The evolution of femoral morphology in giant non-avian theropod dinosaurs.

Theropods are obligate bipedal dinosaurs that appeared 230 million years ago and are still extant as birds. Their history is characterized by extreme variations in body mass, with gigantism evolving convergently between many lineages. However, no quantification of hindlimb functional morphology has shown if these body mass increases led to similar specializations between distinct lineages. Here we studied femoral shape variation across 41 species of theropods (n= 68 specimens) using a high-density 3D geometric morphometric approach. We demonstrated that the heaviest theropods evolved wider epiphyses and a more distally located fourth trochanter, as previously demonstrated in early archosaurs, along with an upturned femoral head and a mediodistal crest that extended proximally along the shaft. Phylogenetically informed analyses highlighted that these traits evolved convergently within six major theropod lineages, regardless of their maximum body mass. Conversely, the most gracile femora were distinct from the rest of the dataset, which we interpret as a femoral specialization to "miniaturization" evolving close to Avialae (bird lineage). Our results support a gradual evolution of known "avian" features, such as the fusion between lesser and greater trochanters and a reduction of the epiphyses' offset, independently from body mass variations, which may relate to a more "avian" type of locomotion (more knee-than hip-driven). The distinction between body mass variations and a more "avian" locomotion is represented by a decoupling in the mediodistal crest morphology, whose biomechanical nature should be studied to better understand the importance of its functional role in gigantism, miniaturization and higher parasagittal abilities.

Proton therapy for high-risk prostate cancer: Results from the Proton Collaborative Group PCG 001-09 prospective registry trial.

BACKGROUND: Data for proton therapy in high-risk prostate cancer (HRPC) are limited. Using the Proton Collaborative Group prospective registry, we evaluated outcomes for HRPC patients treated with proton therapy. METHODS: A totsl of 605 men with localized HRPC treated with proton therapy from 8/2009 to 3/2019 at nine institutions were selected. Outcomes examined included freedom from progression (FFP), metastasis free survival (MFS), overall survival (OS), and toxicity. Multivariable cox/binomial regression models were used to assess predictors of FFP and toxicity. RESULTS: Median age was 71 years. Gleason grade groups 4 (49.4%) and 5 (31.7%) were most common, as were clinical stage T1c (46.1%) and cT2 (41.3%). The median pretreatment prostate specific antigen (PSA) was 9.18 and median International Prostate Symptom Score (IPSS) was 6. Androgen deprivation therapy was given in 63.6%. Median dose was 79.2 GyE in 44 fractions. Pelvic lymph nodes were treated in 58.2% of cases. Pencil beam scanning was used in 54.5%, uniform scanning in 38.8%, and a rectal spacer in 14.2%. At a median followup of 22 months, the 3- and 5-year FFP were 90.7% and 81.4%, respectively. Five-year MFS and OS were 92.8% and 95.9%, respectively. Independent correlates of FFP included Gleason ≥8, PSA > 10, and cT2 (all p < 0.05). No grade 4 or 5 adverse events were reported. There were 23 (5%) grade 2 and 0 grade 3 gastrointestinal events. Prevalence of late grade 3, late grade 2, acute grade 3, and acute grade 2 genitourinary toxicity was 1.7%, 5.8%, 0%, and 21.8%, respectively. Prevalence of grade 2 and 3 erectile dysfunction at 2 years was 48.4% and 8.4%, respectively. CONCLUSIONS: In the largest series published to date, our results suggest early outcomes using proton therapy for HRPC are encouraging for both safety and efficacy. Further evaluation is needed to determine if an advantage exists to use protons over other radiation techniques in this population.

The dinosaurian femoral head experienced a morphogenetic shift from torsion to growth along the avian stem.

Significant evolutionary shifts in locomotor behaviour often involve comparatively subtle anatomical transitions. For dinosaurian and avian evolution, medial overhang of the proximal femur has been central to discussions. However, there is an apparent conflict with regard to the evolutionary origin of the dinosaurian femoral head, with neontological and palaeontological data suggesting seemingly incongruent hypotheses. To reconcile this, we reconstructed the evolutionary history of morphogenesis of the proximal end of the femur from early archosaurs to crown birds. Embryological comparison of living archosaurs (crocodylians and birds) suggests the acquisition of the greater overhang of the femoral head in dinosaurs results from additional growth of the proximal end in the medial-ward direction. On the other hand, the fossil record suggests that this overhang was acquired by torsion of the proximal end, which projected in a more rostral direction ancestrally. We reconcile this apparent conflict by inferring that the medial overhang of the dinosaur femoral head was initially acquired by torsion, which was then superseded by mediad growth. Details of anatomical shifts in fossil forms support this hypothesis, and their biomechanical implications are congruent with the general consensus regarding broader morpho-functional evolution on the avian stem.

Design, synthesis and biological evaluation of glycolamide, glycinamide, and ß-amino carbonyl 1,2,4-triazole derivatives as DPP-4 inhibitors.

Through modification of the skeleton of Sitagliptin and Vildagliptin, we successfully synthesized and built-up four series of 1,2,4-triazole derivatives, containing N,O-disubstituted glycolamide, N,N'-disubstituted glycinamide, ß-amino ester, and ß-amino amide as linkers, for the development of new dipeptidyl peptidase 4 (DPP-4) inhibitors. The synthetic strategy for glycolamides or glycinamides involved convenient two-steps reaction: functionalized transformation of 2-chloro-N-(2,4,5-triflurophenyl)acetamide 9 (hydroxylation or amination) and esterification or amidation of 1,2,4-triazole-3-carboxylic acid. On the other hand, the one-pot synthesis procedure, including substitution and deprotection, was developed for the preparation of ß-amino carbonyl 1,2,4-triazoles from (1H-1,2,4-triazol-3-yl)methanol 12 or (1H-1,2,4-triazol-3-yl)methanamine 13 and Boc-(R)-3-amino-4-(2,4,5-trifluoro-phenyl)-butyric acid 14. All of glycolamides, glycinamides, and ß-amino carbonyl 1,2,4-triazoles were also evaluated against DPP-4 inhibitory activity. Based on the SAR study of DPP-4 inhibitory capacity, ß-amino ester 5n and ß-amino amide 1,2,4-triazoles 6d and 6p possessed the significant inhibition of DPP-4 (IC50 < 51.0 nM), particularly for compound 6d (IC50 = 34.4 nM). The selectivity evaluation indicated compound 5n and 6p had excellent selectivity over QPP, DPP-8, and DPP-9. In addition, the docking results revealed compounds 5n and 6p provided stronger π-π stacking interaction with residue Phe357 than 1,5-disubstituted 1,2,4-triazole 6d and Sitagliptin 1. In summary, compounds 5n and 6p could be promising lead compounds for further development of DPP-4 inhibitor.

Contrast-enhanced XROMM reveals in vivo soft tissue interactions in the hip of Alligator mississippiensis.

Extant archosaurs exhibit highly divergent articular soft tissue anatomies between avian and crocodilian lineages. However, the general lack of understanding of the dynamic interactions among archosaur joint soft tissues has hampered further inferences about the function and evolution of these joints. Here we use contrast-enhanced computed tomography to generate 3D surface models of the pelvis, femora, and hip joint soft tissues in an extant archosaur, the American alligator. The hip joints were then animated using marker-based X-Ray Reconstruction of Moving Morphology (XROMM) to visualize soft tissue articulation during forward terrestrial locomotion. We found that the anatomical femoral head of the alligator travels beyond the cranial extent of the bony acetabulum and does not act as a central pivot, as has been suggested for some extinct archosaurs. Additionally, the fibrocartilaginous surfaces of the alligator's antitrochanter and femoral neck remain engaged during hip flexion and extension, similar to the articulation between homologous structures in birds. Moreover, the femoral insertion of the ligamentum capitis moves dorsoventrally against the membrane-bound portion of the medial acetabular wall, suggesting that the inner acetabular foramen constrains the excursion of this ligament as it undergoes cyclical stretching during the step cycle. Finally, the articular surface of the femoral cartilage model interpenetrates with those of the acetabular labrum and antitrochanter menisci; we interpret such interpenetration as evidence of compressive deformation of the labrum and of sliding movement of the menisci. Our data illustrate the utility of XROMM for studying in vivo articular soft tissue interactions. These results also allow us to propose functional hypotheses for crocodilian hip joint soft tissues, expanding our knowledge of vertebrate connective tissue biology and the role of joint soft tissues in locomotor behavior.

Minimal acute toxicity from proton beam therapy for major salivary gland cancer.

Introduction: Proton beam therapy (PBT) reduces normal organ dose compared to intensity-modulated radiation therapy (IMRT) for patients with major salivary gland tumors. It is not known whether this dosimetric advantage is clinically meaningful for reducing acute toxicity.Methods: We evaluated treatment parameters and acute toxicity outcomes of patients with major salivary gland cancers enrolled on the Proton Collaborative Group REG001-09 trial (NCT01255748).Results: One-hundred and five patients with a median age of 61 years were included. The majority had parotid (N = 90) versus submandibular gland (N = 15) tumors. The patients were treated across seven institutions in the United States between 2010 and 2017, most commonly in the postoperative setting (70.5%) although a minority were treated definitively (29.5%). Median PBT dose was 66.5 GyE in 33 fractions; only one patient was prescribed less than 50 GyE. Chemotherapy was given concurrently to 20%. Median follow-up was 14.3 months. Acute grade 2 or higher toxicity included nausea (1.5%), dysgeusia (4.8%), xerostomia (7.6%), mucositis (10.5%) and dysphagia (10.5%).Conclusions: PBT should be strongly considered when ipsilateral radiation therapy is indicated for major salivary gland cancer based on a considerably lower incidence of acute grade 2 or higher toxicity in this analysis compared to historical IMRT outcomes.

Acute toxicities after proton beam therapy following breast-conserving surgery for breast cancer: Multi-institutional prospective PCG registry analysis.

We investigated adverse events (AEs) and clinical outcomes for proton beam therapy (PBT) after breast-conserving surgery (BCS) for breast cancer. From 2012 to 2016, 82 patients received PBT in the prospective multi-institutional Proton Collaborative Group registry. AEs were recorded prospectively at each institution. Median follow-up was 8.1 months. Median dose was 50.4 Gy in 28 fractions. Most patients received a lumpectomy bed boost (90%) and regional nodal irradiation (RNI)(83%). Six patients (7.3%) experienced grade 3 AEs (5 with dermatitis, 5 with breast pain). Body mass index (BMI) was associated with grade 3 dermatitis (P = .015). Fifty-eight patients (70.7%) experienced grade ≥2 dermatitis. PBT including RNI after BCS is well-tolerated. Elevated BMI is associated with grade 3 dermatitis.

Proton therapy for thymic malignancies: multi-institutional patterns-of-care and early clinical outcomes from the proton collaborative group and the university of Florida prospective registries.

Objective: Thymic malignancies (TM) are rare tumors with long-term survivorship, causing concerns for radiotherapy-related late side effects. Proton therapy (PT) reduces the radiation dose to organs at risk, potentially decreasing long-term toxicities while preserving disease control. We report patterns-of-care and early clinical outcomes after PT for thymoma and thymic carcinoma. Methods: Between January 2008 and March 2017, 30 patients with TMs enrolled on one of two IRB-approved prospective protocols and received postoperative or definitive PT. Clinical outcomes, pathology, treatment dose, toxicities, and follow-up information were analyzed. Results: Twenty-two thymoma patients with a median age of 52.1 years (range, 23-72) received a median RT dose of 54 Gy (RBE) (range, 45-70) either postoperatively (91%) or definitively (9%); 23% received adjuvant chemotherapy. Among eight thymic carcinoma patients, the median age was 65.5 years (range, 38-88) and median RT dose was 60 Gy (RBE) (range, 42-70) delivered postoperatively (75%) or definitively (25%); 50% received chemotherapy. Median follow-up for all patients was 13 months (range, 2-59 months). Five patients relapsed, one locally (3%). Three patients died of disease progression, including two thymomas and one thymic carcinoma patient; a fourth died of intercurrent disease. One patient with thymic carcinoma and 1 with thymoma are alive with disease. No patients treated with PT for their initial disease (de novo) experienced grade ≥3 toxicities. The most common grade 2 toxicities were dermatitis (37%), cough (13%), and esophagitis (10%). Conclusion: Adjuvant and definitive PT are being used in the treatment of TMs. Early results of the largest such cohort reported to date demonstrates an acceptable rate of recurrence with a favorable toxicity profile. Longer follow-up and a larger patient cohort are needed to confirm these findings.

Proton beam therapy reirradiation for breast cancer: Multi-institutional prospective PCG registry analysis.

To investigate adverse events (AEs, CTCAE v4.0) and clinical outcomes for proton beam therapy (PBT) reirradiation (reRT) for breast cancer. From 2011 to 2016, 50 patients received PBT reRT for breast cancer in the prospective Proton Collaborative Group (PCG) registry. Acute AEs occurred within 180 days from start of reRT. Late AEs began or persisted beyond 180 days. Fisher's exact and Mann-Whitney rank-sum tests were utilized. Kaplan-Meier methods were used to estimate overall survival (OS) and local recurrence-free survival (LFRS). Median follow-up was 12.7 months (0-41.8). Median prior RT dose was 60 Gy (10-96.7). Median reRT dose was 55.1 Gy (45.1-76.3). Median cumulative dose was 110.6 Gy (70.6-156.8). Median interval between RT courses was 103.8 months (5.5-430.8). ReRT included regional nodes in 84% (66% internal mammary node [IMN]). Surgery included the following: 44% mastectomy, 22% wide local excision, 6% lumpectomy, 2% reduction mammoplasty, and 26% no surgery. Grade 3 AEs were experienced by 16% of patients (10% acute, 8% late) and were associated with body mass index (BMI) > 30 kg/m2 (P = 0.04), bilateral recurrence (P = 0.02), and bilateral reRT (P = 0.004). All grade 3 AEs occurred in patients receiving IMN reRT (P = 0.08). At 1 year, LRFS was 93%, and OS was 97%. Patients with gross disease at time of PBT trended toward worse 1-year LRFS (100% without vs. 84% with, P = 0.06). PBT reRT is well tolerated with favorable local control. BMI > 30, bilateral disease, and IMN reRT were associated with grade 3 AEs. Toxicity was acceptable despite median cumulative dose > 110 Gy.

Minimal toxicity after proton beam therapy for prostate and pelvic nodal irradiation: results from the proton collaborative group REG001-09 trial.

BACKGROUND: Proton beam therapy (PBT) reduces normal organ dose compared to intensity modulated radiation therapy (IMXT) for prostate cancer patients who receive pelvic radiation therapy. It is not known whether this dosimetric advantage results in less gastrointestinal (GI) and genitourinary (GU) toxicity than would be expected from IMXT. MATERIAL AND METHODS: We evaluated treatment parameters and toxicity outcomes for non-metastatic prostate cancer patients who received pelvic radiation therapy and enrolled on the PCG REG001-09 trial. Patients who received X-ray therapy and/or brachytherapy were excluded. Of 3210 total enrolled prostate cancer patients, 85 received prostate and pelvic radiation therapy exclusively with PBT. Most had clinically and radiographically negative lymph nodes although 6 had pelvic nodal disease and one also had para-aortic involvement. Pelvic radiation therapy was delivered using either 2 fields (opposed laterals) or 3 fields (opposed laterals and a posterior beam). Median pelvic dose was 46.9 GyE (range 39.7-56) in 25 fractions (range 24-30). Median boost dose to the prostate +/- seminal vesicles was 30 GyE (range 20-41.4) in 16 fractions (range 10-24). RESULTS: Median follow-up was 14.5 months (range 2.8-49.2). Acute grade 1, 2, and 3 GI toxicity rates were 16.4, 2.4, 0%, respectively. Acute grade 1, 2, and 3 GU toxicity rates were 60, 34.1, 0%, respectively. CONCLUSIONS: Prostate cancer patients who receive pelvic radiation therapy using PBT experience significantly less acute GI toxicity than is expected using IMXT. Further investigation is warranted to confirm whether this favorable acute GI toxicity profile is related to small bowel sparing from PBT.

Persistent foot ulcer due to ruxolitinib therapy for primary myelofibrosis.

Primary myelofibrosis is characterized by bone marrow fibrosis, splenomegaly and presence of JAK-2 V617F mutation in more than 90% of patients. Ruxolitinib is a Janus kinase inhibitor used for the treatment of primary myelofibrosis. We describe herein a persistent foot ulcer development attributed to ruxolitinib therapy. We are unaware of any previous reports of this phenomenon in the scientific literature. A thorough examination of the lower extremities is perhaps necessary before initiating this oral agent. If ruxolitinib therapy cannot be safely discontinued, diligent wound care and a course of antibiotics are warranted.

Durable Complete Response of Primary CNS Lymphoma in an 80-Year-Old Patient with Retroviral Infection.

People aging with human immunodeficiencyvirus (HIV) present a unique set of challenges for their providers. Cardiovascular, metabolic, neurodegenerative, and renal disorders, and certain cancers are more common in this cohort, which is attributed to elevated rates of inflammation. Although survival remains compromised, integration of efficacious antiretrovirals and high-dose methotrexate (HD-MTX) was shown to improve clinical results in HIV-infected patients with primary central nervous system lymphoma (PCNSL). However, optimal management of PCNSL in the elderly is not known. We present the case of an 80-year-old patientwith HIV-associated PCNSL who achieved a durable complete response with HD-MTX andrituximab. He remains in complete remission 18 months after the diagnosis. Our case supports using the HD-MTX/rituximab combination in the very old subjects with HIV-related PCNSL.

Diffusible iodine-based contrast-enhanced computed tomography (diceCT): an emerging tool for rapid, high-resolution, 3-D imaging of metazoan soft tissues.

Morphologists have historically had to rely on destructive procedures to visualize the three-dimensional (3-D) anatomy of animals. More recently, however, non-destructive techniques have come to the forefront. These include X-ray computed tomography (CT), which has been used most commonly to examine the mineralized, hard-tissue anatomy of living and fossil metazoans. One relatively new and potentially transformative aspect of current CT-based research is the use of chemical agents to render visible, and differentiate between, soft-tissue structures in X-ray images. Specifically, iodine has emerged as one of the most widely used of these contrast agents among animal morphologists due to its ease of handling, cost effectiveness, and differential affinities for major types of soft tissues. The rapid adoption of iodine-based contrast agents has resulted in a proliferation of distinct specimen preparations and scanning parameter choices, as well as an increasing variety of imaging hardware and software preferences. Here we provide a critical review of the recent contributions to iodine-based, contrast-enhanced CT research to enable researchers just beginning to employ contrast enhancement to make sense of this complex new landscape of methodologies. We provide a detailed summary of recent case studies, assess factors that govern success at each step of the specimen storage, preparation, and imaging processes, and make recommendations for standardizing both techniques and reporting practices. Finally, we discuss potential cutting-edge applications of diffusible iodine-based contrast-enhanced computed tomography (diceCT) and the issues that must still be overcome to facilitate the broader adoption of diceCT going forward.

Association between the growth rate of subependymal giant cell astrocytoma and age in patients with tuberous sclerosis complex.

PURPOSE: The most common neurological complications associated with tuberous sclerosis complex (TSC) include intractable seizures that begin in infancy and subependymal giant cell astrocytoma (SEGA) complicated by hydrocephalus with increasing age. Information on SEGA growth of TSC patients is limited. This study aimed to examine the TSC-SEGA growth rates by periodic neuroimaging. METHODS: This study evaluated the TSC-SEGA growth rates by serial neuroimaging. Fifty-eight patients with TSC underwent systematic evaluation, including a review of medical history and serial brain neuroimaging. RESULTS: While magnetic resonance imaging was more sensitive in detecting cortical tubers than computed tomography (73.1 vs. 0 %, p < 0.001), its efficacy in identifying intracranial lesions was comparable to that of computed tomography (96.2 vs. 100 %, p = 0.658). Significant tumor growth was observed in children (p = 0.012) and adults (p = 0.028) during follow-up periods, respectively (median for children 23.5 months, interquartile range 18-40 months and median for adults 23 months, interquartile range 12-34 months). Further, the SEGA growth rate in children was significantly higher than that in adults (75.6 vs. 16.5 %, p = 0.03). CONCLUSIONS: The results of the study show that SEGA has a significantly higher growth rate in children using serial follow-up brain imaging, suggesting the importance of performing follow-up neuroimaging at yearly intervals in childhood to identify and prevent potential comorbidities.

Fixed Drug Eruption Late in the Course of Capecitabine Therapy.

A fixed drug eruption (FDE) is a toxic skin effect thought to be caused by delayed cell-mediated hypersensitivity to a pharmaceutical agent. We report herein the first known patient with capecitabine-induced FDE that appeared relatively late in the course of adjuvant therapy for rectal cancer. The temporal association with capecitabine use and prompt disappearance after capecitabine discontinuation make this relationship probable. Knowledge about this dermatologic skin effect seen with oral fluoropyrimidines should avoid unnecessary diagnostic workup and provide the necessary patient reassurance.

Multicentric Neuroendocrine Carcinoma of the Breast Presenting with Multiple Osteolytic Bone Metastases.

An uncommon subtype of breast cancer, primary neuroendocrine carcinoma of the breast (NECB), usually presents as a single nodule arising in the breast tissue. Distant metastases at presentation are rare. Optimal management of advanced disease is still debated, given the lack of evidence stemming from clinical trials. We describe a patient who presented with clinically aggressive, multicentric NECB with multiple metastatic lytic bone lesions. Ihe disease responded to systemic therapy with an oral aromatase inhibitor and monthly biphosphonate infusions. We further review the existing literature on this intriguing clinicopathologic entity.

Prolonged Survival in Colon Cancer with Malignant Pericardial Effusion and Pulmonary Lymphangitic Carcinomatosis: A Case for Monoclonal Antibodies?

Traditionally, cardiac metastases and lymphangitic carcinomatosis have been associated with survival of only two to four months. We report herein a patient with malignant pericardial. effusion, and lymphangitic carcinomatosis due to colon cancer who remains in partial remission 12 months after the diagnosis. We postulate that the newer agents bevacizumab and cetuximab used in two different combination regimens contributed significantly to his longer survival. If confirmed, increased survival in this group of patients treated with novel regimens will have to be considered before any life-changing decisions (such as early referral to hospice) are made. In addition, a multitude of newer agents are in the pipeline and will soon join the battle against gastrointestinal malignancies, which could further increase survival in these patients.

Anterior-oriented proton beams for prostate cancer: A multi-institutional experience.

BACKGROUND: Proton beam therapy (PBT) for prostate cancer generally involves the use of two lateral beams that transverse the hips. In patients with hip replacements or a previously irradiated hip, this arrangement is contraindicated. The use of non-lateral beams is possible, but not well described. Here we report a multi-institutional experience for patients treated with at least one non-lateral proton beam for prostate cancer. MATERIAL AND METHODS: Between 2010 and 2014, 20 patients with organ-confined prostate cancer and a history of hip prosthesis underwent proton therapy utilizing at least one anterior oblique beam (defined as between 10° and 85° from vertical) at one of three proton centers. RESULTS: The median follow-up was 6.4 months. No patients have developed PSA failure or distant metastases. The median planning target volume (PTV) D95 was 79.2 Gy (RBE) (range 69.7-79.9). The median rectal V70 was 9.2% (2.5-15.4). The median bladder V50, V80, and mean dose were 12.4% (3.7-27.1), 3.5 cm3 (0-7.1), and 14.9 Gy (RBE) (4.6-37.8), respectively. The median contralateral femur head V45 and max dose were 0.01 cm3 (0-16.6) and 43.7 Gy (RBE) (15.6-52.5), respectively. The incidence of acute Grade 2 urinary toxicity was 40%. There were no Grade≥3 urinary toxicities. There was one patient who developed late Grade 2 rectal proctitis, with no other cases of acute or late ≥Grade 2 gastrointestinal toxicity. Grade 2 erectile dysfunction occurred in two patients (11.1%). Mild hip pain was experienced by five patients (25%). There were no cases of hip fracture. CONCLUSION: PBT for prostate cancer utilizing anterior oblique beam trajectories is feasible with favorable dosimetry and acceptable toxicity. Further follow-up is needed to assess for long-term outcomes and toxicities.

Low contralateral failure rate with unilateral proton beam radiotherapy for oropharyngeal squamous cell carcinoma: A multi-institutional prospective study from the proton collaborative group.

INTRODUCTION: Unilateral radiation therapy is appropriate for select patients with oropharyngeal squamous cell carcinoma (OPSCC). The use of proton beam therapy (PBT) in the unilateral setting decreases the dose to the contralateral neck and organs at risk. This study aims to evaluate contralateral recurrences in patients who received ipsilateral PBT. METHODS: We evaluated the Proton Collaborative Group database for patients treated with PBT for head and neck squamous cell carcinoma between the years 2015-2020 at 12 institutions. Dosimetric analysis was performed in five cases. RESULTS: Our analysis included 41 patients that received ipsilateral PBT with a mean follow-up of 14.7 months. 37% patients (n = 15) were treated for recurrent disease, and 63% (n = 26) were treated for de novo disease. Oropharyngeal sites included tonsillar fossa (n = 30) and base of tongue (n = 11). The median dose and BED delivered were 69.96 CGE and 84 Gy, respectively. Eight (20%) patients experienced at least one grade 3 dysphagia (n = 4) or esophagitis (n = 4) toxicity. No grade ≥ 4 toxicities were reported. There was one (2.4%) failure in the contralateral neck. The 1-year locoregional control was 88.9% and the freedom from distant metastasis was 95.5% (n = 2). The dosimetric analysis demonstrated similar ipsilateral level II cervical nodal region doses, whereas contralateral doses were higher with photon plans, mean: 15.5 Gy and 0.7CGE, D5%: 25.1 Gy and 6.6CGE. CONCLUSIONS: Our series is the first to report outcomes for patients with OPSCC receiving unilateral PBT. The contralateral neck failure rate was excellent and comparable to failure rates with photon irradiation.

Predicting the Effect of Proton Beam Therapy Technology on Pulmonary Toxicities for Patients With Locally Advanced Lung Cancer Enrolled in the Proton Collaborative Group Prospective Clinical Trial.

PURPOSE: This study aimed to predict the probability of grade ≥2 pneumonitis or dyspnea within 12 months of receiving conventionally fractionated or mildly hypofractionated proton beam therapy for locally advanced lung cancer using machine learning. METHODS AND MATERIALS: Demographic and treatment characteristics were analyzed for 965 consecutive patients treated for lung cancer with conventionally fractionated or mildly hypofractionated (2.2-3 Gy/fraction) proton beam therapy across 12 institutions. Three machine learning models (gradient boosting, additive tree, and logistic regression with lasso regularization) were implemented to predict Common Terminology Criteria for Adverse Events version 4 grade ≥2 pulmonary toxicities using double 10-fold cross-validation for parameter hyper-tuning without leak of information. Balanced accuracy and area under the curve were calculated, and 95% confidence intervals were obtained using bootstrap sampling. RESULTS: The median age of the patients was 70 years (range, 20-97), and they had predominantly stage IIIA or IIIB disease. They received a median dose of 60 Gy in 2 Gy/fraction, and 46.4% received concurrent chemotherapy. In total, 250 (25.9%) had grade ≥2 pulmonary toxicity. The probability of pulmonary toxicity was 0.08 for patients treated with pencil beam scanning and 0.34 for those treated with other techniques (P = 8.97e-13). Use of abdominal compression and breath hold were highly significant predictors of less toxicity (P = 2.88e-08). Higher total radiation delivered dose (P = .0182) and higher average dose to the ipsilateral lung (P = .0035) increased the likelihood of pulmonary toxicities. The gradient boosting model performed the best of the models tested, and when demographic and dosimetric features were combined, the area under the curve and balanced accuracy were 0.75 ± 0.02 and 0.67 ± 0.02, respectively. After analyzing performance versus the number of data points used for training, we observed that accuracy was limited by the number of observations. CONCLUSIONS: In the largest analysis of prospectively enrolled patients with lung cancer assessing pulmonary toxicities from proton therapy to date, advanced machine learning methods revealed that pencil beam scanning, abdominal compression, and lower normal lung doses can lead to significantly lower probability of developing grade ≥2 pneumonitis or dyspnea.