Factors Associated With and Characteristics of Patients Receiving Proton Therapy at the End of Life.

Purpose: To identify the characteristics, indications, and toxicities among patients receiving proton beam therapy (PBT) in the final year of life at an academic medical center. Materials and Methods: A retrospective review of patients who received PBT within the final 12 months of life was performed. Electronic medical records were reviewed for patient and treatment details from 2010 to 2019. Patients were followed from the start of PBT until death or last follow-up. Acute (3 months) toxicities were graded using the Common Terminology Criteria for Adverse Events v5.0. Imaging response was assessed using the Response Evaluation Criteria in Solid Tumors v1.1. The χ2 test was used to evaluate factors associated with palliative treatment. Simple logistic regression was used to evaluate factors associated with toxicity. Results: Bet299 patients were treated at the end of life (EOL) out of 5802 total patients treated with PBT (5.2%). Median age was 68 years (19-94 years), 58% male. The most common cancer was nonsmall cell lung cancer (27%). Patients were treated for symptom palliation alone (11%), durable control (57%), curative intent (16%), local recurrence (14%), or oligometastatic disease (2%). Forty-five percent received reirradiation. Median treatment time was 32 days (1-189 days). Acute toxicity was noted in 85% of the patients (31% G1, 53% G2, 15% G3). Thirteen patients (4%) experienced chronic toxicity. Breast and hematologic malignancy were associated with palliative intent χ2 (1, N = 14) = 17, P = .013; (χ2 (1, N = 14) = 18, P = .009). Conclusion: The number of patients treated with PBT at the EOL was low compared to all comers. Many of these patients received treatment with definitive doses and concurrent systemic therapy. Some patients spent a large portion of their remaining days on treatment. A prognostic indicator may better optimize patient selection for PBT at the EOL.

Proton FLASH Radiotherapy Ameliorates Radiation-induced Salivary Gland Dysfunction and Oral Mucositis and Increases Survival in a Mouse Model of Head and Neck Cancer.

Head and neck cancer radiotherapy often damages salivary glands and oral mucosa, severely negatively impacting patients' quality of life. The ability of FLASH proton radiotherapy (F-PRT) to decrease normal tissue toxicity while maintaining tumor control compared with standard proton radiotherapy (S-PRT) has been previously demonstrated for several tissues. However, its potential in ameliorating radiation-induced salivary gland dysfunction and oral mucositis and controlling orthotopic head and neck tumor growth has not been reported. The head and neck area of C57BL/6 mice was irradiated with a single dose of radiotherapy (ranging from 14-18 Gy) or a fractionated dose of 8 Gy × 3 of F-PRT (128 Gy/second) or S-PRT (0.95 Gy/second). Following irradiation, the mice were studied for radiation-induced xerostomia by measuring their salivary flow. Oral mucositis was analyzed by histopathologic examination. To determine the ability of F-PRT to control orthotopic head and neck tumors, tongue tumors were generated in the mice and then irradiated with either F-PRT or S-PRT. Mice treated with either a single dose or fractionated dose of F-PRT showed significantly improved survival than those irradiated with S-PRT. F-PRT-treated mice showed improvement in their salivary flow. S-PRT-irradiated mice demonstrated increased fibrosis in their tongue epithelium. F-PRT significantly increased the overall survival of the mice with orthotopic tumors compared with the S-PRT-treated mice. The demonstration that F-PRT decreases radiation-induced normal tissue toxicity without compromising tumor control, suggests that this modality could be useful for the clinical management of patients with head and neck cancer.

FLASH Proton Radiation Therapy Mitigates Inflammatory and Fibrotic Pathways and Preserves Cardiac Function in a Preclinical Mouse Model of Radiation-Induced Heart Disease.

PURPOSE: Studies during the past 9 years suggest that delivering radiation at dose rates exceeding 40 Gy/s, known as "FLASH" radiation therapy, enhances the therapeutic index of radiation therapy (RT) by decreasing normal tissue damage while maintaining tumor response compared with conventional (or standard) RT. This study demonstrates the cardioprotective benefits of FLASH proton RT (F-PRT) compared with standard (conventional) proton RT (S-PRT), as evidenced by reduced acute and chronic cardiac toxicities. METHODS AND MATERIALS: Mice were imaged using cone beam computed tomography to precisely determine the heart's apex as the beam isocenter. Irradiation was conducted using a shoot-through technique with a 5-mm diameter circular collimator. Bulk RNA-sequencing was performed on nonirradiated samples, as well as apexes treated with F-PRT or S-PRT, at 2 weeks after a single 40 Gy dose. Inflammatory responses were assessed through multiplex cytokine/chemokine microbead assay and immunofluorescence analyses. Levels of perivascular fibrosis were quantified using Masson's Trichrome and Picrosirius red staining. Additionally, cardiac tissue functionality was evaluated by 2-dimensional echocardiograms at 8- and 30-weeks post-PRT. RESULTS: Radiation damage was specifically localized to the heart's apex. RNA profiling of cardiac tissues treated with PRT revealed that S-PRT uniquely upregulated pathways associated with DNA damage response, induction of tumor necrosis factor superfamily, and inflammatory response, and F-PRT primarily affected cytoplasmic translation, mitochondrion organization, and adenosine triphosphate synthesis. Notably, F-PRT led to a milder inflammatory response, accompanied by significantly attenuated changes in transforming growth factor ß1 and α smooth muscle actin levels. Critically, F-PRT decreased collagen deposition and better preserved cardiac functionality compared with S-PRT. CONCLUSIONS: This study demonstrated that F-PRT reduces the induction of an inflammatory environment with lower expression of inflammatory cytokines and profibrotic factors. Importantly, the results indicate that F-PRT better preserves cardiac functionality, as confirmed by echocardiography analysis, while also mitigating the development of long-term fibrosis.

Temporal Evolution and Diagnostic Diversification of Patients Receiving Proton Therapy in the United States: A Ten-Year Trend Analysis (2012 to 2021) From the National Association for Proton Therapy.

PURPOSE: The National Association for Proton Therapy conducted 8 surveys of all operational United States proton centers (2012-2021) and analyzed the patients treated, diagnoses, and treatment complexity to evaluate trends and diversification of patients receiving proton therapy. METHODS AND MATERIALS: Detailed surveys were sent in 2015, which requested data from 2012 to 2014, and then annually thereafter to active proton centers in the United States. The numbers of patient treated at each center for the preceding calendar year(s) were collated for tumors in the following categories: central nervous system, intraocular, pituitary, skull base/skeleton, head/neck, lung, retroperitoneal/soft tissue sarcoma, pediatric (solid tumors in children of age ≤18), gastrointestinal tract, urinary tract, female pelvic, prostate, breast, and "other." Complexity levels were assessed using Current Procedural Terminology codes 77520-77525. RESULTS: Survey response rates were excellent (100% in 2015 to 94.9% in 2021); additional publicly available information provided near-complete information on all centers. Trend comparisons between 2012 and 2021 showed that the total annual number of patients treated with protons gradually increased from 5377 to 15,829. The largest numeric increases were for head/neck (316 to 2303; 7.3-fold), breast (93 to 1452; 15.6-fold), and gastrointestinal tumors (170 to 1259; 7.4-fold). Patient numbers also increased significantly for central nervous system (598 to 1743; 2.9-fold), pediatric (685 to 1870; 2.7-fold), and skull base tumors (179 to 514; 2.9-fold). For prostate cancer, the percentage of proton-treated patients decreased from 43.4% to 25.0% of the total. Simple compensated treatments decreased from 43% in 2012 to 7% in 2021, whereas intermediate complexity treatments increased from 45% to 73%. CONCLUSIONS: The number of patients treated with protons is gradually increasing, with a substantial proportionate decline in patients with prostate cancer receiving proton therapy. The number of patients treated for "commonly accepted" indications for protons (eg, pediatric, central nervous system, and skull base tumors) is gradually increasing. Greater proportional increases were observed for breast, lung, head/neck, and gastrointestinal tumors. Treatment complexity is gradually increasing over time.

SMAD4 loss predicts worse overall and distant metastasis-free survival in patients with resected pancreatic adenocarcinoma.

BACKGROUND: In select patients, pancreatic adenocarcinoma remains a local disease, yet there are no validated biomarkers to predict this behavior and who may benefit from aggressive local treatments. This study sought to determine if SMAD4 (mothers against decapentaplegic homolog 4) messenger RNA-sequencing (RNA-seq) expression is a robust method for predicting overall survival (OS) and distant metastasis-free survival (DMFS) in patients with resected pancreatic adenocarcinoma. METHODS: Utilizing The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), 322 patients with resected stage I-III pancreatic adenocarcinoma were identified. In TCGA, multivariable proportional hazards models were used to determine the association of SMAD4 genomic aberrations and RNA-seq expression with OS and DMFS. In the ICGC, analysis sought to confirm the predictive performance of RNA-seq via multivariable models and receiver operator characteristic curves. RESULTS: In TCGA, the presence of SMAD4 genomic aberrations was associated with worse OS (hazard ratio [HR], 1.55; 95% CI, 1.00-2.40; p = .048) but not DMFS (HR, 1.33; 95% CI, .87-2.03; p = .19). Low SMAD4 RNA-seq expression was associated with worse OS (HR, 1.83; 95% CI, 1.17-2.86; p = .008) and DMFS (HR, 1.70; 95% CI, 1.14-2.54; p = .009). In the ICGC, increased SMAD4 RNA-seq expression correlated with improved OS (area under the curve [AUC], .92; 95% CI, .86-.94) and DMFS (AUC, .84; 95% CI, .82-.87). CONCLUSIONS: In patients with resected pancreatic adenocarcinoma, SMAD4 genomic aberrations are associated with worse OS but do not predict for DMFS. Increased SMAD4 RNA-seq expression is associated with improved OS and DMFS in patients with resected pancreatic adenocarcinoma. This reproducible finding suggests SMAD4 RNA-seq expression may be a useful marker to predict metastatic spread.

Radiation dose is associated with improved local control for large, but not small, hepatocellular carcinomas.

BACKGROUND: With advances in understanding liver tolerance, conformal techniques, image guidance, and motion management, dose-escalated radiotherapy has become a potential treatment for inoperable hepatocellular carcinoma (HCC). We aimed to evaluate the possible impact of biologically effective dose (BED) on local control and toxicity among patients with HCC. METHODS AND MATERIALS: Patients treated at our institution from 2009 to 2018 were included in this retrospective analysis if they received definitive-intent radiotherapy with a nominal BED of at least 60 Gy. Patients were stratified into small and large tumors using a cutoff of 5 cm, based on our clinical practice. Toxicity was assessed using ALBI scores and rates of clinical liver function deterioration. RESULTS: One hundred and twenty-eight patients were included, with a mean follow-up of 16 months. The majority of patients (90.5%) had a good performance status (ECOG 0-1), with Child-Pugh A (66.4%) and ALBI Grade 2 liver function at baseline (55.4%). Twenty (15.6%) patients had a local recurrence in the irradiated field during the follow-up period. Univariate and multivariate Cox proportional hazard analyses showed that only BED significantly predicted local tumor recurrence. Higher BED was associated with improved local control in tumors with equivalent diameters over 5 cm but not in smaller tumors. There was no difference in liver toxicity between the low and high-dose groups. CONCLUSIONS: Higher radiotherapy dose is associated with improved local control in large tumors but not in tumors smaller than 5 cm in diameter. High-dose radiotherapy was not associated with increased liver toxicity.

Annual review of selected scientific literature: A report of the Committee on Scientific Investigation of the American Academy of Restorative Dentistry.

The Scientific Investigation Committee of the American Academy of Restorative Dentistry offers this review of the 2022 dental literature to briefly touch on several topics of interest to modern restorative dentistry. Each committee member brings discipline-specific expertise in their subject areas that include (in order of the appearance in this report): prosthodontics; periodontics, alveolar bone, and peri-implant tissues; dental materials and therapeutics; occlusion and temporomandibular disorders; sleep-related breathing disorders; oral medicine and oral and maxillofacial surgery; and dental caries and cariology. The authors focused their efforts on reporting information likely to influence the daily dental treatment decisions of the reader with an emphasis on innovations, new materials and processes, and future trends in dentistry. With the tremendous volume of literature published daily in dentistry and related disciplines, this review cannot be comprehensive. Instead, its purpose is to update interested readers and provide valuable resource material for those willing to subsequently pursue greater detail on their own. Our intent remains to assist colleagues in navigating the tremendous volume of newly minted information produced annually. Finally, we hope that readers find this work helpful in managing patients.

Assessment of Differences in Academic Rank and Compensation by Gender and Race/Ethnicity Among Academic Radiation Oncologists in the United States.

Purpose: Advancing equity, diversity, and inclusion in the physician workforce is essential to providing high-quality and culturally responsive patient care and has been shown to improve patient outcomes. To better characterize equity in the field of radiation oncology, we sought to describe the current academic radiation oncology workforce, including any contemporary differences in compensation and rank by gender and race/ethnicity. Methods and Materials: We conducted a retrospective cohort study using data from the Society of Chairs of Academic Radiation Oncology Programs (SCAROP) 2018 Financial Survey. Multivariable logistic regression models were used to identify factors associated with associate or full professor rank. Compensation was compared by gender and race/ethnicity overall and stratified by rank and was further analyzed using multivariable linear regression models. Results: Of the 858 academic radiation oncologists from 63 departments in the United States in the sample, 33.2% were female, 65.2% were White, 27.2% were Asian, and 7.6% were underrepresented in medicine (URiM). There were 44.0% assistant professors, 32.0% associate professors, and 22.8% full professors. Multivariable logistic regression analysis for factors associated with associate or full professor rank did not reveal statistically significant associations between gender or race/ethnicity with academic rank (odds ratio [OR], 0.86; 95% confidence interval [CI], 0.56-1.32; P = .48 for gender; OR, 0.81; 95% CI, 0.5-1.30; P = .37 for Asian vs White; and OR, 0.69; 95% CI, 0.31-1.55; P = .37 for URiM vs White), but CIs were wide due to sample size, and point estimates were <1. Similarly, multivariable linear regression analysis modeling the log relative total compensation did not detect statistically significant differences between radiation oncologists by gender (-1.7%; 95% CI, -6.8% to 3.4%; P = .51 for female vs male) or race/ethnicity (-1.6%; 95% CI, -7.3% to 4.0%; P = .57 for Asian vs White and -3.0%; 95% CI, -12.1% to 6.0%; P = .51 for URiM vs White). Conclusions: The low numbers of women and faculty with URiM race/ethnicity in this radiation oncology faculty sample limits the ability to compare career trajectory and compensation by those characteristics. Given that point estimates were <1, our findings do not contradict larger multispecialty studies that suggest an ongoing need to monitor equity.

Using Holistic Residency Applicant Review and Selection in Radiation Oncology to Enhance Diversity and Inclusion-An ASTRO SCAROP-ADROP-ARRO Collaboration.

Disproportionate sex, racial, and ethnic diversity remains in the radiation oncology physician workforce despite widespread awareness and longitudinal efforts to improve representation. In this collaborative review, we define the rationale and components of holistic review and how it can be best used to provide a comprehensive evaluation of applicants to residency programs in radiation oncology. We initially discuss the current state of diversity in the field of radiation oncology and highlight the components of the residency selection process that may serve to perpetuate existing biases. Subsequently, the Accreditation Council for Graduate Medical Education and Association of American Medical Colleges holistic review framework is reviewed in detail to demonstrate the balanced assessment of potential applicants. The implementation of holistic review in medical school and residency selection to date is examined to underscore the potential value of holistic review in the radiation oncology residency selection process. Finally, recommendations for the practical implementation of holistic review in radiation oncology trainee selection are outlined.

Design and implementation of an Internet-Based cancer risk assessment tool: Use over 10 years.

BACKGROUND: Prevention and early intervention can improve survival and quality of life across all cancers. Patient understanding of risk factors and associated actionable lifestyle changes and screening programs is not well understood by clinicians METHODS: An Internet-based tool, Reduce My Risk, was created in 2009 and made available on oncolink.org. Users voluntarily completed a survey regarding demographics and cancer risk factors, and received information about their cancer risk RESULTS: Twenty eight thousand and one surveys were completed from 2009 to 2019. Median age was 26 years (18-101); 60% were females, 87% lived in North America, and 37% had at least a bachelor's degree. Users reported on behavioral/ modifiable risk factors: 13% were current smokers, 52% were current consumers of alcohol, and 8% of those had ≥14 drinks/week. Body mass index (BMI) was ≥30 in 19%; 74% of all surveys reported dietary risks and 36% reported infrequent exercise. Excess UV exposure was reported by 19%. Among women, 36% reported performing breast self-examinations monthly, and 50% reported receiving clinician breast examinations at least once every 3 years. Sixty seven percent of men 55-75 years reported screening prostate specific antigen testing, with 50% receiving annual digital rectal examinations. Nonmodifiable risk factors included family cancer history (64%), genetic syndrome (3%), and cancer-predisposing health conditions (26%) CONCLUSIONS: Ninety-seven percent of users reported modifiable risk factors, and 60% reported ≥4 of these risk factors. Understanding detailed characteristics of a large number of respondents has the potential to improve educational interventions to reduce cancer risk through behavioral modification and cancer screening across the general public.

A phenomenological model of proton FLASH oxygen depletion effects depending on tissue vasculature and oxygen supply.

Introduction: Radiation-induced oxygen depletion in tissue is assumed as a contributor to the FLASH sparing effects. In this study, we simulated the heterogeneous oxygen depletion in the tissue surrounding the vessels and calculated the proton FLASH effective-dose-modifying factor (FEDMF), which could be used for biology-based treatment planning. Methods: The dose and dose-weighted linear energy transfer (LET) of a small animal proton irradiator was simulated with Monte Carlo simulation. We deployed a parabolic partial differential equation to account for the generalized radiation oxygen depletion, tissue oxygen diffusion, and metabolic processes to investigate oxygen distribution in 1D, 2D, and 3D solution space. Dose and dose rates, particle LET, vasculature spacing, and blood oxygen supplies were considered. Using a similar framework for the hypoxic reduction factor (HRF) developed previously, the FEDMF was derived as the ratio of the cumulative normoxic-equivalent dose (CNED) between CONV and UHDR deliveries. Results: Dynamic equilibrium between oxygen diffusion and tissue metabolism can result in tissue hypoxia. The hypoxic region displayed enhanced radio-resistance and resulted in lower CNED under UHDR deliveries. In 1D solution, comparing 15 Gy proton dose delivered at CONV 0.5 and UHDR 125 Gy/s, 61.5% of the tissue exhibited ≥20% FEDMF at 175 µm vasculature spacing and 18.9 µM boundary condition. This percentage reduced to 34.5% and 0% for 8 and 2 Gy deliveries, respectively. Similar trends were observed in the 3D solution space. The FLASH versus CONV differential effect remained at larger vasculature spacings. A higher FLASH dose rate showed an increased region with ≥20% FEDMF. A higher LET near the proton Bragg peak region did not appear to alter the FLASH effect. Conclusion: We developed 1D, 2D, and 3D oxygen depletion simulation process to obtain the dynamic HRF and derive the proton FEDMF related to the dose delivery parameters and the local tissue vasculature information. The phenomenological model can be used to simulate or predict FLASH effects based on tissue vasculature and oxygen concentration data obtained from other experiments.

Annual review of selected scientific literature: A report of the Committee on Scientific Investigation of the American Academy of Restorative Dentistry.

The Scientific Investigation Committee of the American Academy of Restorative Dentistry offers this review of the 2021 dental literature in restorative dentistry to inform busy dentists regarding noteworthy scientific and clinical progress over the past year. Each member of the committee brings discipline-specific expertise to coverage of this broad topical area. Specific subject areas addressed, in order of the appearance in this report, include COVID-19 and the dental profession (new); prosthodontics; periodontics, alveolar bone, and peri-implant tissues; implant dentistry; dental materials and therapeutics; occlusion and temporomandibular disorders; sleep-related breathing disorders; oral medicine and oral and maxillofacial surgery; and dental caries and cariology. The authors focused their efforts on reporting information likely to influence daily dental treatment decisions with an emphasis on future trends in dentistry. With the tremendous volume of dentistry and related literature being published daily, this review cannot possibly be comprehensive. Rather, its purpose is to update interested readers and provide important resource material for those interested in pursuing greater details on their own. It remains our intent to assist colleagues in negotiating the extensive volume of important information being published annually. It is our hope that readers find this work useful in successfully managing the patients and dental problems they encounter.

Acute toxicity in patients treated with concurrent chemoradiotherapy with proton versus intensity-modulated radiation therapy for nonmetastatic head and neck cancers.

BACKGROUND: We evaluated if proton therapy is associated with decreased acute toxicities compared to intensity-modulated radiation therapy (IMRT) in patients receiving concurrent chemoradiotherapy for head and neck cancers. METHODS: We analyzed 580 patients with nonmetastatic head and neck cancers. Primary endpoint was any 90-day grade ≥3 toxicity, prospectively collected and graded per CTCAEv4. Modified Poisson regression models were used. RESULTS: Ninety-five patients received proton and 485 IMRT. The proton group had more HPV-positive tumors (65.6 vs. 58.0%, p = 0.049), postoperative treatment (76.8 vs. 62.1%, p = 0.008), unilateral neck treatment (18.9 vs. 6.6%, p < 0.001) and significantly lower doses to organs-at-risk compared to IMRT group. Adjusted for patient and treatment characteristics, the proton group had decreased grade 2 dysgeusia (RR0.67, 95%CI 0.53-0.84, p = 0.004) and a trend toward lower grade ≥3 toxicities (RR0.60, 95%CI 0.41-0.88, p = 0.06). CONCLUSIONS: Proton therapy was associated with significantly reduced grade 2 dysgeusia and nonstatistically significant decrease in acute grade ≥3 toxicities compared to IMRT.

Activity Monitoring for Toxicity Detection and Management in Patients Undergoing Chemoradiation for Gastrointestinal Malignancies.

PURPOSE: Physical activity is associated with decreased hospitalization during cancer treatment. We hypothesize that activity data can help identify and triage high-risk patients with GI cancer undergoing concurrent chemoradiation. MATERIALS AND METHODS: This prospective study randomly assigned patients to activity monitoring versus observation. In the intervention arm, a 20% decrease in daily steps or 20% increase in heart rate triggered triage visits to provide supportive care, medication changes, and escalation of care. In the observation group, activity data were recorded but not monitored. The primary objective was to show a 20% increase in triage visits in the intervention group. Secondary objectives were estimating the rates of emergency department (ED) visits and hospitalizations. Crude and adjusted odds ratios were computed using logistic regression modeling. RESULTS: There were 22 patients in the intervention and 18 in the observation group. Baseline patient and treatment characteristics were similar. The primary objective was met, with 3.4 more triage visits in the intervention group than in the observation group (95% CI, 2.10 to 5.50; P < .0001). Twenty-six (65.0%) patients required at least one triage visit, with a higher rate in the intervention arm compared with that in the observation arm (86.4% v 38.9%; odds ratio, 9.95; 95% CI, 2.13 to 46.56; P = .004). There was no statistically significant difference in ED visit (9.1% v 22.2%; P = .38) or hospitalization (4.5% v 16.7%; P = .31). CONCLUSION: It is feasible to use activity data to trigger triage visits for symptom management. Further studies are investigating whether automated activity monitoring can assist with early outpatient management to decrease ED visits and hospitalizations.

Multi-institutional Comparison of Intensity Modulated Photon Versus Proton Radiation Therapy in the Management of Squamous Cell Carcinoma of the Anus.

PURPOSE: Concurrent chemoradiation therapy is a curative treatment for squamous cell carcinoma of the anus, but patients can suffer from significant treatment-related toxicities. This study was undertaken to determine whether intensity modulated proton therapy (IMPT) is associated with less acute toxicity than intensity modulated radiation therapy (IMRT) using photons. MATERIALS AND METHODS: We performed a multi-institutional retrospective study comparing toxicity and oncologic outcomes of IMRT versus IMPT. Patients with stage I-IV (for positive infrarenal para-aortic or common iliac nodes only) squamous cell carcinoma of the anus, as defined by the American Joint Committee on Cancer's AJCC Staging Manual, eighth edition, were included. Patients with nonsquamous histology or mixed IMPT and IMRT treatment courses were excluded. Acute nonhematologic toxicities, per the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 4, were recorded prospectively at all sites. Acute and late toxicities, dose metrics, and oncologic outcomes were compared between IMRT and IMPT using univariable and multivariable statistical methods. To improve the robustness of our analysis, we also analyzed the data using propensity score weighting methods. RESULTS: A total of 208 patients were treated with either IMPT (58 patients) or IMRT (150 patients). Of the 208 total patients, 13% had stage I disease, 36% stage II, 50% stage III, and 1% stage IV. IMPT reduced the volume of normal tissue receiving low-dose radiation but not high-dose radiation to bladder and bowel. There was no significant difference between treatment groups in overall grade 3 or greater acute toxicity (IMRT, 68%; IMPT, 67%; P = .96) or 2-year overall grade 3 or greater late toxicity (IMRT, 3.5%; IMPT, 1.8%; P = .88). There was no significant difference in 2-year progression-free survival (hazard ratio, 0.8; 95% CI, 0.3-2.0). CONCLUSIONS: Despite reducing the volume of normal tissue receiving low-dose radiation, IMPT was not associated with decreased grade 3 or greater acute toxicity as measured by CTCAE. Additional follow-up is needed to assess whether important differences arise in late toxicities and if further prospective evaluation is warranted.

Annual review of selected scientific literature: A report of the Committee on Scientific Investigation of the American Academy of Restorative Dentistry.

The Scientific Investigation Committee of the American Academy of Restorative Dentistry offers this review of the 2020 professional literature in restorative dentistry to inform busy dentists regarding noteworthy scientific and clinical progress over the past year. Each member of the committee brings discipline-specific expertise to this work to cover this broad topic. Specific subject areas addressed include prosthodontics; periodontics, alveolar bone, and peri-implant tissues; implant dentistry; dental materials and therapeutics; occlusion and temporomandibular disorders (TMDs); sleep-related breathing disorders; oral medicine and oral and maxillofacial surgery; and dental caries and cariology. The authors focused their efforts on reporting information likely to influence day-to-day dental treatment decisions with a keen eye on future trends in the profession. With the tremendous volume of dentistry and related literature being published today, this review cannot possibly be comprehensive. The purpose is to update interested readers and provide important resource material for those interested in pursuing greater detail. It remains our intent to assist colleagues in navigating the extensive volume of important information being published annually. It is our hope that readers find this work useful in successfully managing the dental patients they encounter.

Comparison of FLASH Proton Entrance and the Spread-Out Bragg Peak Dose Regions in the Sparing of Mouse Intestinal Crypts and in a Pancreatic Tumor Model.

Ultra-high dose rate FLASH proton radiotherapy (F-PRT) has been shown to reduce normal tissue toxicity compared to standard dose rate proton radiotherapy (S-PRT) in experiments using the entrance portion of the proton depth dose profile, while proton therapy uses a spread-out Bragg peak (SOBP) with unknown effects on FLASH toxicity sparing. To investigate, the biological effects of F-PRT using an SOBP and the entrance region were compared to S-PRT in mouse intestine. In this study, 8-10-week-old C57BL/6J mice underwent 15 Gy (absorbed dose) whole abdomen irradiation in four groups: (1) SOBP F-PRT, (2) SOBP S-PRT, (3) entrance F-PRT, and (4) entrance S-PRT. Mice were injected with EdU 3.5 days after irradiation, and jejunum segments were harvested and preserved. EdU-positive proliferating cells and regenerated intestinal crypts were quantified. The SOBP had a modulation (width) of 2.5 cm from the proximal to distal 90%. Dose rates with a SOBP for F-PRT or S-PRT were 108.2 ± 8.3 Gy/s or 0.82 ± 0.14 Gy/s, respectively. In the entrance region, dose rates were 107.1 ± 15.2 Gy/s and 0.83 ± 0.19 Gy/s, respectively. Both entrance and SOBP F-PRT preserved a significantly higher number of EdU + /crypt cells and percentage of regenerated crypts compared to S-PRT. Moreover, tumor growth studies showed no difference between SOBP and entrance for either of the treatment modalities.

Plant and algal lysophosphatidic acid acyltransferases increase docosahexaenoic acid accumulation at the sn-2 position of triacylglycerol in transgenic Arabidopsis seed oil.

Although docosahexaenoic acid (DHA), an important dietary omega-3 polyunsaturated fatty acid (PUFA), is at present primarily sourced from marine fish, bioengineered crops producing DHA may offer a more sustainable and cost-effective source. DHA has been produced in transgenic oilseed crops, however, DHA in seed oil primarily occupies the sn-1/3 positions of triacylglycerol (TAG) with relatively low amounts of DHA in the sn-2 position. To increase the amount of DHA in the sn-2 position of TAG and in seed oil, putative lysophosphatidic acid acyltransferases (LPAATs) were identified and characterized from the DHA-producing alga Schizochytrium sp. and from soybean (Glycine max). The affinity-purified proteins were confirmed to have LPAAT activity. Expression of the Schizochytrium or soybean LPAATs in DHA-producing Arabidopsis expressing the Schizochytrium PUFA synthase system significantly increased the total amount of DHA in seed oil. A novel sensitive band-selective heteronuclear single quantum coherence (HSQC) NMR method was developed to quantify DHA at the sn-2 position of glycerolipids. More than two-fold increases in sn-2 DHA were observed for Arabidopsis lines expressing Schizochytrium or soybean LPAATs, with one Schizochytrium LPAAT driving DHA accumulation in the sn-2 position to 61% of the total DHA. Furthermore, expression of a soybean LPAAT led to a redistribution of DHA-containing TAG species, with two new TAG species identified. Our results demonstrate that transgenic expression of Schizochytrium or soybean LPAATs can increase the proportion of DHA at the sn-2 position of TAG and the total amount of DHA in the seed oil of a DHA-accumulating oilseed plant. Additionally, the band-selective HSQC NMR method that we developed provides a sensitive and robust method for determining the regiochemistry of DHA in glycerolipids. These findings will benefit the advancement of sustainable sources of DHA via transgenic crops such as canola and soybean.

FLASH Proton Radiotherapy Spares Normal Epithelial and Mesenchymal Tissues While Preserving Sarcoma Response.

In studies of electron and proton radiotherapy, ultrahigh dose rates of FLASH radiotherapy appear to produce fewer toxicities than standard dose rates while maintaining local tumor control. FLASH-proton radiotherapy (F-PRT) brings the spatial advantages of PRT to FLASH dose rates (>40 Gy/second), making it important to understand if and how F-PRT spares normal tissues while providing antitumor efficacy that is equivalent to standard-proton radiotherapy (S-PRT). Here we studied PRT damage to skin and mesenchymal tissues of muscle and bone and found that F-PRT of the C57BL/6 murine hind leg produced fewer severe toxicities leading to death or requiring euthanasia than S-PRT of the same dose. RNA-seq analyses of murine skin and bone revealed pathways upregulated by S-PRT yet unaltered by F-PRT, such as apoptosis signaling and keratinocyte differentiation in skin, as well as osteoclast differentiation and chondrocyte development in bone. Corroborating these findings, F-PRT reduced skin injury, stem cell depletion, and inflammation, mitigated late effects including lymphedema, and decreased histopathologically detected myofiber atrophy, bone resorption, hair follicle atrophy, and epidermal hyperplasia. F-PRT was equipotent to S-PRT in control of two murine sarcoma models, including at an orthotopic intramuscular site, thereby establishing its relevance to mesenchymal cancers. Finally, S-PRT produced greater increases in TGFß1 in murine skin and the skin of canines enrolled in a phase I study of F-PRT versus S-PRT. Collectively, these data provide novel insights into F-PRT-mediated tissue sparing and support its ongoing investigation in applications that would benefit from this sparing of skin and mesenchymal tissues. SIGNIFICANCE: These findings will spur investigation of FLASH radiotherapy in sarcoma and additional cancers where mesenchymal tissues are at risk, including head and neck cancer, breast cancer, and pelvic malignancies.

Concurrent Nab-paclitaxel and Radiotherapy: Novel Radiosensitization for Borderline Resectable or Unresectable Pancreatic Cancer.

PURPOSE: This study evaluates the toxicity and tumor response with concurrent nab-paclitaxel chemoradiotherapy (CRT) compared with standard (5-fluorouracil or gemcitabine) CRT. MATERIALS AND METHODS: Fifty patients with borderline resectable or unresectable pancreatic adenocarcinoma from 2014 to 2017 were divided into 2 groups: concurrent nab-paclitaxel (100 to 125 mg/m2 weekly) CRT (median: 2.1 Gy fraction size and 52.5 Gy total) or standard CRT (median: 1.8 Gy fraction size, 54.5 Gy total). The primary endpoint was toxicity, and secondary endpoints were local failure and conversion to resectability. Comparisons were made using rank-sum or Fisher exact test and multivariable competing risk regression for the cumulative incidence of local failure. RESULTS: There were 28 patients in the nab-paclitaxel CRT group and 22 in the standard CRT group; 88% had the unresectable disease. The median follow-up was 18 months. The median duration of chemotherapy before concurrent CRT was 1.9 and 2.3 months in the nab-paclitaxel and standard CRT groups (P=0.337), and radiotherapy dose was 52.5 Gy (range, 52.5 to 59.4 Gy) and 54.5 Gy (range, 45.0 to 59.4 Gy), respectively. There were no statistically significant grade ≥2 toxicities. The nab-paclitaxel CRT group experienced a nonstatistically significant lower incidence of local failure (hazard ratio=0.91, 95% confidence interval: 0.27-3.03, P=0.536). More patients in the nab-paclitaxel CRT group proceeded to surgery (9/28 compared with 3/22 in the standard CRT, P=0.186); of which 6 (25%) in the nab-paclitaxel CRT and 2 (10%) in the standard CRT groups were initially unresectable. CONCLUSIONS: Nab-paclitaxel CRT had similar toxicity compared with standard CRT in the treatment of borderline resectable or unresectable pancreatic cancer. Its use was associated with an arithmetically lower cumulative incidence of local failure and an arithmetically higher conversion to resectability, both of which were not statistically significant.