Clinical commissioning of an adaptive radiotherapy platform: Results and recommendations.

Online adaptive radiotherapy platforms present a unique challenge for commissioning as guidance is lacking and specialized adaptive equipment, such as deformable phantoms, are rare. We designed a novel adaptive commissioning process consisting of end-to-end tests using standard clinical resources. These tests were designed to simulate anatomical changes regularly observed at patient treatments. The test results will inform users of the magnitude of uncertainty from on-treatment changes during the adaptive workflow and the limitations of their systems. We implemented these tests for the cone-beam computed tomography (CT)-based Varian Ethos online adaptive platform. Many adaptive platforms perform online dose calculation on a synthetic CT (synCT). To assess the impact of the synCT generation and online dose calculation on dosimetric accuracy, we conducted end-to-end tests using commonly available equipment: a CIRS IMRT Thorax phantom, PinPoint ionization chamber, Gafchromic film, and bolus. Four clinical scenarios were evaluated: weight gain and weight loss were simulated by adding and removing bolus, internal target shifts were simulated by editing the CTV during the adaptive workflow to displace it, and changes in gas were simulated by removing and reinserting rods in varying phantom locations. The effect of overriding gas pockets during planning was also assessed. All point dose measurements agreed within 2.7% of the calculated dose, with one exception: a scenario simulating gas present in the planning CT, not overridden during planning, and dissipating at treatment. Relative film measurements passed gamma analysis (3%/3 mm criteria) for all scenarios. Our process validated the Ethos dose calculation for online adapted treatment plans. Based on our results, we made several recommendations for our clinical adaptive workflow. This commissioning process used commonly available equipment and, therefore, can be applied in other clinics for their respective online adaptive platforms.

Prospects for daily online adaptive radiotherapy via ethos for prostate cancer patients without nodal involvement using unedited CBCT auto-segmentation.

PURPOSE:  Implementing new online adaptive radiation therapy technologies is challenging because extra clinical resources are required particularly expert contour review. Here, we provide the first assessment of Varian's Ethos™ adaptive platform for prostate cancer using no manual edits after auto-segmentation to minimize this impact on clinical efficiency. METHODS: Twenty-five prostate patients previously treated at our clinic were re-planned using an Ethos™ emulator. Clinical target volumes (CTV) included intact prostate and proximal seminal vesicles. The following clinical margins were used: 3 mm posterior, 5 mm left/right/anterior, and 7 mm superior/inferior. Adapted plans were calculated for 10 fractions per patient using Ethos's auto-segmentation and auto-planning workflow without manual contouring edits. Doses and auto-segmented structures were exported to our clinical treatment planning system where contours were modified as needed for all 250 CTVs and organs-at-risk. Dose metrics from adapted plans were compared to unadapted plans to evaluate CTV and OAR dose changes. RESULTS: Overall 96% of fractions required auto-segmentation edits, although corrections were generally minor (<10% of the volume for 70% of CTVs, 88% of bladders, and 90% of rectums). However, for one patient the auto-segmented CTV failed to include the superior portion of prostate that extended into the bladder at all 10 fractions resulting in under-contouring of the CTV by 31.3% ± 6.7%. For the 24 patients with minor auto-segmentation corrections, adaptation improved CTV D98% by 2.9% ± 5.3%. For non-adapted fractions where bladder or rectum V90% exceeded clinical thresholds, adaptation reduced them by 13.1% ± 1.0% and 6.5% ± 7.3%, respectively. CONCLUSION:  For most patients, Ethos's online adaptive radiation therapy workflow improved CTV D98% and reduced normal tissue dose when structures would otherwise exceed clinical thresholds, even without time-consuming manual edits. However, for one in 25 patients, large contour edits were required and thus scrutiny of the daily auto-segmentation is necessary and not all patients will be good candidates for adaptation.

A practical method to quantify knowledge-based DVH prediction accuracy and uncertainty with reference cohorts.

The adoption of knowledge-based dose-volume histogram (DVH) prediction models for assessing organ-at-risk (OAR) sparing in radiotherapy necessitates quantification of prediction accuracy and uncertainty. Moreover, DVH prediction error bands should be readily interpretable as confidence intervals in which to find a percentage of clinically acceptable DVHs. In the event such DVH error bands are not available, we present an independent error quantification methodology using a local reference cohort of high-quality treatment plans, and apply it to two DVH prediction models, ORBIT-RT and RapidPlan, trained on the same set of 90 volumetric modulated arc therapy (VMAT) plans. Organ-at-risk DVH predictions from each model were then generated for a separate set of 45 prostate VMAT plans. Dose-volume histogram predictions were then compared to their analogous clinical DVHs to define prediction errors V c l i n , i - V p r e d , i (ith plan), from which prediction bias µ, prediction error variation σ, and root-mean-square error R M S E pred ≡ 1 N ∑ i V c l i n , i - V p r e d , i 2 ≅ σ 2 + µ 2 could be calculated for the cohort. The empirical R M S E pred was then contrasted to the model-provided DVH error estimates. For all prostate OARs, above 50% Rx dose, ORBIT-RT µ and σ were comparable to or less than those of RapidPlan. Above 80% Rx dose, µ < 1% and σ < 3-4% for both models. As a result, above 50% Rx dose, ORBIT-RT R M S E pred was below that of RapidPlan, indicating slightly improved accuracy in this cohort. Because µ ≈ 0, R M S E pred is readily interpretable as a canonical standard deviation σ, whose error band is expected to correctly predict 68% of normally distributed clinical DVHs. By contrast, RapidPlan's provided error band, although described in literature as a standard deviation range, was slightly less predictive than R M S E pred (55-70% success), while the provided ORBIT-RT error band was confirmed to resemble an interquartile range (40-65% success) as described. Clinicians can apply this methodology using their own institutions' reference cohorts to (a) independently assess a knowledge-based model's predictive accuracy of local treatment plans, and (b) interpret from any error band whether further OAR dose sparing is likely attainable.

A review of patient questions from physicist-patient consults.

PURPOSE: To provide insight into the types of questions asked to medical physicists by patients during one-on-one physicist-patient consults at one institution. MATERIALS AND METHODS: Medical physicists trained in patient communication techniques met with patients to provide an overview of the treatment planning and delivery processes, discuss the patient's treatment plan, and answer any technical questions. From August 2016 to December 2019, 152 physicist-patient consults were conducted. In the initial months of the study (August 2016-December 2017), following each physicist-patient consult, all patient questions were documented by the physicists. For the remaining time period (January 2018-December 2019), any newly encountered questions were periodically added to the list. The questions were compiled into a comprehensive list and organized into categories. RESULTS: There were a total of 88 unique patient questions. These questions fit into four topical categories. Fifty-four questions (61.4%) were in the "Treatment Planning and Delivery Questions" category, 15 questions (17.1%) were in the "General Radiation Questions or Concerns" category, 13 questions (14.8%) were in the "Safety and Quality Assurance Questions" category, and 6 questions (6.8%) were in the "Medical Questions" category. Overall, patients were primarily concerned about how radiation works, the treatment planning and delivery processes, and what is being done to keep them safe throughout their treatment. CONCLUSION: Physicist-patient consults provided an opportunity to address the technical aspects of radiation therapy with patients in greater detail. The fact that patient questions could be conveniently grouped into only four topical categories indicates that it may be straightforward for other medical physicists to prepare for effectively addressing technical questions during physicist-patient consults.

Evaluating the sensitivity of Halcyon's automatic transit image acquisition for treatment error detection: A phantom study using static IMRT.

PURPOSE: The Varian Halcyon™ electronic portal imaging detector is always in-line with the beam and automatically acquires transit images for every patient with full-field coverage. These images could be used for "every patient, every monitor unit" quality assurance (QA) and eventually adaptive radiotherapy. This study evaluated the imager's sensitivity to potential clinical errors and day-to-day variations from clinical exit images. METHODS: Open and modulated fields were delivered for each potential error. To evaluate output changes, monitor units were scaled by 2%-10% and delivered to solid water slabs and a homogeneous CIRS phantom. To mimic weight changes, 0.5-5.0 cm of buildup was added to the solid water. To evaluate positioning changes, a homogeneous and heterogeneous CIRS phantom were shifted 2-10 cm and 0.2-1.5 cm, respectively. For each test, mean relative differences (MRDs) and standard deviations in the pixel-difference histograms (σRD ) between test and baseline images were calculated. Lateral shift magnitudes were calculated using cross-correlation and edge-detection filtration. To assess patient variations, MRD and σRD were calculated from six prostate patients' daily exit images and compared between fractions with and without gas present. RESULTS: MRDs responded linearly to output and buildup changes with a standard deviation of 0.3%, implying a 1% output change and 0.2 cm changes in buildup could be detected with 2.5σ confidence. Shifting the homogenous phantom laterally resulted in detectable MRD and σRD changes, and the cross-correlation function calculated the shift to within 0.5 mm for the heterogeneous phantom. MRD and σRD values were significantly associated with the presence of gas for five of the six patients. CONCLUSIONS: Rapid analyses of automatically acquired Halcyon™ exit images could detect mid-treatment changes with high sensitivity, though appropriate thresholds will need to be set. This study presents the first steps toward developing effortless image evaluation for all aspects of every patient's treatment.

A program to train medical physicists for direct patient care responsibilities.

OBJECTIVES: To develop a training program designed to meet the specific needs of medical physicists as they transition into a clinical role with direct patient care responsibilities. MATERIALS AND METHODS: The training program was designed in collaboration with the faculty at the UC San Diego School of Medicine and incorporates training techniques that have been shown to be effective in improving communication skills. The program emphasizes experiential, practice-based learning over didactic presentations. RESULTS: The training program is comprised of 5 components: 1) a 1-day Clinician-Patient Communication Workshop run by the UC San Diego School of Medicine, 2) Communication Strategies for Radiation Oncology, which consists of two, 2-hour sessions designed to provide trainees with patient communication skills that are specific to patient interactions in radiation oncology, 3) Simulated Patient Interactions, in which trainees perform mock physicist-patient consults with trained patient actors, 4) Faculty-Observed Patient Consults, and 5) a Case-Based Treatment Toxicity Course. A competency assessment mechanism was also developed to provide a clear set of objectives and to guide trainer feedback. [Correction added after first online publication on November 7, 2018: The phrase ", which consists of two, 2-hour" was added above.] CONCLUSIONS: The training program that we have developed incorporates an array of established education techniques and provides a comprehensive, accessible, means of improving medical physicists' patient communication skills.

WITHDRAWN: Fibulin 2, a tyrosine o-sulfated protein, is up-regulated following retinal detachment.

The manuscript has been withdrawn by the author.

SPACA7 is a novel male germ cell-specific protein localized to the sperm acrosome that is involved in fertilization in mice.

Sperm acrosome associated 7 (SPACA7) is a novel protein of unknown function with no homology to any known protein. Spaca7 transcripts are detected only in testis and predict a 158-residue mature polypeptide with one potential N-glycosylation site and no cysteines. Orthologs are present in various species, including mice and humans. We developed a polyclonal antibody to mouse SPACA7 to study its expression and function. Western blotting and immunofluorescence microscopy detected SPACA7 only in testis, and it was detected in testis starting at Postnatal Day 21 and into adulthood. Immunofluorescence staining of testicular germ cells detected weak SPACA7 expression as early as zygotene spermatocytes. Higher expression was observed in round spermatids, where SPACA7 was localized to a perinuclear spot adjacent to the Golgi and to the acrosome of elongating spermatids and spermatozoa. Immunogold electron microscopy demonstrated that SPACA7 is localized within the proacrosomal granule of round spermatids and the acrosome of spermatozoa. Finally, we showed that SPACA7 was retained within the acrosome of epididymal sperm and was released upon the acrosome reaction. To assess if SPACA7 was involved in fertilization, in vitro fertilization assays in the presence of anti-SPACA7 IgG were performed. Anti-SPACA7 inhibited fertilization of cumulus-intact eggs and prominently delayed cumulus dispersal. However, anti-SPACA7 did not inhibit fertilization of cumulus-free eggs. Our findings indicate that release of SPACA7 from the acrosome accelerates cumulus dispersal and facilitates fertilization via unknown mechanisms. This study is the first to document the expression of endogenous SPACA7 and a function for this novel acrosomal protein.

Impaired sperm maturation in RNASE9 knockout mice.

Ribonuclease, RNase A family, 9 (RNASE9) is a ribonuclease A superfamily member that is expressed only in the epididymis. It is a small, secreted polypeptide, it lacks ribonuclease activity, and its function(s) is unknown. However, epididymis-specific expression suggests a role in sperm maturation. We generated Rnase9(-/-) mice to study RNASE9 function in vivo. We confirm that RNASE9 expression is restricted to the epididymis. Within the epididymis, RNASE9 is first detected in midcaput, persists through the distal caput and corpus, and wanes in the cauda. Rnase9(-/-) mice are born at the expected Mendelian ratio, have normal postnatal growth and development, and have no outwardly apparent phenotype. Spermatogenesis is normal, and Rnase9-null sperm are morphologically normal. Rnase9(-/-) males have normal fertility in unrestricted mating trials, and fertilization rates in in vitro fertilization assays are indistinguishable from wild-type mice. Visual observations coupled with analyses of sperm velocities shortly after swim out from the corpus shows that motility of Rnase9-null sperm is significantly impaired. However, no differences between wild-type and Rnase9-null sperm are detected by computer-assisted sperm analysis 10-90 min after sperm isolation from the corpus or cauda. Assessment of capacitation-dependent signaling pathways in Rnase9-null sperm showed that, while levels of tyrosine phosphorylation of sperm proteins were normal, there was decreased phosphorylation of protein kinase A substrates upon capacitation compared to wild-type mice. In conclusion, RNASE9 is dispensable for fertility, but the absence of RNASE9 during epididymal transit results in impaired sperm maturation.

Binding of alpha-thrombin to surface-anchored platelet glycoprotein Ib(alpha) sulfotyrosines through a two-site mechanism involving exosite I.

The involvement of exosite I in α-thrombin (FIIa) binding to platelet glycoprotein Ibα (GPIbα), which could influence interactions with other substrates, remains undefined. To address the problem, we generated the GPIbα amino terminal domain (GPIbα-N) fully sulfated on three tyrosine residues and solved the structure of its complex with FIIa. We found that sulfotyrosine (Tys) 278 enhances the interaction mainly by establishing contacts with exosite I. We then evaluated how substituting tyrosine with phenylalanine, which cannot be sulfated, affects FIIa binding to soluble or surface-immobilized GPIbα-N. Mutating Tyr(276), which mostly contacts exosite II residues, markedly reduced FIIa interaction with both soluble and immobilized GPIbα-N; mutating Tyr(278) or Tyr(279), which mostly contact exosite I residues, reduced FIIa complexing in solution by 0-20% but affinity for immobilized GPIbα-N 2 to 6-fold, respectively. Moreover, three exosite I ligands--aptamer HD1, hirugen, and lepirudin--did not interfere with soluble FIIa complexing to GPIbα-N, excluding that their binding caused allosteric effects influencing the interaction; nonetheless, all impaired FIIa binding to immobilized GPIbα-N and platelet GPIb nearly as much as aptamer HD22 and heparin, both exosite II ligands. Bound HD1 and hirugen alter Trp(148) orientation in a loop near exosite I preventing contacts with the sulfate oxygen atoms of Tys(279). These results support a mechanism in which binding occurs when the two exosites of one FIIa molecule independently interact with two immobilized GPIbα molecules. Through exosite engagement, GPIbα may influence FIIa-dependent processes relevant to hemostasis and thrombosis.

Improving linear accelerator service response with a real- time electronic event reporting system.

To track linear accelerator performance issues, an online event recording system was developed in-house for use by therapists and physicists to log the details of technical problems arising on our institution's four linear accelerators. In use since October 2010, the system was designed so that all clinical physicists would receive email notification when an event was logged. Starting in October 2012, we initiated a pilot project in collaboration with our linear accelerator vendor to explore a new model of service and support, in which event notifications were also sent electronically directly to dedicated engineers at the vendor's technical help desk, who then initiated a response to technical issues. Previously, technical issues were reported by telephone to the vendor's call center, which then disseminated information and coordinated a response with the Technical Support help desk and local service engineers. The purpose of this work was to investigate the improvements to clinical operations resulting from this new service model. The new and old service models were quantitatively compared by reviewing event logs and the oncology information system database in the nine months prior to and after initiation of the project. Here, we focus on events that resulted in an inoperative linear accelerator ("down" machine). Machine downtime, vendor response time, treatment cancellations, and event resolution were evaluated and compared over two equivalent time periods. In 389 clinical days, there were 119 machine-down events: 59 events before and 60 after introduction of the new model. In the new model, median time to service response decreased from 45 to 8 min, service engineer dispatch time decreased 44%, downtime per event decreased from 45 to 20 min, and treatment cancellations decreased 68%. The decreased vendor response time and reduced number of on-site visits by a service engineer resulted in decreased downtime and decreased patient treatment cancellations.

Open RT Structures: A Solution for TG-263 Accessibility.

PURPOSE: Consistency of nomenclature within radiation oncology is increasingly important as big data efforts and data sharing become more feasible. Automation of radiation oncology workflows depends on standardized contour nomenclature that enables toxicity and outcomes research, while also reducing medical errors and facilitating quality improvement activities. Recommendations for standardized nomenclature have been published in the American Association of Physicists in Medicine (AAPM) report from Task Group 263 (TG-263). Transitioning to TG-263 requires creation and management of structure template libraries and retraining of staff, which can be a considerable burden on clinical resources. Our aim is to develop a program that allows users to create TG-263-compliant structure templates in English, Spanish, or French to facilitate data sharing. METHODS AND MATERIALS: Fifty-three premade structure templates were arranged by treated organ based on an American Society for Radiation Oncology (ASTRO) consensus paper. Templates were further customized with common target structures, relevant organs at risk (OARs) (eg, spleen for anatomically relevant sites such as the gastroesophageal junction or stomach), subsite- specific templates (eg, partial breast, whole breast, intact prostate, postoperative prostate, etc) and brachytherapy templates. An informal consensus on OAR and target coloration was also achieved, although color selections are fully customizable within the program. RESULTS: The resulting program is usable on any Windows system and generates template files in practice-specific Digital Imaging and Communications In Medicine (DICOM) or XML formats, extracting standardized structure nomenclature from an online database maintained by members of the TG-263U1, which ensures continuous access to up-to-date templates. CONCLUSIONS: We have developed a tool to easily create and name DICOM radiation therapy (DICOM-RT) structures sets that are TG-263-compliant for all planning systems using the DICOM standard. The program and source code are publicly available via GitHub to encourage feedback from community users for improvement and guide further development.

Forecasting patient-specific dosimetric benefit from daily online adaptive radiotherapy for cervical cancer.

Objective. Adaptive Radiotherapy (ART) is an emerging technique for treating cancer patients which facilitates higher delivery accuracy and has the potential to reduce toxicity. However, ART is also resource-intensive, Requiring extra human and machine time compared to standard treatment methods. In this analysis, we sought to predict the subset of node-negative cervical cancer patients with the greatest benefit from ART, so resources might be properly allocated to the highest-yield patients.Approach. CT images, initial plan data, and on-treatment Cone-Beam CT (CBCT) images for 20 retrospective cervical cancer patients were used to simulate doses from daily non-adaptive and adaptive techniques. We evaluated the coefficient of determination (R2) between dose and volume metrics from initial treatment plans and the dosimetric benefits to theBowelV40Gy,BowelV45Gy,BladderDmean,andRectumDmeanfrom adaptive radiotherapy using reduced 3 mm or 5 mm CTV-to-PTV margins. The LASSO technique was used to identify the most predictive metrics forBowelV40Gy.The three highest performing metrics were used to build multivariate models with leave-one-out validation forBowelV40Gy.Main results. Patients with higher initial bowel doses were correlated with the largest decreases in BowelV40Gyfrom daily adaptation (linear best fit R2= 0.77 for a 3 mm PTV margin and R2= 0.8 for a 5 mm PTV margin). Other metrics had intermediate or no correlation. Selected covariates for the multivariate model were differences in the initialBowelV40GyandBladderDmeanusing standard versus reduced margins and the initial bladder volume. Leave-one-out validation had an R2of 0.66 between predicted and true adaptiveBowelV40Gybenefits for both margins.Significance. The resulting models could be used to prospectively triage cervical cancer patients on or off daily adaptation to optimally manage clinical resources. Additionally, this work presents a critical foundation for predicting benefits from daily adaptation that can be extended to other patient cohorts.

Automated treatment planning framework for brachytherapy of cervical cancer using 3D dose predictions.

Objective. To lay the foundation for automated knowledge-based brachytherapy treatment planning using 3D dose estimations, we describe an optimization framework to convert brachytherapy dose distributions directly into dwell times (DTs).Approach. A dose rate kerneld(r,θ,φ)was produced by exporting 3D dose for one dwell position from the treatment planning system and normalizing by DT. By translating and rotating this kernel to each dwell position, scaling by DT and summing over all dwell positions, dose was computed (Dcalc). We used a Python-coded COBYLA optimizer to iteratively determine the DTs that minimize the mean squared error betweenDcalcand reference doseDref, computed using voxels withDref80%-120% of prescription. As validation of the optimization, we showed that the optimizer replicates clinical plans whenDref= clinical dose in 40 patients treated with tandem-and-ovoid (T&O) or tandem-and-ring (T&R) and 0-3 needles. Then we demonstrated automated planning in 10 T&O usingDref= dose predicted from a convolutional neural network developed in past work. Validation and automated plans were compared to clinical plans using mean absolute differences (MAD=1N∑n=1Nabsxn-xn') over all voxels (xn= Dose,N= #voxels) and DTs (xn= DT,N= #dwell positions), mean differences (MD) in organD2ccand high-risk CTV D90 over all patients (where positive indicates higher clinical dose), and mean Dice similarity coefficients (DSC) for 100% isodose contours.Main results. Validation plans agreed well with clinical plans (MADdose= 1.1%, MADDT= 4 s or 0.8% of total plan time,D2ccMD = -0.2% to 0.2% and D90 MD = -0.6%, DSC = 0.99). For automated plans, MADdose= 6.5% and MADDT= 10.3 s (2.1%). The slightly higher clinical metrics in automated plans (D2ccMD = -3.8% to 1.3% and D90 MD = -5.1%) were due to higher neural network dose predictions. The overall shape of the automated dose distributions were similar to clinical doses (DSC = 0.91).Significance. Automated planning with 3D dose predictions could provide significant time savings and standardize treatment planning across practitioners, regardless of experience.

Examining the Effect of Direct Patient Care for Medical Physicists: A Randomized Prospective Phase III Trial.

PURPOSE: Our purpose was to investigate the effect of physicist-patient consults on patient anxiety and patient satisfaction with a randomized prospective phase III clinical trial. METHODS AND MATERIALS: Sixty-six patients were randomly assigned to the physics direct patient care (PDPC) arm or the control arm of the trial. Patients assigned to the PDPC arm received 2 physicist-patient consults to educate them on the technical aspects of their radiation therapy, while patients assigned to the control arm received the standard of care (ie, standard radiation therapy workflow without any additional physicist-patient consults). Questionnaires were administered to all patients at 4 time points (after enrollment, after the simulation, after the first treatment, and after the last treatment) to assess anxiety and satisfaction. RESULTS: The decrease in anxiety for the PDPC arm, compared with the control arm, was statistically significant at the first treatment (P = .027) time point. The increase in technical satisfaction for the PDPC arm, compared with the control arm, was statistically significant at the simulation (P = .005), first treatment (P < .001), and last treatment (P = .002) time points. The increase in overall satisfaction for the PDPC arm, compared with the control arm, was statistically significant at the first treatment (P = .014) and last treatment (P = .001) time points. CONCLUSIONS: Physicist-patient consults improved the patient experience by decreasing anxiety and increasing satisfaction. Future work is needed to modify current radiation oncology workflows and medical physics responsibilities to allow all patients to benefit from this advancement in patient care.

Safety of Nivolumab Added to Chemoradiation Therapy Platforms for Intermediate and High-Risk Locoregionally Advanced Head and Neck Squamous Cell Carcinoma: RTOG Foundation 3504.

PURPOSE: Programmed death-1 immune checkpoint blockade improves survival of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but the benefits of addition to (chemo)radiation for newly diagnosed patients with HNSCC remain unknown. METHODS AND MATERIALS: We evaluated the safety of nivolumab concomitant with 70 Gy intensity modulated radiation therapy and weekly cisplatin (arm 1), every 3-week cisplatin (arm 2), cetuximab (arm 3), or alone for platinum-ineligible patients (arm 4) in newly diagnosed intermediate- or high-risk locoregionally advanced HNSCC. Patients received nivolumab from 2 weeks prior to radiation therapy until 3 months post-radiation therapy. The primary endpoint was dose-limiting toxicity (DLT). If ≤2 of the first 8 evaluable patients experienced a DLT, an arm was considered safe. Secondary endpoints included toxicity and feasibility of adjuvant nivolumab to 1 year, defined as all 7 additional doses received by ≥4 of the first 8 evaluable patients across arms. RESULTS: Of 39 patients (10 in arms 1, 3, 4 and 9 in arm 2), 72% had T3-4 tumors, 85% had N2-3 nodal disease, and 67% had >10 pack-years of smoking. There were no DLTs in arms 1 and 2, 1 in arm 3 (mucositis), and 2 in arm 4 (lipase elevation and mucositis in 1 and fatigue in another). The most common grade ≥3 nivolumab-related adverse events were lipase increase, mucositis, diarrhea, lymphopenia, hyponatremia, leukopenia, fatigue, and serum amylase increase. Adjuvant nivolumab was feasible as defined in the protocol. CONCLUSIONS: Concomitant nivolumab with the 4 tested regimens was safe for patients with intermediate- and high-risk HNSCC, and subsequent adjuvant nivolumab was feasible as defined (NCT02764593).

Lack of tyrosylprotein sulfotransferase-2 activity results in altered sperm-egg interactions and loss of ADAM3 and ADAM6 in epididymal sperm.

Tyrosine O-sulfation is a post-translational modification catalyzed by two tyrosylprotein sulfotransferases (TPST-1 and TPST-2) in the trans-Golgi network. Tpst2-deficient mice have male infertility, sperm motility defects, and possible abnormalities in sperm-egg membrane interactions. Studies here show that compared with wild-type sperm, fewer Tpst2-null sperm bind to the egg membrane, but more of these bound sperm progress to membrane fusion. Similar outcomes were observed with wild-type sperm treated with the anti-sulfotyrosine antibody PSG2. The increased extent of sperm-egg fusion is not due to a failure of Tpst2-null sperm to trigger establishment of the egg membrane block to polyspermy. Anti-sulfotyrosine staining of sperm showed localization similar to that of IZUMO1, a sperm protein that is essential for gamete fusion, but we detected little to no tyrosine sulfation of IZUMO1 and found that IZUMO1 expression and localization were normal in Tpst2-null sperm. Turning to a discovery-driven approach, we used mass spectrometry to characterize sperm proteins that associated with PSG2. This identified ADAM6, a member of the A disintegrin and A metalloprotease (ADAM) family; members of this protein family are associated with multiple sperm functions. Subsequent studies revealed that Tpst2-null sperm lack ADAM6 and ADAM3. Loss of ADAM3 is strongly associated with male infertility and is observed in knockouts of male germ line-specific endoplasmic reticulum-resident chaperones, raising the possibility that TPST-2 may function in quality control in the secretory pathway. These data suggest that TPST-2-mediated tyrosine O-sulfation participates in regulating the sperm surface proteome or membrane order, ultimately affecting male fertility.

Automated radiotherapy treatment plan integrity verification.

PURPOSE: In our clinic, physicists spend from 15 to 60 min to verify the physical and dosimetric integrity of radiotherapy plans before presentation to radiation oncology physicians for approval. The purpose of this study was to design and implement a framework to automate as many elements of this quality control (QC) step as possible. METHODS: A comprehensive computer application was developed to carry out a majority of these verification tasks in the Philips PINNACLE treatment planning system (TPS). This QC tool functions based on both PINNACLE scripting elements and PERL sub-routines. The core of this technique is the method of dynamic scripting, which involves a PERL programming module that is flexible and powerful for treatment plan data handling. Run-time plan data are collected, saved into temporary files, and analyzed against standard values and predefined logical rules. The results were summarized in a hypertext markup language (HTML) report that is displayed to the user. RESULTS: This tool has been in clinical use for over a year. The occurrence frequency of technical problems, which would cause delays and suboptimal plans, has been reduced since clinical implementation. CONCLUSIONS: In addition to drastically reducing the set of human-driven logical comparisons, this QC tool also accomplished some tasks that are otherwise either quite laborious or impractical for humans to verify, e.g., identifying conflicts amongst IMRT optimization objectives.

Predicting dose-volume histograms for organs-at-risk in IMRT planning.

PURPOSE: The objective of this work was to develop a quality control (QC) tool to reduce intensity modulated radiotherapy (IMRT) planning variability and improve treatment plan quality using mathematical models that predict achievable organ-at-risk (OAR) dose-volume histograms (DVHs) based on individual patient anatomy. METHODS: A mathematical framework to predict achievable OAR DVHs was derived based on the correlation of expected dose to the minimum distance from a voxel to the PTV surface. OAR voxels sharing a range of minimum distances were computed as subvolumes. A three-parameter, skew-normal probability distribution was used to fit subvolume dose distributions, and DVH prediction models were developed by fitting the evolution of the skew-normal parameters as a function of distance with polynomials. Cohorts of 20 prostate and 24 head-and-neck IMRT plans with identical clinical objectives were used to train organ-specific average models for rectum, bladder, and parotids. A sum of residuals analysis quantifying the integrated difference between the clinically approved DVH and predicted DVH evaluated similarity between DVHs. The ability of the average models to prospectively predict DVHs was evaluated on an independent validation cohort of 20 prostate plans. Statistical comparison of the sums of residuals between training and validation cohorts quantified the accuracy of the average model. Restricted sums of residuals (RSR) were used to identify potential outliers, where large values of RSR indicate a clinical DVH that exceeds the predicted DVH by a considerable amount. A refined model was obtained for each organ by excluding outliers with large RSR values from the training cohort. The refined model was applied to the original training cohort and restricted sums of residuals were utilized to estimate potential DVH improvements. All cases were replanned and evaluated by the physician that approved the original plan. The ability of the refined models to correctly identify outliers was assessed using the residual sum between the original and replanned DVHs to quantify dosimetric gains realized under replanning. RESULTS: Statistical analysis of average sum of residuals for rectum (SR(rectum)=0.003±0.037), bladder (SR(bladder)=-0.008±0.037), and parotid (SR(parotid)=-0.003±0.060) training cohorts yielded mean values near zero and small with respect to the standard deviations, indicating that the average models are capturing the essential behavior of the training cohorts. The predictive abilities of the average rectum and bladder models were statistically indistinguishable between the training and validation sets, with SR(rectum)=0.002±0.044 and SR(bladder)=-0.018±0.058 for the validation set. The refined models' ability to detect outliers and predict achievable OAR DVHs was demonstrated by a strong correlation between predicted gains (RSR) and realized gains after replanning with sample correlation coefficients of r = 0.92 for the rectum, r = 0.88 for the bladder, and r = 0.84 for the parotid glands. CONCLUSIONS: The results demonstrate that our mathematical framework and modest training cohorts successfully predict achievable OAR DVHs based on individual patient anatomy. The models correctly identified suboptimal plans that demonstrated further OAR sparing after replanning. This modeling technique requires no manual intervention except for appropriate selection of a training set with identical evaluation criteria. Clinical implementation is in progress to evaluate impact on real-time IMRT QC.

Knowledge-based three-dimensional dose prediction for tandem-and-ovoid brachytherapy.

PURPOSE: The purpose of this work was to develop a knowledge-based dose prediction system using a convolution neural network (CNN) for cervical brachytherapy treatments with a tandem-and-ovoid applicator. METHODS: A 3D U-NET CNN was utilized to make voxel-wise dose predictions based on organ-at-risk (OAR), high-risk clinical target volume (HRCTV), and possible source location geometry. The model comprised 395 previously treated cases: training (273), validation (61), test (61). To assess voxel prediction accuracy, we evaluated dose differences in all cohorts across the dose range of 20-130% of prescription, mean (SD) and standard deviation (σ), as well as isodose dice similarity coefficients for clinical and/or predicted dose distributions. We examined discrete Dose-Volume Histogram (DVH) metrics utilized for brachytherapy plan quality assessment (HRCTV D90%; bladder, rectum, and sigmoid D2cc) with ΔDx=Dx,actual-Dx,predicted mean, standard deviation, and Pearson correlation coefficient further quantifying model performance. RESULTS: Ranges of voxel-wise dose difference accuracy (δD¯±σ) for 20-130% dose interval in training (test) sets ranged from [-0.5% ± 2.0% to +2.0% ± 14.0%] ([-0.1% ± 4.0% to +4.0% ± 26.0%]) in all voxels, [-1.7% ± 5.1% to -3.5% ± 12.8%] ([-2.9% ± 4.8% to -2.6% ± 18.9%]) in HRCTV, [-0.02% ± 2.40% to +3.2% ± 12.0%] ([-2.5% ± 3.6% to +0.8% ± 12.7%]) in bladder, [-0.7% ± 2.4% to +15.5% ± 11.0%] ([-0.9% ± 3.2% to +27.8% ± 11.6%]) in rectum, and [-0.7% ± 2.3% to +10.7% ± 15.0%] ([-0.4% ± 3.0% to +18.4% ± 11.4%]) in sigmoid. Isodose dice similarity coefficients ranged from [0.96,0.91] for training and [0.94,0.87] for test cohorts. Relative DVH metric prediction in the training (test) set were HRCTV ΔD¯90±σΔD = -0.19 ± 0.55Gy (-0.09 ± 0.67 Gy), bladder ΔD¯2cc±σΔD = -0.06 ± 0.54Gy (-0.17 ± 0.67 Gy), rectum ΔD¯2cc±σΔD= -0.03 ± 0.36Gy (-0.04 ± 0.46 Gy), and sigmoid ΔD¯2cc±σΔD = -0.01 ± 0.34Gy (0.00 ± 0.44 Gy). CONCLUSIONS: A 3D knowledge-based dose predictions provide voxel-level and DVH metric estimates that could be used for treatment plan quality control and data-driven plan guidance.