A prospective evaluation of neck and shoulder function following treatments of early-stage human papillomavirus-associated oropharynx cancer.

OBJECTIVES: To compare post-treatment neck and shoulder function between human papillomavirus-associated oropharynx squamous cell carcinoma (HPV + OPSCC) treatments. DESIGN: Prospective, repeated-measures study. SETTING: Tertiary care center. PARTICIPANTS: Treatment-naïve patients with American Joint Committee on Cancer eighth edition stage T0-3/N0-2 HPV+OPSCC. MAIN OUTCOME MEASURES: Patients completed the Neck Dissection Impairment Index (NDII) pre-treatment and 3-months and 1-year post-treatment. The NDII assesses 10 neck and shoulder functions scored 0-5 (total score 0-100), with higher scores suggesting better function. RESULTS: A total of 106 patients underwent: surgery alone (SA, n = 46, 43%), surgery with adjuvant radiation ± chemotherapy (S + a[C]XRT, n = 18, 17%), or definitive radiation ± chemotherapy (d[C]XRT, n = 42, 40%). cTN classification and pre-treatment NDII scores did not differ between groups. SA patients reported worsened 3-month post-treatment versus pre-treatment self-care (4.6 vs. 5.0), lifting light (4.6 vs. 5.0) and heavy (4.2 vs. 4.8) objects, overhead reach (4.5 vs. 4.9), activity (4.5 vs. 4.9), socialization (4.7 vs. 4.9), recreation (4.6 vs. 4.9), and overall score (86.8 vs. 95.3) (all p < 0.05). One-year post-treatment scores (n = 34) were no different than pre-treatment in all domains. S + a[C]XRT patients reported worsened 3-month versus pre-treatment stiffness (4.0 vs. 4.8), lifting heavy objects (3.8 vs. 4.9), overhead reach (4.2 vs. 4.9), socialization (4.6 vs. 5.0), recreation (4.4 vs. 4.9) and overall score (82.4 vs. 96.0) (all p < 0.05). One-year post-treatment scores (n = 13) were no different than pre-treatment in all domains. d[C]XRT patients reported worsened 3-month versus pre-treatment difficulty lifting heavy objects (4.3 vs. 4.7) and recreation (4.3 vs. 4.7). One-year posttreatment scores (n = 21) were no different than pre-treatment in all domains. CONCLUSION: HPV + OPSCC patients may experience mild shoulder/neck dysfunction 3 months after treatment that usually resolves by 1 year, independent of treatment modality.

Reducing radiation-related morbidity in the treatment of nasopharyngeal carcinoma.

While radiation therapy is the mainstay of treatment for nasopharyngeal carcinoma, the anatomic location of the nasopharynx in close proximity to radiation-sensitive organs such as the salivary glands, optic nerves and chiasm, cochlea, brainstem and temporal lobes presents a special challenge. Technological approaches to reducing the morbidity of nasopharyngeal cancer irradiation have been historically successful with the evolution from 2D techniques to increasingly conformal forms of radiation therapy. This report reviews normal tissue dose constraints and major considerations in target delineation for patients with nasopharyngeal cancer in the intensity-modulated radiation therapy era. Furthermore, this report discusses more contemporary approaches to toxicity reduction such as the judicious reduction or omission of radiation to low-risk regions and the potential role of particle beam therapy.

Higher area deprivation index is associated with poorer local control and overall survival in non-metastatic nasopharyngeal carcinoma.

BACKGROUND: Neighborhood socioeconomic deprivation impacts outcomes in various cancers. We examined this association in nasopharyngeal carcinoma (NPC) patients using the area deprivation index (ADI). METHODS: We conducted a single-institution retrospective cohort study on NPC patients treated with definitive radiotherapy from 1980 to 2023. ADI was used as the primary exposure measure. Higher ADI indicates higher levels of socioeconomic deprivation. RESULTS: Of 561 patients, those with higher ADI (6-10 vs. 1-5) presented more commonly with AJCC stage III/IV compared to I/II (87% vs. 76%, p = 0.03). Increasing ADI decile score correlated with poorer overall survival (HR 1.14, 95% CI 1.01-1.28, p = 0.04). Local control was worse in patients from the most deprived quartile in the cohort ADI 5-10 (HR 2.11, 95% CI 1.01-4.41, p = 0.05). CONCLUSIONS: NPC patients from more disadvantaged neighborhoods undergoing radiotherapy had worse local control and survival outcomes. Interventions to address structural determinants of health and neighborhood disparities may improve these outcomes.

Incidental findings and safety events from magnetic resonance imaging simulation for head and neck radiation treatment planning: A single institution experience.

Purpose: Having dedicated MRI scanners within radiation oncology departments may present unexpected challenges since radiation oncologists and radiation therapists are generally not trained in this modality and there are potential patient safety concerns. This study retrospectively reviews the incidental findings and safety events that were observed at a single institution during introduction of MRI sim for head and neck radiotherapy planning. Methods: Consecutive patients from March 1, 2020, to May 31, 2022, who were scheduled for MRI sim after having completed CT simulation for head and neck radiotherapy were included for analysis. Patients first underwent a CT simulation with a thermoplastic mask and in most cases with an intraoral stent. The same setup was then reproduced in the MRI simulator. Safety events were instances where scheduled MRI sims were not completed due to the MRI technologist identifying MRI-incompatible devices or objects at the time of sim. Incidental findings were identified during weekly quality assurance rounds as a joint enterprise of head and neck radiation oncology and neuroradiology. Categorical variables between completed and not completed MRI sims were compared using the Chi-Square test and continuous variables were compared using the Mann-Whitney U test with a p-value of < 0.05 considered to be statistically significant. Results: 148 of 169 MRI sims (88 %) were completed as scheduled and 21 (12 %) were not completed (Table 1). Among the 21 aborted MRI sims, the most common reason was due to safety events flagged by the MRI technologist (n = 8, 38 %) because of the presence of metal or a medical device that was not noted at the time of initial screening by the administrative coordinator. Patients who did not complete MRI sim were more likely to be treated for non-squamous head and neck primary tumor (p = 0.016) and were being treated post-operatively (p < 0.001). CT and MRI sim scans each had 17 incidental findings. CT simulation detected 3 cases of new metastases in lungs, which were outside the scan parameters of MRI sim. MRI sim detected one case of dural venous thrombosis and one case of cervical spine epidural abscess, which were not detected by CT simulation. Conclusions: Radiation oncology departments with dedicated MRI simulation scanners would benefit from diagnostic radiology review for incidental findings and having therapists with MRI safety credentialing to catch near-miss events.

Treatment Modality Impact on Patient-Reported Quality of Life in Human Papilloma Virus-Associated Oropharyngeal Carcinoma.

OBJECTIVE: To prospectively compare the impact of treatment modality on patient-reported quality of life (QOL) in human papillomavirus-associated oropharynx squamous cell carcinoma (HPV + OPSCC). STUDY DESIGN: Prospective cohort study. SETTING: Academic medical center. METHODS: One hundred one patients with American Joint Committee on Cancer (AJCC) 8th edition T1-3 N0-2 HPV + OPSCC completed the European Organization for Research and Treatment of Cancer Quality of Life Core questionnaire and Head and Neck Module pretreatment and 3-month and 1-year posttreatment. Mean score changes were compared to published minimal clinically important differences. RESULTS: Patients underwent surgery alone (SA: N = 42, 42%), surgery with adjuvant radiation (S-RT: N = 10, 10%), surgery with adjuvant chemoradiation (S-CRT: N = 8, 8%), definitive radiation (RT: N = 11, 11%), or definitive chemoradiation (CRT: N = 30, 30%). SA, S-[C]RT, and [C]RT patients all reported clinically significant difficulty with sense of taste/smell persisting at 1 year. S-[C]RT and [C]RT patients reported statistically and clinically significant worse salivary dysfunction and problems with social eating at 1 year than SA. S-[C]RT patients reported statistically and clinically significant worse fatigue and head and neck pain compared to [C]RT and SA patients at 3 months, but normalized at 1 year. S-CRT compared to S-RT had statistically and clinically worse physical and role functioning and swallowing difficulties at 3 months but this difference was resolved by 1-year posttreatment. CONCLUSION: HPV + OPSCC patients after SA report the lowest posttreatment QOL impact, whereas after S-CRT report the highest symptom burden. Careful selection for definitive surgery is important given the possibility of adjuvant CRT. Patients can experience persistent sense taste and smell difficulties at 1 year with all treatment modalities. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:1687-1695, 2024.

Longitudinal Analysis of Swallowing Displacement Kinematics After Oropharyngeal Cancer Treatment.

BACKGROUND/OBJECTIVE: Quantitative swallowing displacement kinematics evolve in patients treated for oropharyngeal squamous cell carcinoma (OPSCC). We aimed to longitudinally assess these measurements and correlate them with functional swallowing outcomes. METHOD: A retrospective review was conducted on patients with OPSCC treated with definitive (chemo)radiation ([C]RT) or surgery with adjuvant (chemo)radiation (S-[C]RT) who completed at least two videofluoroscopic swallow studies (VFSS). Longitudinal analysis was accomplished via mixed-effects logistic regression for the Functional Oral Intake Scale (FOIS), and Penetration Aspiration Scale (PAS), and mixed-effects linear regression for kinematic measures. Spearman's correlation was conducted between changes in FOIS/PAS and kinematic measures. RESULTS: Ninety-seven patients (76 males; mean age 61) completed 245 VFSS studies. A total of 94% had human papillomavirus (HPV)/p16 positive OPSCC and 74% were T0-T2. Sixty-four patients underwent [C]RT while 33 patients underwent S-[C]RT. After treatment, posterior pharyngeal wall at hold (PPWhold) increased 3.2 standard deviation (SD) between 0 and 6 months (p < 0.001), then decreased 2.2 SD between 6 and 12 months (p < 0.001) and did not return to baseline. Hyoid-to-larynx (HL) (p = 0.046) and maximal hyoid displacement (Hmax) + HL (p = 0.042) increased between 6 and 12 months. Hmax (p = 0.020) and Hmax + HL (p < 0.001) decreased between 12-24 months beyond baseline values. The decrease in HL and increase in PPWhold (p < 0.05) correlated with an increase in PAS. From baseline, increased pharyngeal constriction ratio correlated with decreased FOIS and PPWhold (p < 0.05). CONCLUSIONS: Quantitative swallowing kinematic measures can effectively track changes in swallowing physiology. Increased PPWhold and restricted hyolaryngeal movement were seen in patients with OPSCC after treatment and correlated with a change in swallowing outcome, emphasizing the need for serial VFSS monitoring and targeted intervention. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1339-1348, 2023.

Integrating CT-based radiomic model with clinical features improves long-term prognostication in high-risk prostate cancer.

Objective: High-risk prostate cancer (PCa) is often treated by prostate-only radiotherapy (PORT) owing to its favourable toxicity profile compared to whole-pelvic radiotherapy. Unfortunately, more than 50% patients still developed disease progression following PORT. Conventional clinical factors may be unable to identify at-risk subgroups in the era of precision medicine. In this study, we aimed to investigate the prognostic value of pre-treatment planning computed tomography (pCT)-based radiomic features and clinical attributes to predict 5-year progression-free survival (PFS) in high-risk PCa patients following PORT. Materials and methods: A total of 176 biopsy-confirmed PCa patients who were treated at the Hong Kong Princess Margaret Hospital were retrospectively screened for eligibility. Clinical data and pCT of one hundred eligible high-risk PCa patients were analysed. Radiomic features were extracted from the gross-tumour-volume (GTV) with and without applying Laplacian-of-Gaussian (LoG) filter. The entire patient cohort was temporally stratified into a training and an independent validation cohort in a ratio of 3:1. Radiomics (R), clinical (C) and radiomic-clinical (RC) combined models were developed by Ridge regression through 5-fold cross-validation with 100 iterations on the training cohort. A model score was calculated for each model based on the included features. Model classification performance on 5-year PFS was evaluated in the independent validation cohort by average area-under-curve (AUC) of receiver-operating-characteristics (ROC) curve and precision-recall curve (PRC). Delong's test was used for model comparison. Results: The RC combined model which contains 6 predictive features (tumour flatness, root-mean-square on fine LoG-filtered image, prostate-specific antigen serum concentration, Gleason score, Roach score and GTV volume) was the best-performing model (AUC = 0.797, 95%CI = 0.768-0.826), which significantly outperformed the R-model (AUC = 0.795, 95%CI = 0.774-0.816) and C-model (AUC = 0.625, 95%CI = 0.585-0.665) in the independent validation cohort. Besides, only the RC model score significantly classified patients in both cohorts into progression and progression-free groups regarding their 5-year PFS (p< 0.05). Conclusion: Combining pCT-based radiomic and clinical attributes provided superior prognostication value regarding 5-year PFS in high-risk PCa patients following PORT. A large multi-centre study will potentially aid clinicians in implementing personalised treatment for this vulnerable subgroup in the future.

Adverse radiation effect and freedom from progression following repeat stereotactic radiosurgery for brain metastases.

OBJECTIVE: The authors previously evaluated risk and time course of adverse radiation effects (AREs) following stereotactic radiosurgery (SRS) for brain metastases, excluding lesions treated after prior SRS. In the present analysis they focus specifically on single-fraction salvage SRS to brain metastases previously treated with SRS or hypofractionated SRS (HFSRS), evaluating freedom from progression (FFP) and the risk and time course of AREs. METHODS: Brain metastases treated from September 1998 to May 2019 with single-fraction SRS after prior SRS or HFSRS were analyzed. Serial follow-up magnetic resonance imaging (MRI) and surgical pathology reports were reviewed to score local treatment failure and AREs. The Kaplan-Meier method was used to estimate FFP and risk of ARE measured from the date of repeat SRS with censoring at the last brain MRI. RESULTS: A total of 229 retreated brain metastases in 124 patients were evaluable. The most common primary cancers were breast, lung, and melanoma. The median interval from prior SRS/HFSRS to repeat SRS was 15.4 months, the median prescription dose was 18 Gy, and the median duration of follow-up imaging was 14.5 months. At 1 year after repeat SRS, FFP was 80% and the risk of symptomatic ARE was 11%. The 1-year risk of imaging changes, including asymptomatic RE and symptomatic ARE, was 30%. Among lesions that demonstrated RE, the median time to onset was 6.7 months (IQR 4.7-9.9 months) and the median time to peak imaging changes was 10.1 months (IQR 5.6-13.6 months). Lesion size by quadratic mean diameter (QMD) showed similar results for QMDs ranging from 0.75 to 2.0 cm (1-year FFP 82%, 1-year risk of symptomatic ARE 11%). For QMD < 0.75 cm, the 1-year FFP was 86% and the 1-year risk of symptomatic ARE was only 2%. Outcomes were worse for QMDs 2.01-3.0 cm (1-year FFP 65%, 1-year risk of symptomatic ARE 24%). The risk of symptomatic ARE was not increased with tyrosine kinase inhibitors or immunotherapy before or after repeat SRS. CONCLUSIONS: RE on imaging was common after repeat SRS (30% at 1 year), but the risk of a symptomatic ARE was much less (11% at 1 year). The results of repeat single-fraction SRS were good for brain metastases ≤ 2 cm. The authors recommend an interval ≥ 6 months from prior SRS and a prescription dose ≥ 18 Gy. Alternatives such as HFSRS, laser interstitial thermal therapy, or resection with adjuvant radiation should be considered for recurrent brain metastases > 2 cm.

Early-Stage Primary Lung Neuroendocrine Tumors Treated With Stereotactic Body Radiation Therapy: A Multi-Institution Experience.

PURPOSE: Current guidelines recommend surgery as standard of care for primary lung neuroendocrine tumor (LNET). Given that LNET is a rare clinical entity, there is a lack of literature regarding treatment of LNET with stereotactic body radiation therapy (SBRT). We hypothesized that SBRT could lead to effective locoregional tumor control and long-term outcomes. METHODS AND MATERIALS: We retrospectively reviewed 48 tumors in 46 patients from 11 institutions with a histologically confirmed diagnosis of LNET, treated with primary radiation therapy. Data were collected for patients treated nonoperatively with primary radiation therapy between 2006 and 2020. Patient records were reviewed for lesion characteristics and clinical risk factors. Kaplan-Meier analysis, log-rank tests, and Cox multivariate models were used to compare outcomes. RESULTS: Median age at treatment was 71 years and mean tumor size was 2 cm. Thirty-two lesions were typical carcinoid histology, 7 were atypical, and 9 were indeterminate. The most common SBRT fractionation schedule was 50 to 60 Gy in 5 daily fractions. Overall survival at 3, 6, and 9 years was 64%, 43%, and 26%, respectively. Progression-free survival at 3, 6, and 9 years was 88%, 78%, and 78%, respectively. Local control at 3, 6, and 9 years was 97%, 91%, and 91%, respectively. There was 1 regional recurrence in a paraesophageal lymph node. No grade 3 or higher toxicity was identified. CONCLUSIONS: This is the largest series evaluating outcomes in patients with LNET treated with SBRT. This treatment is well tolerated, provides excellent locoregional control, and should be offered as an alternative to surgical resection for patients with early-stage LNET, particularly those who may not be ideal surgical candidates.

18F-FDG PET/CT Prediction of Treatment Outcomes in Human Papillomavirus-Positive, Locally Advanced Oropharyngeal Cancer Patients Receiving Deintensified Therapy: Results from NRG-HN002.

The purpose of this study was to determine the negative predictive value (NPV) of a 12- to 14-wk posttreatment PET/CT for 2-y progression-free survival (PFS) and locoregional control (LRC) in patients with p16-positive locoregionally advanced oropharyngeal cancer (LA-OPC). Study was a secondary endpoint in NRG-HN002, a noncomparative phase II trial in p16-positive LA-OPC, stage T1-T2, N1-N2b or T3, N0-N2b, and ≤10 pack-year smoking. Patients were randomized in a 1:1 ratio to reduced-dose intensity-modulated radiotherapy (IMRT) with or without cisplatin. Methods: PET/CT scans were reviewed centrally. Tumor response evaluations for the primary site, right neck, and left neck were performed using a 5-point ordinal scale (Hopkins criteria). Overall scores were then assigned as negative, positive, or indeterminate. Patients with a negative score for all 3 evaluation sites were given an overall score of negative. The hypotheses were NPV for PFS and LRC at 2-y posttreatment ≤ 90% versus >90% (1-sided P value, 0.10). Results: A total of 316 patients were enrolled, of whom 306 were randomized and eligible. Of these, 131 (42.8%) patients consented to a posttherapy PET/CT, and 117 (89.3%) patients were eligible for PET/CT analysis. The median time from the end of treatment to PET/CT scan was 94 d (range, 52-139 d). Estimated 2-y PFS and LRC rates in the analysis subgroup were 91.3% (95% CI, 84.6, 95.8%) and 93.8% (95% CI, 87.6, 97.5%), respectively. Posttreatment scans were negative for residual tumor for 115 patients (98.3%) and positive for 2 patients (1.7%). NPV for 2-y PFS was 92.0% (90% lower confidence bound [LCB] 87.7%; P = 0.30) and for LRC was 94.5% (90% LCB 90.6%; P = 0.07). Conclusion: In the context of deintensification with reduced-dose radiation, the NPV of a 12- to 14-wk posttherapy PET/CT for 2-y LRC is estimated to be >90%, similar to that reported for patients receiving standard chemoradiation. However, there is insufficient evidence to conclude that the NPV is >90% for PFS.

Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses.

Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% confidence interval 0.37 to 0.78, P = 0.0001) and suggested postoperative management could be refined for 29.8% of patients. In sum, our results identify a targeted gene expression biomarker that improves discrimination of meningioma outcomes, including prediction of postoperative radiotherapy responses.

Approaches to the Management of Metastatic Adenoid Cystic Carcinoma.

High rates of recurrence and distant metastasis are a foremost challenge in the management of adenoid cystic carcinoma (ACC), occurring in approximately 40% of all ACC patients. Despite the morbidity and mortality resulting from recurrent/metastatic (R/M) disease, there are no FDA-approved systemic agents for these patients. In this review, we summarize pertinent ACC pathophysiology and its implications for different systemic treatment regimens in R/M ACC. We review the evidence for the most widely used systemic agents - cytotoxic chemotherapy and tyrosine kinase inhibitors (TKIs) targeting VEGFR - in addition to immune checkpoint inhibitors and non-TKI biologic agents. Exciting emerging targets for R/M ACC, including inhibitors of Notch signaling, stemness, PRMT5, and Axl, are also discussed. Lastly, we review local therapies for small-volume lung disease in patients with oligometastatic ACC, specifically pulmonary metastasectomy and stereotactic body radiation therapy (SBRT). Future development of targeted molecular agents which exploit the underlying biology of this disease may yield novel therapeutic options to improve clinical outcomes in patients with R/M ACC.

Safety of accelerated hypofractionated whole pelvis radiation therapy prior to high dose rate brachytherapy or stereotactic body radiation therapy prostate boost.

BACKGROUND: To evaluate acute and late genitourinary and gastrointestinal toxicities and patient reported urinary and sexual function following accelerated, hypofractionated external beam radiotherapy to the prostate, seminal vesicles and pelvic lymph nodes and high dose rate (HDR) brachytherapy or stereotactic body radiation therapy (SBRT) prostate boost. METHODS: Patients at a single institution with NCCN intermediate- and high-risk localized prostate cancer with logistical barriers to completing five weeks of whole pelvic radiotherapy (WPRT) were retrospectively reviewed for toxicity following accelerated, hypofractionated WPRT (41.25 Gy in 15 fractions of 2.75 Gy). Patients also received prostate boost radiotherapy with either HDR brachytherapy (1 fraction of 15 Gy) or SBRT (19 Gy in 2 fractions of 9.5 Gy). The duration of androgen deprivation therapy was at the discretion of the treating radiation oncologist. Toxicity was evaluated by NCI CTCAE v 5.0. RESULTS: Between 2015 and 2017, 22 patients with a median age of 71 years completed accelerated, hypofractionated WPRT. Median follow-up from the end of radiotherapy was 32 months (range 2-57). 5%, 73%, and 23% of patients had clinical T1, T2, and T3 disease, respectively. 86% of tumors were Gleason grade 7 and 14% were Gleason grade 9. 68% and 32% of patients had NCCN intermediate- and high-risk disease, respectively. 91% and 9% of patients received HDR brachytherapy and SBRT prostate boost following WPRT, respectively. Crude rates of grade 2 or higher GI and GU toxicities were 23% and 23%, respectively. 3 patients (14%) had late or persistent grade 2 toxicities of urinary frequency and 1 patient (5%) had late or persistent GI toxicity of diarrhea. No patient experienced grade 3 or higher toxicity at any time. No difference in patient-reported urinary or sexual function was noted at 12 months. CONCLUSIONS: Accelerated, hypofractionated whole pelvis radiotherapy was associated with acceptable GU and GI toxicities and should be further validated for those at risk for harboring occult nodal disease.

Feasibility of accelerated image-guided high-dose-rate interstitial brachytherapy with inverse planning simulated annealing (IPSA-HDRBT) for post-operative treatment of pathologically node-negative squamous cell carcinomas of the oral tongue.

PURPOSE: Inverse planning simulated annealing (IPSA) produces highly conformal dose distributions and quick optimizations for high-dose-rate interstitial brachytherapy (HDRBT). We report our dosimetry and overall outcomes using this approach for the accelerated post-operative treatment of pathologically node-negative squamous cell carcinomas of the oral tongue (OTSCC) with high risk of local recurrence. METHODS: Patients with newly diagnosed pN0 OTSCC treated with partial glossectomy, neck dissection, and post-operative HDRBT alone from 2007 to 2021 were retrospectively reviewed. Patients received 30 Gy in 5 fractions over 2.5 days. Target volume and mandible dosimetry are reported. Actuarial rates of local control, regional control, disease-specific survival, and overall survival were estimated using the Kaplan-Meier method. Toxicity was categorized using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: 19 consecutive patients were reviewed. Median follow-up was 3.2 years (IQR 1.4-8.2 years) with a 3-year estimated local control rate of 81%. Target volumes were generally small, as the median volume was 12.66 cc. Median V150% and V200% were 52% and 24%, respectively. D1cc and D2cc to the mandible were 17.31 Gy and 14.42 Gy, respectively. CONCLUSIONS: IPSA-HDRBT is feasible and highly efficient for post-operative treatment of the primary tumor bed in patients with pathologically node-negative squamous cell carcinomas of the oral tongue. Further technical optimization and prospective clinical evaluation in a larger patient cohort are planned.

Artificial Intelligence-Guided Prediction of Dental Doses Before Planning of Radiation Therapy for Oropharyngeal Cancer: Technical Development and Initial Feasibility of Implementation.

Purpose: The aim was to develop a novel artificial intelligence (AI)-guided clinical decision support system, to predict radiation doses to subsites of the mandible using diagnostic computed tomography scans acquired before any planning of head and neck radiation therapy (RT). Methods and Materials: A dose classifier was trained using RT plans from 86 patients with oropharyngeal cancer; the test set consisted of an additional 20 plans. The classifier was trained to predict whether mandible subsites would receive a mean dose >50 Gy. The AI predictions were prospectively evaluated and compared with those of a specialist head and neck radiation oncologist for 9 patients. Positive predictive value (PPV), negative predictive value (NPV), Pearson correlation coefficient, and Lin concordance correlation coefficient were calculated to compare the AI predictions to those of the physician. Results: In the test data set, the AI predictions had a PPV of 0.95 and NPV of 0.88. For 9 patients evaluated prospectively, there was a strong correlation between the predictions of the AI algorithm and physician (P = .72, P < .001). Comparing the AI algorithm versus the physician, the PPVs were 0.82 versus 0.25, and the NPVs were 0.94 versus 1.0, respectively. Concordance between physician estimates and final planned doses was 0.62; this was 0.71 between AI-based estimates and final planned doses. Conclusion: AI-guided decision support increased precision and accuracy of pre-RT dental dose estimates.

The Role of Chemotherapy Plus Immune Checkpoint Inhibitors in Oncogenic-Driven NSCLC: A University of California Lung Cancer Consortium Retrospective Study.

Introduction: There is a paucity of data on immune checkpoint inhibitors (ICIs) plus doublet chemotherapy (C) in patients with advanced lung cancer whose tumor harbors an actionable mutation. We sought to provide insight into the role of this combination in relation to chemotherapy alone in this patient population. Methods: We conducted a retrospective study at the five University of California National Cancer Institute-designated Comprehensive Cancer Centers. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and significant adverse events. Adverse events in patients who received a tyrosine kinase inhibitor (TKI) post-ICI were also captured. Results: A total of 246 patients were identified, 170 treated with C plus ICI and 76 treated with C alone. Driver alterations included EGFR (54.9%), KRAS (32.9%), ALK (5.3%), HER2/ERBB2 (2.9%), ROS1 (1.2%), MET (1.2%), RET (0.8%), and BRAF non-V600 (0.8%). The overall PFS and OS hazard ratios were not significant at 1.12 (95% confidence interval 0.83-1.51; p = 0.472) and 0.86 (95% confidence interval: 0.60-1.24, p = 0.429), respectively. No significant differences in PFS or OS were observed in the mutational subgroups. Grade 3 or greater adverse events were lower in the C plus ICI group. The multivariate analysis for PFS and OS revealed a performance status (Eastern Cooperative Oncology Group) score of 2, and previous TKI treatment was associated with poorer outcomes with C plus ICI. Conclusions: Our study suggests that patients with oncogenic-driven NSCLC, primarily those with EGFR-driven tumors, treated with a TKI should not subsequently receive C plus ICI. Analysis from prospective clinical trials will provide additional information on the role of ICIs in this group of patients.

Complexes of 2,4,6-trihydroxybenzoic acid: effects of intramolecular hydrogen bonding on ligand geometry and metal binding modes.

This article describes a series of more than 20 new compounds formed by the combination of 2,4,6-trihydroxybenzoic acid (H4thba) with metal ions in the presence of a base, with structures that include discrete molecular units, chains, and two- and three-dimensional networks. As a result of the presence of two ortho-hydroxy groups, H4thba is a relatively strong acid (pKa1 = 1.68). The carboxylate group in H3thba- is therefore considerably less basic than most carboxylates with intramolecular hydrogen bonds, conferring a rigid planar geometry upon the anion. These characteristics of H3thba- significantly impact upon the way it interacts with metal ions. In s-block metal compounds, where the interaction of the metal centres with the carboxylate O atoms is essentially ionic, the anion bonds to up to three metal centres via a variety of binding modes. In cases where the metal ion is able to form directional coordinate bonds, however, the carboxylate group tends to bond in a monodentate mode, interacting with just one metal centre in the syn mode. A dominant influence on the structures of the complexes seems to be the face-to-face stacking of the aromatic rings, which creates networks containing layers of metal-oxygen polyhedra that participate in hydrogen bonding. This investigation was undertaken, in part, by a group of secondary school students as an educational exercise designed to introduce school students to the technique of single-crystal X-ray diffraction and enhance their understanding of primary and secondary bonding.

Adverse radiation effects in volume-staged radiosurgery for large arteriovenous malformations: a multiinstitutional study.

OBJECTIVE: The optimal treatment paradigm for large arteriovenous malformations (AVMs) is controversial. One approach is volume-staged stereotactic radiosurgery (VS-SRS). The authors previously reported efficacy of VS-SRS for large AVMs in a multiinstitutional cohort; here they focus on risk of symptomatic adverse radiation effects (AREs). METHODS: This is a multicentered retrospective review of patients treated with a planned prospective volume staging approach to stereotactically treat the entire nidus of an AVM, with volume stages separated by intervals of 3-6 months. A total of 9 radiosurgical centers treated 257 patients with VS-SRS between 1991 and 2016. The authors evaluated permanent, transient, and total ARE events that were symptomatic. RESULTS: Patients received 2-4 total volume stages. The median age was 33 years at the time of the first SRS volume stage, and the median follow-up was 5.7 years after VS-SRS. The median total AVM nidus volume was 23.25 cm3 (range 7.7-94.4 cm3), with a median margin dose per stage of 17 Gy (range 12-20 Gy). A total of 64 patients (25%) experienced an ARE, of which 19 were permanent. Rather than volume, maximal linear dimension in the Z (craniocaudal) dimension was associated with toxicity; a threshold length of 3.28 cm was associated with an ARE, with a 72.5% sensitivity and a 58.3% specificity. In addition, parietal lobe involvement for superficial lesions and temporal lobe involvement for deep lesions were associated with an ARE. CONCLUSIONS: Size remains the dominant predictor of toxicity following SRS, but overall rates of AREs were lower than anticipated based on baseline features, suggesting that dose and size were relatively dissociated through volume staging. Further techniques need to be assessed to optimize outcomes.

Meningioma DNA methylation groups identify biological drivers and therapeutic vulnerabilities.

Meningiomas are the most common primary intracranial tumors. There are no effective medical therapies for meningioma patients, and new treatments have been encumbered by limited understanding of meningioma biology. Here, we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, proteomic and single-cell approaches to show meningiomas are composed of three DNA methylation groups with distinct clinical outcomes, biological drivers and therapeutic vulnerabilities. Merlin-intact meningiomas (34%) have the best outcomes and are distinguished by NF2/Merlin regulation of susceptibility to cytotoxic therapy. Immune-enriched meningiomas (38%) have intermediate outcomes and are distinguished by immune infiltration, HLA expression and lymphatic vessels. Hypermitotic meningiomas (28%) have the worst outcomes and are distinguished by convergent genetic and epigenetic mechanisms driving the cell cycle and resistance to cytotoxic therapy. To translate these findings into clinical practice, we show cytostatic cell cycle inhibitors attenuate meningioma growth in cell culture, organoids, xenografts and patients.

Timing of Urgent Inpatient Palliative Radiation Therapy.

PURPOSE: Urgent indications for palliative radiation therapy (RT) include malignant spinal cord compression, symptomatic brain metastases, pain, airway obstruction, and bleeding. Data on the timing of palliative RT in the inpatient setting are limited. We report our experience with inpatient palliative RT at a tertiary academic center and evaluate the effect of a dedicated inpatient palliative RT nurse practitioner (NP) on treatment timelines. METHODS AND MATERIALS: We performed a retrospective, single-institution review of 219 inpatients consulted for RT to sites of metastatic disease between May 2012 and May 2018. We compared time-to-treatment intervals before and after integrating an NP for palliative RT in August 2017. RESULTS: The median age of the 219 patients receiving RT was 61 years (interquartile range [IQR], 51-69 years). The most frequent indications were symptomatic brain metastases (73 patients [33%]), pain (61 patients [28%]), and cord/cauda compression (48 patients [22%]). The median time from consultation request to consult was 1 day (IQR, 0-2 days), and the median time from consultation request to first RT fraction was 3 days (IQR, 2-6 days). The median time from consultation request to RT was shorter for cord compression (2 [IQR, 1-4] days) than for pain (5 [IQR, 2-7] days) (P = .001) or symptomatic brain metastases (3 [IQR, 1-6] days; P = .037). With an NP, patients were more likely to undergo same-day consultation and simulation (75% vs 60%; P = .045), which was associated with shorter median duration from consultation to initiation of RT (1 [IQR, 0-3] days vs 4 [IQR, 2-7] days; P <.001). After the integration of an NP for palliative RT, patients had a higher median Karnofsky Performance Score (70 [IQR, 60-80] vs 50 [IQR, 40-60]; P < .001) and were more likely to complete their prescribed RT course (93% vs 82%; P = .05). CONCLUSIONS: Time from consultation request to RT is necessarily short for urgent inpatient palliative RT. Advanced practice providers may facilitate and potentially expedite treatment, with significantly shorter times to treatment among patients who undergo same-day consultation and simulation.