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.

Reirradiation With Proton Therapy for Recurrent Malignancies of the Esophagus and Gastroesophageal Junction: Results of the Proton Collaborative Group Multi-Institutional Prospective Registry Trial.

Purpose: Treatment options for recurrent esophageal cancer (EC) previously treated with radiation therapy (RT) are limited. Reirradiation (reRT) with proton beam therapy (PBT) can offer lower toxicities by limiting doses to surrounding tissues. In this study, we present the first multi-institutional series reporting on toxicities and outcomes after reRT for locoregionally recurrent EC with PBT. Methods and Materials: Analysis of the prospective, multicenter, Proton Collaborative Group registry of patients with recurrent EC who had previously received photon-based RT and underwent PBT reRT was performed. Patient/tumor characteristics, treatment details, outcomes, and toxicities were collected. Local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Event time was determined from reRT start. Results: Between 2012 and 2020, 31 patients received reRT via uniform scanning/passive scattering (61.3%) or pencil beam scanning (38.7%) PBT at 7 institutions. Median prior RT, PBT reRT, and cumulative doses were 50.4 Gy (range, 37.5-110.4), 48.6 Gy (relative biological effectiveness) (25.2-72.1), and 99.9 Gy (79.1-182.5), respectively. Of these patients, 12.9% had 2 prior RT courses, and 67.7% received PBT with concurrent chemotherapy. Median follow-up was 7.2 months (0.9-64.7). Post-PBT, there were 16.7% locoregional only, 11.1% distant only, and 16.7% locoregional and distant recurrences. Six-month LC, DMFS, and OS were 80.5%, 83.4%, and 69.1%, respectively. One-year LC, DMFS, and OS were 67.1%, 83.4%, and 27%, respectively. Acute grade ≥3 toxicities occurred in 23% of patients, with 1 acute grade 5 toxicity secondary to esophageal hemorrhage, unclear if related to reRT or disease progression. No grade ≥3 late toxicities were reported. Conclusions: In the largest report to date of PBT for reRT in patients with recurrent EC, we observed acceptable acute toxicities and encouraging rates of disease control. However, these findings are limited by the poor prognoses of these patients, who are at high risk of mortality. Further research is needed to better assess the long-term benefits and toxicities of PBT in this specific patient population.

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.

Proton Therapy for Unresectable and Medically Inoperable Locally Advanced Pancreatic Cancer: Results From a Multi-Institutional Prospective Registry.

Purpose: Compared with photon-based techniques, proton beam radiation therapy (PBT) may improve the therapeutic ratio of radiation therapy (RT) for locally advanced pancreatic cancer (LAPC), but available data have been limited to single-institutional experiences. This study examined the toxicity, survival, and disease control rates among patients enrolled in a multi-institutional prospective registry study and treated with PBT for LAPC. Methods and Materials: Between March 2013 and November 2019, 19 patients with inoperable disease across 7 institutions underwent PBT with definitive intent for LAPC. Patients received a median radiation dose/fractionation of 54 Gy/30 fractions (range, 50.4-60.0 Gy/19-33 fractions). Most received prior (68.4%) or concurrent (78.9%) chemotherapy. Patients were assessed prospectively for toxicities using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Kaplan-Meier analysis was used to analyze overall survival, locoregional recurrence-free survival, time to locoregional recurrence, distant metastasis-free survival, and time to new progression or metastasis for the adenocarcinoma cohort (17 patients). Results: No patients experienced grade ≥3 acute or chronic treatment-related adverse events. Grade 1 and 2 adverse events occurred in 78.7% and 21.3% of patients, respectively. Median overall survival, locoregional recurrence-free survival, distant metastasis-free survival, and time to new progression or metastasis were 14.6, 11.0, 11.0, and 13.9 months, respectively. Freedom from locoregional recurrence at 2 years was 81.7%. All patients completed treatment with one requiring a RT break for stent placement. Conclusions: Proton beam RT for LAPC offered excellent tolerability while still maintaining disease control and survival rates comparable with dose-escalated photon-based RT. These findings are consistent with the known physical and dosimetric advantages offered by proton therapy, but the conclusions are limited owing to the patient sample size. Further clinical studies incorporating dose-escalated PBT are warranted to evaluate whether these dosimetric advantages translate into clinically meaningful benefits.

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.

Clinical outcomes and toxicities of 100 patients treated with proton therapy for chordoma on the proton collaborative group prospective registry.

BACKGROUND: We present efficacy and toxicity outcomes among patients with chordoma treated on the Proton Collaborative Group prospective registry. METHODS: Consecutive chordoma patients treated between 2010-2018 were evaluated. One hundred fifty patients were identified, 100 had adequate follow-up information. Locations included base of skull (61%), spine (23%), and sacrum (16%). Patients had a performance status of ECOG 0-1 (82%) and median age of 58 years. Eighty-five percent of patients underwent surgical resection. The median proton RT dose was 74 Gy (RBE) (range 21-86 Gy (RBE)) using passive scatter proton RT (PS-PBT) (13%), uniform scanning proton RT (US-PBT) (54%) and pencil beam scanning proton RT (PBS-PBT) (33%). Rates of local control (LC), progression-free survival (PFS), overall survival (OS) and acute and late toxicities were assessed. RESULTS: 2/3-year LC, PFS, and OS rates are 97%/94%, 89%/74%, and 89%/83%, respectively. LC did not differ based on surgical resection (p = 0.61), though this is likely limited by most patients having undergone a prior resection. Eight patients experienced acute grade 3 toxicities, most commonly pain (n = 3), radiation dermatitis (n = 2), fatigue (n = 1), insomnia (n = 1) and dizziness (n = 1). No grade ≥ 4 acute toxicities were reported. No grade ≥ 3 late toxicities were reported, and most common grade 2 toxicities were fatigue (n = 5), headache (n = 2), CNS necrosis (n = 1), and pain (n = 1). CONCLUSIONS: In our series, PBT achieved excellent safety and efficacy outcomes with very low rates of treatment failure. CNS necrosis is exceedingly low (<1%) despite the high doses of PBT delivered. Further maturation of data and larger patient numbers are necessary to optimize therapy in chordoma.

Proton therapy for isolated local regional recurrence of breast cancer after mastectomy alone.

Purpose/Objectives: To assess adverse events (AEs) and disease-specific outcomes after proton therapy for isolated local-regional recurrence (LRR) of breast cancer after mastectomy without prior radiotherapy (RT). Materials/Methods: Patients were identified from a multi-institutional prospective registry and included if diagnosed with invasive breast cancer, initially underwent mastectomy without adjuvant RT, experienced an LRR, and subsequently underwent salvage treatment, including proton therapy. Follow-up and cancer outcomes were measured from the date of RT completion. Results: Nineteen patients were included. Seventeen patients were treated with proton therapy to the chest wall and comprehensive regional lymphatics (17/19, 90%). Maximum grade AE was grade 2 in 13 (69%) patients and grade 3 in 4 (21%) patients. All patients with grade 3 AE received > 60 GyE (p=0.04, Spearman correlation coefficient=0.5). At the last follow-up, 90% of patients were alive with no LRR or distant recurrence. Conclusions: For breast cancer patients with isolated LRR after initial mastectomy without adjuvant RT, proton therapy is well-tolerated in the salvage setting with excellent loco-regional control. All grade 3 AEs occurred in patients receiving > 60 GyE.

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.

Proton Therapy Outcomes for Head and Neck Cutaneous Melanoma: Proton Collaborative Group Analysis.

Purpose: Reports of proton beam therapy (PBT) utilization for cutaneous melanoma of the head and neck (HN) region is virtually non-existent. This study reports on the efficacy and acute toxicities of PBT for primary HN cutaneous melanoma. Materials and Methods: We queried the prospectively collected, multi-institutional Proton Collaborative Group registry for all consecutive patients with HN cutaneous melanoma receiving PBT from May 2010 to December 2019. Kaplan-Meier methods were used to estimate overall survival (OS), progression free survival (PFS), and local regional recurrence free survival (LRFS). Toxicity was reported per CTCAE version 4.0. Results: A total of 8 patients were identified with a median age of 69 (range, 37-88). All patients (100%) underwent surgery followed with postoperative PBT. There were 3 patients (37.5%) with T3 or T4 disease and 4 (50%) with N2 or N3 disease. The median radiation dose was 46 GyRBE (range, 27-70) and median dose per fraction was 2.4 GyRBE (range, 2.0-6.0) with the most common dose fractionation being 44 or 48 GyRBE in 20 fractions (n = 4). At a median follow-up of 40.1 months (range, 1.6-62.4) the 1 and 3 year OS rates were 85.7% and 35.7%, respectively. The median PFS was 25.40 months (95% CI, 2.53-58.70) while PFS at 1 year and 3 years was 85.7% and 35.7%, respectively. LRFS was 100% at 1 year and 85.7% at 3 years. Five of the 8 patients developed distant metastases, of which 3 received immunotherapy. Acute G2+ and G3+ toxicities occurred in 5 of 8 patients and 2 of 8 patients, respectively. G3 toxicities included radiation dermatitis (n = 1) and immunotherapy-related rash (n = 1). No G4+ toxicities were reported. Conclusion: Single modality PBT for HN melanomas in the definitive setting provides effective and durable local control rates with tolerable acute toxicity. Distant failure remains the primary pattern of failure.

Synthesis of ß-Amino Carbonyl 6-(Aminomethyl)- and 6-(Hydroxymethyl)pyrazolopyrimidines for DPP-4 Inhibition Study.

BACKGROUND: Type-2 diabetes is a chronic progressive metabolic disease resulting in severe vascular complications and mortality risk. Recently, DPP-4 inhibitors are conceived as a favorable class of agents for the treatment of type 2 diabetes due to the minimal side effects. METHODS: Sitagliptin is the first medicine approved for DPP-4 inhibitor. Its structure involved three fragments: 2,4,5-triflorophenyl fragment pharmacophore, enantiomerically ß-amino carbonyl linker, and tetrahydrotriazolopyridine. Herein, we are drawn to the possibility of substituting tetrahydrotriazolopyridine motif present in Sitagliptin with a series of new fused pyrazolopyrimidine bicyclic fragment to investigate potency and safety. RESULTS: Two series of fused 6-(aminomethyl)pyrazolopyrimidine and 6-(hydroxymethyl)pyrazolopyrimidine derivatives containing ß-amino ester or amide as linkers were successfully designed for the new DPP-4 inhibitors. Most fused 6-methylpyrazolopyrimidines were evaluated against DPP-4 inhibition and selectivity capacity. Based on research study, ß-amino carbonyl fused 6-(hydroxymethyl)pyrazolopyrimidine possesses the significant DPP-4 inhibition (IC50 ≤ 59.8 nM) and presents similar with Sitagliptin (IC50 = 28 nM). Particularly, they had satisfactory selectivity over DPP-8 and DPP-9, except for QPP. CONCLUSION: ß-Amino esters and amides fused 6-(hydroxymethyl)pyrazolopyrimidine were developed as the new DPP-4 inhibitors. Those compounds with a methyl group or hydrogen in N-1 position and methyl substituted group in C-3 of pyrazolopyrimidine moiety showed better potent DPP-4 inhibition (IC50 = 21.4-59.8 nM). Furthermore, they had satisfactory selectivity over DPP-8 and DPP-9 Finally, the docking results revealed that compound 9n was stabilized at DPP-4 active site and would be a potential lead drug.

Clinical Outcomes After Proton Beam Therapy for Locally Advanced Non-Small Cell Lung Cancer: Analysis of a Multi-institutional Prospective Registry.

PURPOSE: For most disease sites, level 1 evidence is lacking for proton beam therapy (PBT). By identifying target populations that would benefit most from PBT, prospective registries could overcome many of the challenges in clinical trial enrollment. Herein, we report clinical outcomes of patients treated with PBT for locally advanced non-small cell lung cancer (LA-NSCLC). METHODS AND MATERIALS: Data were obtained from the multi-institutional prospective database of the Proton Collaborative Group (PCG). Inclusion criteria of our study were stage III de novo or recurrent LA-NSCLC, use of PBT, and availability of follow-up data. Overall survival (OS) time was calculated from the start of treatment until death or last follow-up. Kaplan-Meier curves were generated for groups of interest and compared with log-rank tests. Cox regression modeling was used to evaluate the multivariate association between selected covariates and OS. RESULTS: A total of 195 patients were included in the analysis. PBT was given with a median equivalent dose in 2 Gy fractions (EQD2) of 63.8 Gy (relative biological effectiveness). Pencil beam scanning was used in 20% of treatments. Treatment-related grade 3 adverse events were rare: 1 pneumonitis, 2 dermatitis, and 3 esophagitis. No grade 4 events were reported. Two cardiac-related grade 5 events occurred in patients with multiple risk factors. The median follow-up time for living patients was 37.1 months and the median OS was 19.0 months. On multivariate analysis, good performance status (hazard ratio, 0.27; [95% confidence interval, 0.15-0.46]; P < .0001), pencil beam scanning use (0.55; [0.31-0.97]; P = .04), and increased EQD2 (0.80; [0.71-0.90] - per 10 Gy increase; P = .0002) were associated with decreased mortality. CONCLUSIONS: PBT appears to yield low rates of adverse events with an OS similar to other retrospective studies on PBT for LA-NSCLC. PBS use and increased EQD2 can potentially improve OS.

Dosimetry and Acute Toxicity Profile of Patients With Esophageal Cancer Treated With Proton Beam Radiation Therapy: Outcomes From the Proton Collaborative Group REG001-09 Trial.

PURPOSE: Concurrent chemoradiation plays an integral role in the treatment of esophageal cancer. Proton beam radiation therapy has the potential to spare adjacent critical organs, improving toxicity profiles and potentially improving clinical outcomes. METHODS AND MATERIALS: We evaluated the REG001-09 registry for patients undergoing proton radiation therapy for esophageal cancer. Demographic, clinicopathologic, toxicity, and dosimetry information were compiled. RESULTS: We identified 155 patients treated at 10 institutions between 2010 and 2019. One hundred twenty (77%) had adenocarcinoma and 34 (22%) had squamous cell carcinoma. One hundred thirty-seven (88%) received concurrent chemotherapy. The median delivered dose was 50.51 Gy-equivalent (GyE; range, 41.4-70.1). Grade ≥3 toxicities occurred in 22 (14%) of patients and were most commonly dysphagia (6%), esophagitis (4%), anorexia (4%), and nausea (2%). There were no episodes of grade ≥4 lymphopenia and no grade 5 toxicities. The average mean heart, lung, and liver doses and average maximum spinal cord dose were 10.0 GyE, 4.8 GyE, 3.8 GyE, and 34.2 GyE, respectively. For gastroesophageal junction tumors, 8% of patients developed acute grade ≥3 toxicity and the mean heart, liver, right kidney, and left kidney doses were 10.5 GyE, 3.9 GyE, 0.4 GyE, and 4.9 GyE, respectively. Gastroesophageal junction location was protective against development of grade ≥3 toxicity on univariate (P = .0009) and multivariate (P = .004) analysis. CONCLUSIONS: Proton beam radiation therapy affords excellent dosimetric parameters and low toxicity in patients with esophageal cancer treated with curative intent. Prospective trials are underway investigating the comparative benefit of proton-based therapy.

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.

Selection of Mediastinal Lymphoma Patients for Proton Therapy Within the Proton Collaborative Group Registry: Concordance With the ILROG Guidelines.

PURPOSE: As patients with mediastinal lymphoma are typically young with curable disease, advanced radiation techniques such as proton therapy are often considered to minimize subacute and late toxicity. However, it is unclear which mediastinal lymphoma patients are treated with proton therapy. Within a prospective, multi-institutional proton registry, we characterized mediastinal lymphoma patients treated with proton therapy and assessed concordance with consensus recommendations published in 2018 by the International Lymphoma Radiation Oncology Group (ILROG). METHODS: Eligible patients included those with lymphoma of the mediastinum treated exclusively with proton therapy for whom digital imaging and communications in medicine (DICOM) treatment data were available for review. Given the challenge with reliably visualizing the left mainstem coronary artery, the inferior-most aspect of the left pulmonary artery (PA) was used as a surrogate. Extent of disease was characterized as upper mediastinum (above level of left PA), middle mediastinum (below left PA but at or above level of T8), or low mediastinum (below T8). RESULTS: Between November 2012 and April 2019, 56 patients were treated and met inclusion criteria. Patients treated with proton therapy were young (median, 24 y; range: 12 to 88), with over half being female (55%). Patients were most commonly treated at initial diagnosis (86%) and had Hodgkin lymphoma (79%). Most patients (96%) had mediastinal disease that extended down to the level of the heart: 48% had middle and 48% had low mediastinal involvement. Nearly all patients (96%) met the ILROG consensus recommendations: 95% had lower mediastinal disease, 46% were young females, and 9% were heavily pretreated. Heart (mean) and lung dose (mean, V5, V20) were significantly associated with lowest extent of mediastinal disease. CONCLUSIONS: Mediastinal lymphoma patients treated with proton therapy are typically young with lower mediastinal involvement. Within a prospective, multi-institutional proton registry, nearly all treated patients fit the ILROG consensus recommendations regarding which mediastinal lymphoma patients may most benefit from proton therapy.

Risk of Pneumonitis and Outcomes After Mediastinal Proton Therapy for Relapsed/Refractory Lymphoma: A PTCOG and PCG Collaboration.

PURPOSE: Despite high response rates, there has been reluctance to use radiation therapy for patients with relapsed/refractory (r/r) Hodgkin (HL) or aggressive non-Hodgkin lymphoma (NHL) given concerns for subacute and late toxicities. Symptomatic pneumonitis, a subacute toxicity, has an incidence of 17% to 24% (≥grade 2) even with intensity modulated radiation therapy. Proton therapy (PT), which has no exit radiation dose, is associated with a lower dose to lung compared with other radiation techniques. As risk of radiation pneumonitis is associated with lung dose, we evaluated whether pneumonitis rates are lower with PT. METHODS AND MATERIALS: Within an international, multi-institutional cohort, we retrospectively evaluated the incidence and grade of radiation pneumonitis (National Cancer Institute Common Terminology Criteria for Adverse Events v4) among patients with r/r HL or NHL treated with PT. RESULTS: A total of 85 patients with r/r lymphoma (66% HL, 34% NHL; 46% primary chemorefractory) received thoracic PT from 2009 to 2017 in the consolidation (45%) or salvage (54%) setting. Median dose was 36 Gy(RBE). Before PT, patients underwent a median of 1 salvage systemic therapy (range, 0-4); 40% received PT within 4 months of transplant. With a median follow-up of 26.3 months among living patients, 11 patients developed symptomatic (grade 2) pneumonitis (12.8%). No grade 3 or higher pneumonitis was observed. Dose to lung, including mean lung dose, lung V5, and V20, significantly predicted risk of symptomatic pneumonitis, but not receipt of brentuximab, history of bleomycin toxicity, sex, or peritransplant radiation. CONCLUSIONS: PT for relapsed/refractory lymphoma was associated with favorable rates of pneumonitis compared with historical controls. We confirm that among patients treated with PT, pneumonitis risk is associated with mean lung and lung V20 dose. These findings highlight how advancements in radiation delivery may improve the therapeutic ratio for patients with relapsed/refractory lymphoma. PT may be considered as a treatment modality for patients with relapsed/refractory lymphoma in the consolidation or salvage setting.

Treatment interruptions affect biochemical failure rates in prostate cancer patients treated with proton beam therapy: Report from the multi-institutional proton collaborative group registry.

INTRODUCTION: To date, no studies examining the effect of treatment interruptions (TI) with proton beam therapy (PBT) have been published. The goal of our study was to determine the predictors of TI amongst patients with prostate cancer (PCa) treated with PBT and to determine whether TI are associated with biochemical failure (BF). We hypothesized that any correlation between TI and biochemical control would be more pronounced in high risk groups. METHODS: Data for 4278 patients with PCa was obtained from the prospectively collected Proton Collaborative Group (PCG) data registry. Univariate and multivariate logistic regression analysis (MVA) was used to model possible predictors of BF. A subset analysis was performed for high risk patients treated with ADT and PBT. Finally, propensity score (PS) analysis was performed to account for any indication bias caused by lack of randomization. RESULTS: Total treatment duration (OR, 1.05 [1.04-1.06]; p < 0.001) increased the likelihood of TI on MVA. TI did not have a statistically significant correlation with BF (OR, 1.44 [0.86-2.39]; p = 0.162) amongst PS matched patients. However, on subset analyses of high risk group patients with PS matching, there was a trend towards worse BF in patients with TI (OR 3.85; 95%CI (0.96-15.44); p = 0.057). CONCLUSION: In the first analysis of its kind, the results suggest that TI in high risk PCa patients treated with PBT and ADT have worse BF rates. Interventions such as increased patient education, proper maintenance of proton facilities, and decreasing total treatment duration with alternative fractionation schedules may help avoid the unintended negative effects on tumor control due to TI. However, future analyses on a larger patient population is needed.

Hypofractionated proton beam radiotherapy in patients with unresectable liver tumors: multi-institutional prospective results from the Proton Collaborative Group.

BACKGROUND: Recent advances in radiotherapy techniques have allowed ablative doses to be safely delivered to inoperable liver tumors. In this setting, proton beam radiotherapy (PBT) provides the means to escalate radiation dose to the target volume while sparing the uninvolved liver. This study evaluated the safety and efficacy of hypofractionated PBT for liver tumors, predominantly hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). METHODS: We evaluated the prospective registry of the Proton Collaborative Group for patients undergoing definitive PBT for liver tumors. Demographic, clinicopathologic, toxicity, and dosimetry information were compiled. RESULTS: To date, 63 patients have been treated at 9 institutions between 2013 and 2019. Thirty (48%) had HCC and 25 (40%) had ICC. The median dose and biological equivalent dose (BED) delivered was 58.05 GyE (range 32.5-75) and 80.5 GyE (range 53.6-100), respectively. The median mean liver BED was 13.9 GyE. Three (4.8%) patients experienced at least one grade ≥ 3 toxicity. With median follow-up of 5.1 months (range 0.1-40.8), the local control (LC) rate at 1 year was 91.2% for HCC and 90.9% for ICC. The 1-year LC was significantly higher (95.7%) for patients receiving BED greater than 75.2 GyE than for patients receiving BED of 75.2 GyE or lower (84.6%, p = 0.029). The overall survival rate at 1 year was 65.6% for HCC and 81.8% for ICC. CONCLUSIONS: Hypofractionated PBT results in excellent LC, sparing of the uninvolved liver, and low toxicity, even in the setting of dose-escalation. Higher dose correlates with improved LC, highlighting the importance of PBT especially in patients with recurrent or bulky disease.

Clinical Outcomes in Patients with Recurrent Glioblastoma Treated with Proton Beam Therapy Reirradiation: Analysis of the Multi-Institutional Proton Collaborative Group Registry.

PURPOSE: As a means of limiting normal tissue toxicity, proton-beam therapy (PBT) is an emerging radiation modality for glioblastoma (GBM) reirradiation. However, data for recurrent GBM treated with PBT reirradiation is limited. Therefore, we analyzed treatment patterns, toxicities, and clinical outcomes of patients with recurrent GBM treated with PBT reirradiation using the multi-institutional Proton Collaborative Group registry. METHODS AND MATERIALS: Prospectively collected data for patients with recurrent GBM who underwent PBT while enrolled in Proton Collaborative Group study 01-009 (NCT01255748) were analyzed. We evaluated overall survival (OS), progression-free survival (PFS), and toxicity. Toxicities were scored per the Common Terminology Criteria for Adverse Events, version 4.0. Descriptive statistics were used to report patient, tumor, and treatment characteristics. Multivariable analyses (MVA) for toxicity were conducted using logistic regression. The Kaplan-Meier method was used to calculate OS and PFS. MVA for OS and PFS was conducted using Cox proportional-hazards models. The SAS statistical software was used for the analysis. RESULTS: We identified 45 recurrent patients with GBM who underwent PBT reirradiation between 2012 and 2018. The median time between initial GBM diagnosis and recurrence was 20.2 months. The median follow-up time from PBT reirradiation was 10.7 months. Median PFS was 13.9 months (95% confidence interval [CI], 8.23-20.0 months) and median OS was 14.2 months (95% CI, 9.6-16.9 months) after PBT reirradiation. One patient experienced an acute grade 3 toxicity, 4 patients experienced late grade 3 toxicity (no grade ≥4 toxicities). MVA revealed that prior surgery was associated with a 91.3% decreased hazard of death (hazard ratio: 0.087; 95% CI, 0.02-0.42; P < .01). No explanatory variables were associated with PFS or grade 3 toxicities. CONCLUSIONS: This is the largest series to date reporting outcomes for PBT reirradiation of patients with recurrent GBM. Our analysis indicates that PBT is well tolerated and offers efficacy rates comparable with previously reported photon reirradiation.

Development of a Comprehensive, Contour-Based, Peer Review Workflow at a Community Proton Center.

PURPOSE: Quality assurance and continuing quality improvement are integral parts of any radiation oncology practice. With increasingly conformal radiation treatments, it has become critical to focus on every slice of the target contour to ensure adequate tumor coverage and optimal normal tissue sparing. Proton therapy centers open internationally with increasing frequency, and radiation oncologists with varying degrees of subspecialization apply proton therapy in daily practice. Precise treatment with proton therapy allows us to limit toxicity but requires in-depth knowledge of the unique properties of proton beam delivery. To address this need at our proton therapy center, we developed a comprehensive peer review program to help improve the quality of care that we were providing for our patients. MATERIALS AND METHODS: We implemented a policy of comprehensive peer review for all patients treated at our community proton facility starting in January 2013. Peer review begins at the time of referral with prospective cases being reviewed for appropriateness for proton therapy at daily rounds. There is then biweekly review of target contouring and treatment plans. RESULTS: During a 6-month period from June 2013 to November 2013, a total of 223 new patients were treated. Documentation of peer review at chart rounds was completed for 222 of the 223 patients (99.6%). An average of 10.7 cases were reviewed in each biweekly chart rounds session, with a total of 560 case presentations. The average time required for contour review was 145 seconds (±71 seconds) and plan review was 120 seconds (±64 seconds). Modifications were suggested for 21 patients (7.9%) during contour review and for 19 patients (6.4%) during treatment plan review. An average of 4 physicians were present at each session. CONCLUSIONS: We demonstrated that the implementation of a comprehensive, prospective peer review program is feasible in the community setting. This article can serve as a framework for future quality assurance programs.