; insurance, disability, and income status; vehicle availability; broadband access; and urbanicity. Main Outcomes and Measures: Poor access to proton facilities was defined as having a drive-time commute of at least 4 hours to the nearest location. Median drive time and percentage of population with poor access were calculated for the entire population and by population subgroups. Univariable and multivariable odds of poor access were also calculated for certain population subgroups. Results: Geographic access was considered for 327 536 032 residents of the contiguous US (60 594 624 [18.5%] Hispanic, 17 974 186 [5.5%] non-Hispanic Asian, 40 146 994 [12.3%] non-Hispanic Black, and 195 265 639 [59.6%] non-Hispanic White; 282 031 819 [86.1%] resided in urban counties). The median (IQR) drive time to the nearest proton facility was 96.1 (39.6-195.3) minutes; 119.8 million US residents (36.6%) lived within a 1-hour drive of the nearest proton facility, and 53.6 million (16.4%) required a commute of at least 4 hours. Persons identifying as non-Hispanic White had the longest median (IQR) commute time at 109.8 (48.0-197.6) minutes. Multivariable analysis identified rurality (odds ratio [OR], 2.45 [95% CI, 2.27-2.64]), age 65 years or older (OR, 1.09 [95% CI, 1.06-1.11]), and living below the federal poverty line (OR, 1.22 [1.20-1.25]) as factors associated with commute times of at least 4 hours. Conclusions and Relevance: This cross-sectional study of drive-time access to proton beam therapy found that disparities in access existed among certain populations in the US. These results suggest that such disparities present a barrier to an emerging technology in cancer treatment and inhibit equitable access to ongoing clinical trials.

A Novel Positive-Contrast Magnetic Resonance Imaging Line Marker for High-Dose-Rate (HDR) MRI-Assisted Radiosurgery (MARS).

Magnetic resonance imaging (MRI) can facilitate accurate organ delineation and optimal dose distributions in high-dose-rate (HDR) MRI-Assisted Radiosurgery (MARS). Its use for this purpose has been limited by the lack of positive-contrast MRI markers that can clearly delineate the lumen of the HDR applicator and precisely show the path of the HDR source on T1- and T2-weighted MRI sequences. We investigated a novel MRI positive-contrast HDR brachytherapy or interventional radiotherapy line marker, C4:S, consisting of C4 (visible on T1-weighted images) complexed with saline. Longitudinal relaxation time (T1) and transverse relaxation time (T2) for C4:S were measured on a 1.5 T MRI scanner. High-density polyethylene (HDPE) tubing filled with C4:S as an HDR brachytherapy line marker was tested for visibility on T1- and T2-weighted MRI sequences in a tissue-equivalent female ultrasound training pelvis phantom. Relaxivity measurements indicated that C4:S solution had good T1-weighted contrast (relative to oil [fat] signal intensity) and good T2-weighted contrast (relative to water signal intensity) at both room temperature (relaxivity ratio > 1; r2/r1 = 1.43) and body temperature (relaxivity ratio > 1; r2/r1 = 1.38). These measurements were verified by the positive visualization of the C4:S (C4/saline 50:50) HDPE tube HDR brachytherapy line marker on both T1- and T2-weighted MRI sequences. Orientation did not affect the relaxivity of the C4:S contrast solution. C4:S encapsulated in HDPE tubing can be visualized as a positive line marker on both T1- and T2-weighted MRI sequences. MRI-guided HDR planning may be possible with these novel line markers for HDR MARS for several types of cancer.

Detection of Alteration in Carotid Artery Volumetry Using Standard-of-care Computed Tomography Surveillance Scans Following Unilateral Radiation Therapy for Early-stage Tonsillar Squamous Cell Carcinoma Survivors: A Cross-Sectional Internally-Matched Carotid Isodose Analysis.

Purpose: Radiation induced carotid artery disease (RICAD) is a major cause of morbidity and mortality among survivors of oropharyngeal cancer. This study leveraged standard-of-care CT scans to detect volumetric changes in the carotid arteries of patients receiving unilateral radiotherapy (RT) for early tonsillar cancer, and to determine dose-response relationship between RT and carotid volume changes, which could serve as an early imaging marker of RICAD. Methods and Materials: Disease-free cancer survivors (>3 months since therapy and age >18 years) treated with intensity modulated RT for early (T1-2, N0-2b) tonsillar cancer with pre- and post-therapy contrast-enhanced CT scans available were included. Patients treated with definitive surgery, bilateral RT, or additional RT before the post-RT CT scan were excluded. Pre- and post-treatment CTs were registered to the planning CT and dose grid. Isodose lines from treatment plans were projected onto both scans, facilitating the delineation of carotid artery subvolumes in 5 Gy increments (i.e. received 50-55 Gy, 55-60 Gy, etc.). The percent-change in sub-volumes across each dose range was statistically examined using the Wilcoxon rank-sum test. Results: Among 46 patients analyzed, 72% received RT alone, 24% induction chemotherapy followed by RT, and 4% concurrent chemoradiation. The median interval from RT completion to the latest, post-RT CT scan was 43 months (IQR 32-57). A decrease in the volume of the irradiated carotid artery was observed in 78% of patients, while there was a statistically significant difference in mean %-change (±SD) between the total irradiated and spared carotid volumes (7.0±9.0 vs. +3.5±7.2, respectively, p<.0001). However, no significant dose-response trend was observed in the carotid artery volume change withing 5 Gy ranges (mean %-changes (±SD) for the 50-55, 55-60, 60-65, and 65-70+ Gy ranges [irradiated minus spared]: -13.1±14.7, -9.8±14.9, -6.9±16.2, -11.7±11.1, respectively). Notably, two patients (4%) had a cerebrovascular accident (CVA), both occurring in patients with a greater decrease in carotid artery volume in the irradiated vs the spared side. Conclusions: Our data show that standard-of-care oncologic surveillance CT scans can effectively detect reductions in carotid volume following RT for oropharyngeal cancer. Changes were equivalent between studied dose ranges, denoting no further dose-response effect beyond 50 Gy. The clinical utility of carotid volume changes for risk stratification and CVA prediction warrants further evaluation.

The cost-utility of intraoperative tranexamic acid in adult spinal deformity patients undergoing long posterior spinal fusion.

PURPOSE: This study aims to evaluate the cost-utility of intraoperative tranexamic acid (TXA) in adult spinal deformity (ASD) patients undergoing long posterior (≥ 5 vertebral levels) spinal fusion. METHODS: A decision-analysis model was built for a hypothetical 60-year-old adult patient with spinal deformity undergoing long posterior spinal fusion. A comprehensive review of the literature was performed to obtain event probabilities, costs and health utilities at each node. Health utilities were utilized to calculate Quality-Adjusted Life Years (QALYs). A base-case analysis was carried out to obtain the incremental cost and effectiveness of intraoperative TXA. Probabilistic sensitivity analysis was performed to evaluate uncertainty in our model and obtain mean incremental costs, effectiveness, and net monetary benefits. One-way sensitivity analyses were also performed to identify the variables with the most impact on our model. RESULTS: Use of intraoperative TXA was the favored strategy in 88% of the iterations. The mean incremental utility ratio for using intraoperative TXA demonstrated higher benefit and lower cost while being lower than the willingness-to-pay threshold set at $50,000 per quality adjusted life years. Use of intraoperative TXA was associated with a mean incremental net monetary benefit (INMB) of $3743 (95% CI 3492-3995). One-way sensitivity analysis reported cost of blood transfusions due to post-operative anemia to be a major driver of cost-utility analysis. CONCLUSION: Use of intraoperative TXAs is a cost-effective strategy to reduce overall perioperative costs related to post-operative blood transfusions. Administration of intraoperative TXA should be considered for long fusions in ASD population when not explicitly contra-indicated due to patient factors.

Neoadjuvant Chemotherapy Alone or Combined with EGFR-Directed Targeted Therapy or Anti-PD-1 Immunotherapy for Locally Advanced Lacrimal Sac and Nasolacrimal Duct Carcinomas.

BACKGROUND/AIMS: We describe our findings in patients with locally advanced lacrimal sac and nasolacrimal duct (NLD) carcinoma who received neoadjuvant systemic therapy. METHODS: We identified patients with locally advanced primary lacrimal sac/NLD carcinoma treated with neoadjuvant systemic intravenous therapy at our institution during 2017-2019. RESULTS: The study included seven patients, four men and three women; the mean age was 60.4 years (range: 43-76). All patients had locally advanced disease with significant orbital soft tissue invasion with or without skull base invasion making eye-sparing surgery not feasible as an initial step. Three patients had poorly differentiated squamous cell carcinoma; two, invasive carcinoma with basaloid and squamous features; one, high-grade carcinoma with features suggestive of sebaceous differentiation; and one, undifferentiated carcinoma. The neoadjuvant regimens were cisplatin and docetaxel (n = 1); carboplatin and docetaxel (n = 1); paclitaxel and cetuximab (n = 1); carboplatin, paclitaxel, and cetuximab (EGFR inhibitor) (n = 2); cisplatin, docetaxel, and pembrolizumab (anti-PD-1 immunotherapy) (n = 1); and carboplatin, paclitaxel, and pembrolizumab (n = 1). All patients had radiologic disease regression, and one patient had radiologic near-complete response. After neoadjuvant therapy, all patients underwent wide local excision and adjuvant concurrent chemoradiation. Two patients had a complete pathologic response. At a median follow-up period of 13 months after chemoradiation (range, 8-54 months), all patients were alive without evidence of disease. One patient had nodal metastasis treated with lymph node dissection and adjuvant chemoradiation. CONCLUSIONS: Neoadjuvant systemic therapy can shrink tumors in patients with locally advanced primary lacrimal sac/NLD carcinoma with orbital or skull base invasion.

Differential feeding on ornamental plants by Duponchelia fovealis (Lepidoptera: Crambidae) larvae.

Duponchelia fovealis (Zeller) (Lepidoptera: Crambidae) is a polyphagous pest that feeds on a variety of ornamental and crop plants. At least 47 plant families have been identified as hosts for D. fovealis in literature based on empirical data and observations. This list is surely incomplete based on the broad feeding habits of D. fovealis. We sought to expand the list of known D. fovealis host plants and to identify species that may be less preferred or not fed upon by D. fovealis. We used laboratory feeding assays to measure D. fovealis consumption rate of leaf disks from 32 herbaceous plant species and 32 woody species grown outdoors throughout the Southeastern United States, and 24 tropical species typically grown as house plants. These plants were from 65 genera and 36 families. Between the 3 ornamental plant groups, we tested (herbaceous, woody, and tropical) that, after 24 h, plants in the tropical group were the least consumed by D. fovealis. After 24 h, the average proportion of leaf disks eaten by D. fovealis was 0.80 or higher for 5 herbaceous and 12 woody species. Proportions of leaf disks eaten varied at the family and genus level in many cases. Our research can improve integrated pest management of D. fovealis by informing growers that plants may be at more or less risk of infestation and damage by larvae.

A Novel Polymer-Encapsulated Multi-Imaging Modality Fiducial Marker with Positive Signal Contrast for Image-Guided Radiation Therapy.

BACKGROUND: Current fiducial markers (FMs) in external-beam radiotherapy (EBRT) for prostate cancer (PCa) cannot be positively visualized on magnetic resonance imaging (MRI) and create dose perturbation and significant imaging artifacts on computed tomography (CT) and MRI. We report our initial experience with clinical imaging of a novel multimodality FM, NOVA. METHODS: We tested Gold Anchor [G-FM], BiomarC [carbon, C-FM], and NOVA FMs in phantoms imaged with kilovoltage (kV) X-rays, transrectal ultrasound (TRUS), CT, and MRI. Artifacts of the FMs on CT were quantified by the relative streak artifacts level (rSAL) metric. Proton dose perturbations (PDPs) were measured with Gafchromic EBT3 film, with FMs oriented either perpendicular to or parallel with the beam axis. We also tested the performance of NOVA-FMs in a patient. RESULTS: NOVA-FMs were positively visualized on all 4 imaging modalities tested. The rSAL on CT was 0.750 ± 0.335 for 2-mm reconstructed slices. In F-tests, PDP was associated with marker type and depth of measurement (p < 10-6); at 5-mm depth, PDP was significantly greater for the G-FM (12.9%, p = 10-6) and C-FM (6.0%, p = 0.011) than NOVA (4.5%). EBRT planning with MRI/CT image co-registration and daily alignments using NOVA-FMs in a patient was feasible and reproducible. CONCLUSIONS: NOVA-FMs were positively visible and produced less PDP than G-FMs or C-FMs. NOVA-FMs facilitated MRI/CT fusion and identification of regions of interest.

Clinical acceptability of automatically generated lymph node levels and structures of deglutition and mastication for head and neck radiation therapy.

Background and Purpose: Auto-contouring of complex anatomy in computed tomography (CT) scans is a highly anticipated solution to many problems in radiotherapy. In this study, artificial intelligence (AI)-based auto-contouring models were clinically validated for lymph node levels and structures of swallowing and chewing in the head and neck. Materials and Methods: CT scans of 145 head and neck radiotherapy patients were retrospectively curated. One cohort (n = 47) was used to analyze seven lymph node levels and the other (n = 98) used to analyze 17 swallowing and chewing structures. Separate nnUnet models were trained and validated using the separate cohorts. For the lymph node levels, preference and clinical acceptability of AI vs human contours were scored. For the swallowing and chewing structures, clinical acceptability was scored. Quantitative analyses of the test sets were performed for AI vs human contours for all structures using overlap and distance metrics. Results: Median Dice Similarity Coefficient ranged from 0.77 to 0.89 for lymph node levels and 0.86 to 0.96 for chewing and swallowing structures. The AI contours were superior to or equally preferred to the manual contours at rates ranging from 75% to 91%; there was not a significant difference in clinical acceptability for nodal levels I-V for manual versus AI contours. Across all AI-generated lymph node level contours, 92% were rated as usable with stylistic to no edits. Of the 340 contours in the chewing and swallowing cohort, 4% required minor edits. Conclusions: An accurate approach was developed to auto-contour lymph node levels and chewing and swallowing structures on CT images for patients with intact nodal anatomy. Only a small portion of test set auto-contours required minor edits.

Perioperative Plasma in Addition to Red Blood Cell Transfusions Are Associated With Increased Venous Thromboembolism Risk Postoperatively.

BACKGROUND: Perioperative red blood cell (RBC) transfusions increase venous thromboembolic (VTE) events. Although a previous study found that plasma resuscitation after trauma was associated with increased VTE, the risk associated with additional perioperative plasma is unknown. METHODS: A US claims and EHR database (TriNetX Diamond Network) was queried. We compared surgical patients who received perioperative plasma and RBC to patients who received perioperative RBC but not plasma. Subanalyses included (1) all surgeries (n = 48,580) and (2) cardiovascular surgeries (n = 38,918). Propensity score matching was performed for age at surgery, ethnicity, race, sex, overweight and obesity, type 2 diabetes, disorders of lipoprotein metabolism, essential hypertension, neoplasms, nicotine dependence, coagulopathies, sepsis, chronic kidney disease, liver disease, nonsteroidal anti-inflammatory analgesics, platelet aggregation inhibitors, anticoagulants, hemoglobin level, outpatient service utilization, and inpatient services; surgery type was included for "all surgeries" analyses. Outcomes included 30-day mortality, postoperative VTE, pulmonary embolism (PE), and disseminated intravascular coagulation (DIC). RESULTS: After matching the surgical cohorts, compared to only RBC, plasma + RBC was associated with higher risk of postoperative mortality (4.52% vs 3.32%, risk ratio [RR]: 1.36 [95% confidence interval, 1.24-1.49]), VTE (3.92% vs 2.70%, RR: 1.36 [1.24-1.49]), PE (1.94% vs 1.33%, RR: 1.46 [1.26-1.68]), and DIC (0.96% vs 0.35%, RR: 2.75 [2.15-3.53]). Among perioperative cardiovascular patients, adding plasma to RBC transfusion was associated with similar increased risk. CONCLUSIONS: When compared with perioperative RBC transfusion, adding plasma was associated with increased 30-day postoperative mortality, VTE, PE, and DIC risk among surgical and cardiovascular surgical patients. Reducing unnecessary plasma transfusion should be a focus of patient blood management to improve overall value in health care.

Lacrimal Gland Adenocarcinoma Clinicopathologic Features and Outcomes Compared With Those of Lacrimal Gland Adenoid Cystic Carcinoma.

PURPOSE: Lacrimal gland (LG) adenocarcinomas (ACs) are rare, with limited data. We compared clinicopathologic features and local recurrence, distant metastasis, and survival rates between LG AC and LG adenoid cystic carcinoma (ACC). METHODS: The records of LG AC patients treated from 2008 to 2022 and LG ACC patients treated from 1998 to 2022 at the same center were retrospectively reviewed. RESULTS: The study included 20 patients with AC; 10 de-novo AC, 10 ex-pleomorphic AC; and 51 ACC patients. The median age at diagnosis was 61 years for de-novo AC, 54 years for ex-pleomorphic AC, and 45 years for ACC. All groups had male predominance. The initial T category was T2 in 50% (5/10) of de-novo ACs; 60% (6/10) of ex-pleomorphic ACs; and 59% (30/51) of ACCs. Perineural invasion was present in 33% (5/15) of ACs and 90% (45/50) of ACCs (p < 0.001). Of the 20 AC patients, 14 had eye-sparing surgery; 4 had orbital exenteration; and 2 had unresectable disease. All AC patients received postoperative radiotherapy and 15 (75%) received concurrent chemotherapy. Fourteen AC patients were tested for human growth factor receptor 2 expression, and 10 (71%) were human growth factor receptor 2 positive; 5 received human growth factor receptor 2-targeted therapy. AC and ACC had similar 5-year recurrence rates (20% and 33%, respectively, p = 0.31) and metastasis rates (20% and 34%, respectively, p = 0.30). de-novo AC, ex-pleomorphic AC, and ACC had similar 5-year disease-specific survival rates (80%, 79%, and 81%, respectively, p > 0.99). CONCLUSIONS: LG AC and ACC have similar baseline clinicopathologic features, except that perineural invasion is more common in ACC, and similar recurrence, metastasis, and survival rates. Human growth factor receptor 2-targeted therapy may be appropriate in some patients with LG AC.

Clinical Outcomes, Blood Utilization, and Ethical Considerations for Pediatric Patients in a Bloodless Medicine and Surgery Program.

BACKGROUND: Pediatric patients requesting bloodless care represent a challenging clinical situation, as parents cannot legally refuse lifesaving or optimal interventions for their children. Here, we report clinical outcomes for the largest series of pediatric inpatients requesting bloodless care and also discuss the ethical considerations. METHODS: We performed a single-institution retrospective cohort study assessing 196 pediatric inpatients (<18 years of age) who requested bloodless care between June 2012 and June 2016. Patient characteristics, transfusion rates, and clinical outcomes were compared between pediatric patients receiving bloodless care and those receiving standard care (including transfusions if considered necessary by the clinical team) (n = 37,271). Families were informed that all available measures would be undertaken to avoid blood transfusions, although we were legally obligated to transfuse blood if the child's life was threatened. The primary outcome was composite morbidity or mortality. Secondary outcomes included percentage of patients transfused, individual morbid events, length of stay, total hospital charges, and total costs. Subgroup analyses were performed after stratification into medical and surgical patients. RESULTS: Of the 196 pediatric patients that requested bloodless care, 6.1% (n = 12) received an allogeneic blood component, compared to 9.1% (n = 3392) for standard care patients ( P = .14). The most common indications for transfusion were perioperative bleeding and anemia of prematurity. None of the transfusions were administered under a court order. Overall, pediatric patients receiving bloodless care exhibited lower rates of composite morbidity compared to patients receiving standard care (2.6% vs 6.2%; P = .035). There were no deaths in the bloodless cohort. Individual morbid events, length of stay, and total hospital charges/costs were not significantly different between the 2 groups. After multivariable analysis, bloodless care was not associated with a significant difference in composite morbidity or mortality (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.12-1.11; P = .077). CONCLUSIONS: Pediatric patients receiving bloodless care exhibited similar clinical outcomes compared to patients receiving standard care, although larger studies with adequate power are needed to confirm this finding. There were no mortalities among the pediatric bloodless cohort. Although a subset of our pediatric bloodless patients received an allogeneic transfusion, no patients required a court order. When delivered in a collaborative and patient-centered manner, blood transfusions can be safely limited among pediatric patients.

The Case for Allowing Proton Beam Therapy on Head and Neck Cooperative Group Studies.

This Viewpoint present the case for revisiting the proscription of proton beam therapy in trials of patients with de novo, nonmetastatic head and neck cancer.

Orbital and periocular complications in patients with sinonasal tumours with orbital invasion.

AIMS: The purpose of this study was to determine the frequency and associated risk factors of orbital/periocular complications in patients with sinonasal tumour with orbital invasion managed with eye-sparing treatments. METHODS: A retrospective case series of patients with primary sinonasal tumour with orbital invasion from January 2008 to December 2018. Patient factors were compared between the following groups: (1)patients with orbital/periocular complications versus those who did not and (2) patients who needed secondary oculoplastic surgical procedures versus those who did not. RESULTS: Out of 80 patients, 48 had eye-sparing surgery, 8 had orbital exenteration and 24 were managed non-surgically. The most common histology was squamous cell carcinoma (n=28, 35%). Among the eye-sparing treatment group, 51/72 patients experienced one or more orbital/periocular complication(s), with motility deficit (N=26, 36%) being the most frequent. Factors associated with higher risk of complications included tumour involving the orbital floor (p=0.019), clinical disease stage III/IV (p=0.038), maxillectomy (p=0.004), resection of the orbital floor (p=0.027) and cigarette smoking (p=0.041). Tumour involving the orbital floor had an OR of 3.9 (95% CI 1.3 to 11.6, p=0.016) in predicting orbital/periocular complication. In the eye-sparing surgery group, the most frequent secondary oculoplastic procedures was dacryocystorhinostomy (n=6, 13%). The use of a free flap in reconstruction had an OR of 8.2 (95% CI 2.1 to 31.8, p=0.002) in predicting need for secondary oculoplastic surgery. CONCLUSION: Majority of patients with sinonasal tumours and secondary orbital invasion were managed with eye-sparing multidisciplinary treatments. Preservation of the eye can lead to reasonably good functional outcome despite expected orbital and periocular complications.

Patterns of failure for recurrent head and neck squamous cell carcinoma treated with salvage surgery and postoperative IMRT reirradiation.

Purpose/Objectives: The purpose of this study was to evaluate patterns of locoregional recurrence (LRR) after surgical salvage and adjuvant reirradiation with IMRT for recurrent head and neck squamous cell cancer (HNSCC). Materials/Methods: Patterns of LRR for 61 patients treated consecutively between 2003 and 2014 who received post-operative IMRT reirradiation to ≥ 60 Gy for recurrent HNSCC were determined by 2 methods: 1) physician classification via visual comparison of post-radiotherapy imaging to reirradiation plans; and 2) using deformable image registration (DIR). Those without evaluable CT planning image data were excluded. All recurrences were verified by biopsy or radiological progression. Failures were defined as in-field, marginal, or out-of-field. Logistic regression analyses were performed to identify predictors for LRR. Results: A total of 55 patients were eligible for analysis and 23 (42 %) had documented LRR after reirradiation. Location of recurrent disease prior to salvage surgery (lymphatic vs. mucosal) was the most significant predictor of LRR after post-operative reirradiation with salvage rate of 67 % for lymphatic vs. 33 % for mucosal sites (p = 0.037). Physician classification of LRR yielded 14 (61 %) in-field failures, 3 (13 %) marginal failures, and 6 (26 %) out-of-field failures, while DIR yielded 10 (44 %) in-field failures, 4 (17 %) marginal failures, and 9 (39 %) out-of-field failures. Most failures (57 %) occurred within the original site of recurrence or first echelon lymphatic drainage. Of patients who had a free flap placed during salvage surgery, 56 % of failures occurred within 1 cm of the surgical flap. Conclusion: Our study highlights the role of DIR in enhancing the accuracy and consistency of POF analysis. Compared to traditional visual inspection, DIR reduces interobserver variability and provides more nuanced insights into dose-specific and spatial parameters of locoregional recurrences. Additionally, the study identifies the location of the initial recurrence as a key predictor of subsequent locoregional recurrence after salvage surgery and re-IMRT.

Robustness and complexity.

When a system robustly corrects component-level errors, the direct pressure on component performance declines. Components become less reliable, maintain more genetic variability, or drift neutrally, creating new forms of complexity. Examples include the hourglass pattern of biological development and the hourglass architecture for robustly complex systems in engineering.

Disease from opposing forces in regulatory control.

Danger requires a strong rapid response. Speedy triggers are prone to false signals. False alarms can be costly, requiring strong negative regulators to oppose the initial triggers. Strongly opposed forces can easily be perturbed, leading to imbalance and disease. For example, immunity and fear response balance strong rapid triggers against widespread slow negative regulators. Diseases of immunity and behavior arise from imbalance. A different opposition of forces occurs in mammalian growth, which balances strong paternally expressed accelerators against maternally expressed suppressors. Diseases of overgrowth or undergrowth arise from imbalance. Other examples of opposing forces and disease include control of dopamine expression and male versus female favored traits.

Uncertainty in magnetic resonance imaging-based prostate postimplant dosimetry: Results of a 10-person human observer study, and comparisons with automatic postimplant dosimetry.

PURPOSE: Uncertainties in postimplant quality assessment (QA) for low-dose-rate prostate brachytherapy (LDRPBT) are introduced at two steps: seed localization and contouring. We quantified how interobserver variability (IoV) introduced in both steps impacts dose-volume-histogram (DVH) parameters for MRI-based LDRPBT, and compared it with automatically derived DVH parameters. METHODS AND MATERIALS: Twenty-five patients received MRI-based LDRPBT. Seven clinical observers contoured the prostate and four organs at risk, and 4 dosimetrists performed seed localization, on each MRI. Twenty-eight unique manual postimplant QAs were created for each patient from unique observer pairs. Reference QA and automatic QA were also performed for each patient. IoV of prostate, rectum, and external urinary sphincter (EUS) DVH parameters owing to seed localization and contouring was quantified with coefficients of variation. Automatically derived DVH parameters were compared with those of the reference plans. RESULTS: Coefficients of variation (CoVs) owing to contouring variability (CoVcontours) were significantly higher than those due to seed localization variability (CoVseeds) (median CoVcontours vs. median CoVseeds: prostate D90-15.12% vs. 0.65%, p < 0.001; prostate V100-5.36% vs. 0.37%, p < 0.001; rectum V100-79.23% vs. 8.69%, p < 0.001; EUS V200-107.74% vs. 21.18%, p < 0.001). CoVcontours were lower when the contouring observers were restricted to the 3 radiation oncologists, but were still markedly higher than CoVseeds. Median differences in prostate D90, prostate V100, rectum V100, and EUS V200 between automatically computed and reference dosimetry parameters were 3.16%, 1.63%, -0.00 mL, and -0.00 mL, respectively. CONCLUSIONS: Seed localization introduces substantially less variability in postimplant QA than does contouring for MRI-based LDRPBT. While automatic seed localization may potentially help improve workflow efficiency, it has limited potential for improving the consistency and quality of postimplant dosimetry.

Advances and Challenges in Conducting Clinical Trials With Proton Beam Therapy.

Advances in proton therapy have garnered much attention and speculation in recent years as the indications for proton therapy have grown beyond pediatric, prostate, spine, and ocular tumors. To achieve and maintain consistent access to this cancer treatment and to ensure the future viability and availability of proton centers in the United States, a call for evidence has been heard and answered by proton radiation oncologists. Answers provided in this review include the evolution of proton therapy research, rationale for proton clinical trial design, challenges in and barriers to the conduct of proton therapy research, and other unique considerations for the study of proton therapy.