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Purpose: Cumulative cisplatin doses of ≥ 200 mg/m 2 improve survival in adults with head-and-neck squamous cell carcinoma (HNSCC) undergoing chemoradiation, but many older adults with HNSCC cannot receive this prognostically relevant dose due to toxicities. This study aims to develop predictive models to assess the likelihood of older adults with HNSCC receiving ≥ 200 mg/m 2 cisplatin during chemoradiation., Methods: 366 patients from the SENIOR database, an international cohort of adults ≥ 65 years with HNSCC, received definitive chemoradiation with single-agent cisplatin and were analyzed. A Generalized Linear Model (GLM), Support Vector Machine (SVM), and Random Forest Model (RFM) were trained and compared for their performance in predicting a cumulative cisplatin dose of ≥ 200 mg/m 2 ., Results: 195 (53 %) patients achieved a cumulative cisplatin dose of ≥ 200 mg/m 2 . In the GLM, laryngeal carcinoma (β = 1.37, p = 0.01), tumoral p16 positivity (β = 0.69, p = 0.04), higher hemoglobin levels (β = 0.26, p = 0.002), elevated C-reactive protein (CRP) concentration (β = 0.02, p = 0.003), and increased estimated glomerular filtration rate (eGFR) (β = 0.02, p = 0.008) were associated with a higher probability of reaching ≥ 200 mg/m 2 cisplatin. Hemoglobin, CRP, eGFR, and p16 status constituted the most important features in the SVM and RFM. AUC values for the GLM, SVM, and RFM were 0.70 (95 % CI, 0.67-0.73), 0.71 (95 % CI, 0.68-0.73), and 0.73 (95 % CI, 0.71-0.75), respectively., Conclusions: We developed predictive models to support clinicians in identifying older adults with HNSCC capable of tolerating ≥ 200 mg/m 2 cumulative cisplatin during chemoradiation. Once validated, these models could improve personalized treatments and enhance shared decision-making in older adults with HNSCC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.R. reports personal fees and research grants from Novocure, personal fees from Merck Healthcare Germany, Darmstadt, and consulting fees from Johnson & Johnson. A.F. received honoraria from Merck Sharp & Dohme. S.R.J. reports research funds from Varian Medical Systems. C.B. reports grants from Helmholtz Zentrum Munich, nonfinancial support from LMU Munich, and grants from the German Cancer Consortium during the conduct of the study. C.B. also reports personal fees from Merck Healthcare Germany, Darmstadt, and Bristol-Myers Squibb and grants from Elekta outside the submitted work. A.M. reports grants from Varian Inc during the conduct of the study and personal fees from Merck Serono GmbH outside the submitted work. N.H.N. reports speaker honoraria from Merck Healthcare Germany, Sun Pharmaceuticals, and Novocure, as well as a research grant from Novocure. All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Spine metastases are a major burden of oncologic care, contributing to substantial morbidity. A well-established treatment paradigm for patients with metastatic epidural spinal cord compression includes separation surgery followed by stereotactic body radiotherapy (SBRT). Innovations in implant technology have brought about the incorporation of Carbon fiber-reinforced polyetheretherketone (CFR-PEEK) instrumentation for spinal fixation. We present our experience of CFR-PEEK instrumentation, comparing outcomes and complication profiles with a matched cohort of titanium instrumented cases for spine metastatic disease., Methods: Oncology patients who underwent spinal fusion for metastatic spine disease from 2012 to 2023 were retrospectively reviewed. Ninety-nine cases with CFR-PEEK fusions were case-control matched with 50 titanium controls (2:1 ratio) based upon primary tumor type and spinal instability neoplastic score (SINS) location. Demographic, clinical, radiographic and progression free survival (PFS) were analyzed., Results: In the study years, 263 patients underwent spinal decompression and fusion, for which 148 patients met predetermined inclusion criteria. Of these, 49 had titanium instrumentation, and 99 had CFR-PEEK. Complication profiles, including hardware failure and infection were similar between the groups. There was no significant difference in PFS between all CFR-PEEK and titanium patients (143 days versus 214 days; p = 0.41). When comparing patients in which recurrence was noted, CFR-PEEK patients had recurrence detected two times earlier than titanium patients (94 days versus 189 days; p = 0.013)., Conclusion: In this case matched cohort, CFR-PEEK demonstrated decreased overall PFS suggestive of earlier local recurrence identification. Long-term studies are warranted for better evaluation of the impact on survival and systemic disease progression., Competing Interests: Declarations. Ethical approval: This was a retrospective study approved by the universities Institutional Review Board. No ethical approval is required. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Importance: National Comprehensive Cancer Network guidelines recommend weekly cisplatin as an alternative concurrent systemic therapy for definitive chemoradiation in patients with head and neck cancer. However, the impact of different levels of adherence to weekly cisplatin on outcomes stratified by human papillomavirus p16 status remains unclear., Objective: To evaluate the association between the number of weekly cisplatin cycles and outcomes., Design, Setting, and Participants: This retrospective, observational, single-institution cohort study at The Ohio State Comprehensive Cancer Center included patients with a diagnosis of nonmetastatic head and neck cancer between December 1, 2011, and March 30, 2020, who received chemoradiation. Data analysis was performed between March and May 2024., Exposure: A total of 5, 6, or 7 to 8 weekly cisplatin cycles., Main Outcomes and Measures: The primary outcomes were overall survival (OS), progression-free survival (PFS), locoregional failure (LRF), and distant failure (DF). Cox multivariable analysis was performed for variables associated with OS and PFS, and Fine-Gray multivariable analysis was performed for variables associated with LRF and DF., Results: A total of 142 patients met the criteria (119 men [83.8%]; median [IQR] age, 59 [54-63] years). Median (IQR) follow-up was 46.8 (40.8-55.6) months. Among 92 patients with reasons for cisplatin interruption reported, the most common reason was low blood counts (42 patients [45.7%]). Those who missed weekly cisplatin cycles had worse OS (adjusted hazard ratio [aHR], 2.22; 95% CI, 1.19-4.17; P = .01) and PFS (aHR, 1.83; 95% CI, 1.06-3.15; P = .03) than those who received 7 to 8 cycles. Cancer control outcomes were comparable between these groups (LRF aHR, 0.53; 95% CI, 0.15-1.93; P = .34; DF aHR, 1.51; 95% CI, 0.60-3.82; P = .38). Patients with p16-negative tumors who missed weekly cisplatin cycles had worse OS (for every missing cisplatin cycle, aHR, 11.34, 1.51-84.94; P = .02) than those treated with 7 to 8 cycles. However, for those with p16-positive tumors, there were no statistically significant differences in OS between those who missed weekly cisplatin cycles vs others who received 7 to 8 cycles (aHR, 1.21; 95% CI, 0.47-3.14; P = .69)., Conclusions and Relevance: In this cohort study of patients with head and neck cancer who received definitive chemoradiation, those with p16-negative tumors who missed weekly cisplatin cycles had lower OS than those who received 7 to 8 cycles, although OS was comparable between these groups for p16-positive tumors. Cytopenia represented the most common reason for cisplatin interruption.

Purpose: Carbon fiber-reinforced polyetheretherketone (CFR-PEEK) instrumentation is being used more frequently in the spinal oncology landscape. Better visualization with this material allows for more precise postoperative stereotactic body radiation therapy (SBRT) planning using either computed tomography (CT)-myelography or magnetic resonance imaging (MRI) studies. We compared the dosimetric planning equivalencies and outcomes., Methods and Materials: Thirty-six consecutively treated patients were reviewed who underwent spinal fusion using CFR-PEEK instrumentation for spine metastases followed by postoperative SBRT between January 1, 2022, and April 3, 2023. Patients were divided into 2 cohorts based on the imaging modality, MRI versus CT-myelogram, used for postoperative SBRT planning. Surgical, demographic, postoperative radiation dosimetry, complication, and survival data were collected. Statistical analysis was performed in SPSS (v29.0.1.0)., Results: Eleven patients underwent CT-myelograms, and 25 patients underwent MR-spine imaging for SBRT planning. The median follow-up was 145.5 days (13-530). There were no significant differences between baseline demographic, surgical characteristics, or SBRT dosimetry between the MRI spine and CT-myelogram groups. There was no significant difference between the cohorts for survival (P = .402)., Conclusions: MR scans are an effective choice for postoperative SBRT contouring patients using CFR-PEEK instrumentation for oncologic spinal fusions. Avoidance of CT-myelography reduces the need for an invasive procedure and potential risks including cerebrospinal fluid (CSF) leak, nerve root injury, and increased procedural burden., Competing Interests: Disclosures None., (Copyright © 2024 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

HPV viral E6 and E7 onco-proteins play a well-known role in carcinogenesis. Host genomic alterations also play a key role in the development of HPV-related oropharyngeal cancer and have been under-recognized. We describe a case series of 6 metastatic/locoregionally recurrent HPVOPSCC patients with FGFR alterations. HPVOPSCC presents with distinct pattern of spread both temporally and sites of recurrence compared to  non-HPV-related oropharyngeal cancer. Identification and reporting of genomic alterations in HPV are crucial to the understanding of disease biology and could aid in development of novel therapeutics for these patients. In addition, use of circulating tumor DNA may lead to early detection and supplement imaging in the follow up of these patients. Loco-regional treatments may also play a key role in the management of metastatic HPV OPSCC depending on the pattern of presentation. Our case series highlights all these novelties that could lead to better treatment outcomes., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: Merkel cell carcinoma is a rare skin cancer associated with poor survival. Based on a previous Phase II trial of adults with advanced Merkel cell carcinoma by Kim and colleagues (2022), there is now a strong rationale for combination therapy (i.e., nivolumab and ipilimumab) to become a treatment option for patients with advanced Merkel cell carcinoma. The goal of this paper was to report on the secondary outcome of quality of life (QOL) among patients on this trial., Methods: Patients receiving combined nivolumab and ipilimumab, with or without stereotactic body radiation therapy (SBRT), completed the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 prior to starting treatment and every 2 weeks thereafter. Changes in QOL during treatment and post-treatment were evaluated using piecewise random-effects mixed models. Exploratory analyses compared changes in QOL between study arms. The original trial was registered with ClinicalTrials.gov (NCT03071406)., Results: Study participants (n = 50) reported no changes in overall QOL (ps > 0.05), but emotional functioning improved during treatment (p = 0.01). Cognitive and social functioning worsened post-treatment (ps < 0.01). In general, patients treated with combination therapy only (n = 25) reported no change in QOL over time, whereas patients also treated with SBRT (n = 25) consistently demonstrated worsening QOL post-treatment., Conclusion: QOL is generally preserved in patients treated with combination therapy, but the addition of SBRT may worsen QOL. Combined with clinical efficacy data published previously, results support the use of combination therapy with nivolumab and ipilimumab as a treatment option for patients with advanced Merkel cell carcinoma., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

The Head and Neck Cancer International Group (HNCIG) has undertaken an international modified Delphi process to reach consensus on the essential data variables to be included in a minimum database for HNC research. Endorsed by 19 research organisations representing 34 countries, these recommendations provide the framework to facilitate and harmonise data collection and sharing for HNC research. These variables have also been incorporated into a ready to use downloadable HNCIG minimum database, available from the HNCIG website., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: HM is the director and a shareholder of Warwickshire Head and Neck Clinic; chair of the Head and Neck Cancer International Group (HNCIG); and past president of the British Association of Head and Neck Oncologists. HM also reports receiving honoraria from AstraZeneca; Speakers Bureau on MSD, Sanofi Pasteur, Merck; research Funding from GSK Biologicals, MSD, Sanofi Pasteur, GSK Plc, AstraZeneca; travel Accommodation Expenses from Sanofi, Pasteur, MSD, Merck. AP has the following disclosures: Advisory board member with honoraria: Merck Serono, Roche, MSD, Astrazeneca, BMS, Bayer, Pfizer& Medical Education with honoraria: Medscape, Prime Oncology, Funding for research support: KURA, BMS, Merck Serono, Roche, BI, Genesis. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To explore the potential role of focused radiotherapy in managing the lymphocytic hypophysitis (LH) refractory to medical therapy and surgery., Method: A systematic literature review was conducted following PRISMA guidelines to identify the studies on radiation treatment for hypophysitis, along with the experience in our institution., Results: The study included eight patients, three from our institution and five from existing literature. The age at presentation ranged from 37 to 75 years old, with a median age of 58. The presenting symptoms involved headache in seven patients and diplopia in two patients. Pre-radiation visual field defects were noticed in four patients. All patients exhibited variable degrees of hypopituitarism before radiation, with oral corticosteroids being the initial medical treatment. Immunosuppressive therapy was attempted in two patients prior to radiation. Seven patients had a history of transsphenoidal surgery with a histologically confirmed LH. Three patients underwent stereotactic radiosurgery (SRS), while the remaining received FSRT, with a mean irradiation volume of 2.2 cm 3 . A single-session total dose of 12 -15 Gy was administered in the SRS group. In the FSRT group, doses ranged from 24 to 30 Gy with a median dose of 25 Gy, delivered in 2 Gy fractions. Four patients achieved a resolution of visual field defects, while another two patients demonstrated improvement in their associated focal neurologic deficits. No change in pre-existing endocrine status was shown after radiation, except in one patient. Clinical response was achieved in seven patients after a single course of radiation, while one patient required the second course. Six patients remained stable on low-dose glucocorticoid during at least a 12-month follow-up period, and one discontinued it entirely without experiencing relapse. Three patients demonstrated a complete radiologic response, while the remaining showed a partial radiologic response., Conclusions: Focused radiation, including FSRT, can play a role in symptomatic relief, effective mass shrinkage, and minimizing radiation exposure to critical surrounding structures in patients with refractory LH. However, further research efforts are necessary to better clarify its effects and optimal dose planning., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

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., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: To determine the magnitude of MRI image distortion based on 6 consecutive years of annual quality assurances/measurements on 14 MRI scanners used for radiation therapy and to provide evidence for the inclusion of additional margin for treatment planning., Methods and Materials: We used commercial MRI image phantoms to quantitatively study the MRI image distortion over period of 6 years for up to 14 1.5 and 3 T MRI scanners that could potentially be used to provide MRI images for treatment planning. With the phantom images collected from 2016 to 2022, we investigated the MRI image distortion, the dependence of distortion on the distance from the imaging isocenter, and the possible causes of large distortion discovered., Results: MRI image distortion increases with the distance from the imaging isocenter. For a region of interest (ROI) with a radius of 100 mm centered at the isocenter, the mean magnitude of distortion for all MRI scanners is 0.44 ± 0.18 mm $0.44 \pm 0.18\;{\rm{mm}}$ , and the maximum distortion varies from 0.52 to 1.31 mm $0.52\;{\rm{to}}\;1.31\;{\rm{mm}}$ depending on MRI scanners. For an ROI with a radius of 200 mm centered at the isocenter, the mean magnitude of distortion increases to 0.84 ± 0.45 mm $0.84 \pm 0.45\;{\rm{mm}}$ , and the range of the maximum distortion increases to 1.92 - 5.03 mm $1.92 - 5.03\;{\rm{mm}}$ depending on MRI scanners. The distortion could reach 2 mm at 150 mm from the isocenter., Conclusion: An additional margin to accommodate image distortion should be considered for treatment planning. Imaging with proper patient alignment to the isocenter is vital to reducing image distortion. We recommend performing image distortion checks annually and after major upgrade on MRI scanners., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Background: Merkel cell carcinoma is among the most aggressive and lethal of primary skin cancers, with a high rate of distant metastasis. Anti-programmed death receptor 1 (anti-PD-1) and programmed death ligand 1 (PD-L1) monotherapy is currently standard of care for unresectable, recurrent, or metastatic Merkel cell carcinoma. We assessed treatment with combined nivolumab plus ipilimumab, with or without stereotactic body radiotherapy (SBRT) in patients with advanced Merkel cell carcinoma as a first-line therapy or following previous treatment with anti-PD-1 and PD-L1 monotherapy., Methods: In this randomised, open label, phase 2 trial, we randomly assigned adults from two cancer sites in the USA (one in Florida and one in Ohio) to group A (combined nivolumab and ipilimumab) or group B (combined nivolumab and ipilimumab plus SBRT) in a 1:1 ratio. Eligible patients were aged at least 18 years with histologically proven advanced stage (unresectable, recurrent, or stage IV) Merkel cell carcinoma, a minimum of two tumour lesions measureable by CT, MRI or clinical exam, and tumour tissue available for exploratory biomarker analysis. Patients were stratified by previous immune-checkpoint inhibitor (ICI) status to receive nivolumab 240 mg intravenously every 2 weeks plus ipilimumab 1 mg/kg intravenously every 6 weeks (group A) or the same schedule of combined nivolumab and ipilimumab with the addition of SBRT to at least one tumour site (24 Gy in three fractions at week 2; group B). Patients had to have at least two measurable sites of disease so one non-irradiated site could be followed for response. The primary endpoint was objective response rate (ORR) in all randomly assigned patients who received at least one dose of combined nivolumab and ipilimumab. ORR was defined as the proportion of patients with a complete response or partial response per immune-related Response Evaluation Criteria in Solid Tumours. Response was assessed every 12 weeks. Safety was assessed in all patients. This trial is registered with ClinicalTrials.gov, NCT03071406., Findings: 50 patients (25 in both group A and group B) were enrolled between March 14, 2017, and Dec 21, 2021, including 24 ICI-naive patients (13 [52%] of 25 group A patients and 11 [44%] of 25 group B patients]) and 26 patients with previous ICI (12 [48%] of 25 group A patients and 14 [56%] of 25 group B patients]). One patient in group B did not receive SBRT due to concerns about excess toxicity. Median follow-up was 14·6 months (IQR 9·1-26·5). Two patients in group B were excluded from the analysis of the primary endpoint because the target lesions were irradiated and so the patients were deemed non-evaluable. Of the ICI-naive patients, 22 (100%) of 22 (95% CI 82-100) had an objective response, including nine (41% [95% CI 21-63]) with complete response. Of the patients who had previously had ICI exposure, eight (31%) of 26 patients (95% CI 15-52) had an objective response and four (15% [5-36]) had a complete response. No significant differences in ORR were observed between groups A (18 [72%] of 25 patients) and B (12 [52%] of 23 patients; p=0·26). Grade 3 or 4 treatment-related adverse events were observed in 10 (40%) of 25 patients in group A and 8 (32%) of 25 patients in group B., Interpretation: First-line combined nivolumab and ipilimumab in patients with advanced Merkel cell carcinoma showed a high ORR with durable responses and an expected safety profile. Combined nivolumab and ipilimumab also showed clinical benefit in patients with previous anti-PD-1 and PD-L1 treatment. Addition of SBRT did not improve efficacy of combined nivolumab and ipilimumab. The combination of nivolumab and ipilimumab represents a new first-line and salvage therapeutic option for advanced Merkel cell carcinoma., Funding: Bristol Myers Squibb Rare Population Malignancy Program., Competing Interests: Declaration of interests SK reports research support from Bristol Myers Squibb for the submitted work and research support from Bristol Myers Squibb and AstraZeneca outside the submitted work. EW reports being a member of the advisory board for Viewray, Varian, Alphatau, Castle Biosciences, and Teiko outside the submitted work. ZE reports being a member of the advisory board for Array, Pfizer, OncoSec, Regeneron, Genentech, Novartis, Natera, and Eisai outside the submitted work and research support for Novartis, Pfizer, and Boehringer-Ingelheim outside the submitted work. JJC reports research support for Varian and Galera outside the submitted work. AT reports research support for Bristol Myers Squibb, Genentech-Roche, Regeneron, Sanofi-Genzyme, Nektar, Clinigen, Merck, Acrotech, Pfizer, Checkmate, and OncoSec outside the submitted work and personal fees from Bristol Myers Squibb, Merck, Eisai, Instil Bio, Clinigen, Regeneron, Sanofi-Genzyme, Novartis, Partner Therapeutics, Genentech/Roche, and BioNTech outside the submitted work. JM reports research support from Microba, Jackson Laboratories, Merck, and Morphogenesis outside the submitted work. BAP reports being a member of the advisory board for Bristol Myers Squibb, AstraZeneca, and G1 therapeutics outside the submitted work. VKS reports research support from Neogene and Turnstone outside the submitted work and being a member of the advisory board for Bristol Myers Squibb, Eisai, Iovance, Merck, Novartis, Regeneron, and Statking outside the submitted work. NIK reports being a member of the advisory board for Bristol Myers-Squibb, Regeneron, Merck, Jounce Therapeutics, Iovance Biotherapeutics, Genzyme, Novartis, Castle Biosciences, Nektar, and Instill Bio outside the submitted work; being a member of the steering or scientific committee for Nektar, Regeneron, Replimune, Bristol Myers-Squibb, and National Comprehensive Cancer Network via Pfizer outside the submitted work; being on the data safety monitoring committee for AstraZeneca and Incyte outside the submitted work; research support to his institution outside the submitted work from Bristol Myers-Squibb, Merck, Celgene, Regeneron, Replimune, Novartis, HUYA Bioscience, and GlaxoSmithKline); and common stock from Bellicum, Amarin, Asensus Surgical outside the submitted work. ASB reports being a member of the advisory board for Deciphera and Bayer outside the submitted work. All other authors have no interests to declare., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Radiation treatment planning for meningiomas traditionally involves magnetic resonance imaging (MRI) contrast enhanced images to define residual tumor. However, the gross tumor volume may be difficult to delineate for patients with a meningioma in the skull base sagittal sinus or after resection. Advanced positron emission tomography (PET) imaging using 68 Ga-DOTATATE, which has been shown to be more sensitive and specific than MRI imaging, can be used for target volume delineation in these circumstances. We hypothesized that 68 Ga-DOTATATE PET scan-based treatment planning would lead to smaller radiation volumes and would detect additional areas of disease compared with standard MRI alone., Methods and Materials: Our data evaluated retrospective, deidentified, and blinded gross tumor volume contour delineation with 7 central nervous system (CNS) specialists (4 CNS radiation oncologists and 3 neuroradiologists) for 25 patients with a meningioma diagnosis who received both a 68 Ga-DOTATATE PET and an MRI for radiation treatment planning. Both the MRI and the PET were nonsequentially contoured by each physician for each patient., Results: The median MRI volume for each physician ranged from 16.94-25.53 cm 3 . The median PET volume for each physician ranged from 2.09 to 8.36 cm 3 . The median PET volume was smaller for each physician. In addition, 7 of the 25 patients (28%) had new nonadjacent areas contoured on PET by at least 6 of the 7 physicians that were not contoured by these physicians on the corresponding MRI. These new areas would not have been in the traditional MRI-based volumes., Conclusions: Our study supports that 68 Ga-DOTATATE PET imaging may help radiation oncologists create more precise radiation treatment volumes through finding undetected areas of disease not seen on MRI. Treatment planning guided by 68 Ga-DOTATATE PET should be studied prospectively., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Trametinib is a MEK inhibitor with intracranial activity indicated for BRAF-mutant metastatic malignancies. Yet, the safety of trametinib concurrent with whole brain radiation therapy (WBRT) is unknown. We performed a single-institution, prospective, 3 + 3, phase I clinical trial to determine the maximum tolerated dose (MTD) of trametinib with WBRT., Methods and Materials: Patients with brain metastases (BM) received daily trametinib for 28 days, starting 7 days prior to and continuing through WBRT (37.5 Gy/15 fractions). Dose levels (DL)1-3 were 1.0, 1.5, and 2.0 mg. The MTD of trametinib plus WBRT, the max dose where ≤1 of 6 patients experienced a dose limiting toxicity (DLT), was the primary endpoint., Results: 10 patients were enrolled (median age-59 [47-64], BM-5 [1-10], 50% melanoma). Three and 7 patients were assigned to DL1 and 2. One DL2 patient withdrew. 89% of remaining patients completed therapy per protocol, but 1 DL2 patient with systemic progression discontinued therapy at 30 Gy. Thirteen grade (G)3-4 toxicities were observed, of which 12 occurred at DL2 (4/6 of patients). DLT was reached at DL2 (G4 thrombocytopenia and G3 diarrhea, 1 each). There were no G5 toxicities. Median overall survival was 2.2 months. During the study period, changing practice patterns favored utilization of stereotactic radiosurgery (SRS). Thus, the trial closed early prior to completion., Conclusions: In a patient population representative of modern candidates for WBRT, trametinib plus WBRT is highly toxic with a MTD <1.5 mg. The safety of trametinib with SRS remains an important question for future study., Competing Interests: Conflict of interest None, (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Radiation-induced hypothyroidism is a common toxicity of head and neck radiation. Our re-planning study aimed to reduce thyroid dose while maintaining target coverage with IMRT., Methods: We retrospectively identified patients with oral-cavity (n = 5) and oropharyngeal cancer (n = 5). Treatment plans were re-optimized with 45 Gy thyroid mean dose constraint, then we cropped the thyroid out of PTVs and further reduced thyroid dose. Target coverage was delivering 100% dose to ≥ 93% of PTV and 95% of dose to > 99% of PTV., Results: Originally, average mean dose to thyroid was 5580 cGy. In model I, this dropped to 4325 cGy (p < 0.0001). In model II, average mean dose was reduced to 3154 cGy (p < 0.0001). For PTV low and PTV int, all had acceptable target coverage., Conclusion: In patients with oral-cavity and oropharyngeal cancers, mean dose could be significantly reduced using a thyroid-optimized or thyroid-sparing IMRT technique with adequate coverage., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Background: The COVID-19 pandemic has required triage and delays in surgical care throughout the world. The impact of these surgical delays on survival for patients with head and neck squamous cell carcinoma (HNSCC) remains unknown., Methods: A retrospective cohort study of 37 730 patients in the National Cancer Database with HNSCC who underwent primary surgical management from 2004 to 2016 was performed. Uni- and multivariate analyses were used to identify predictors of overall survival. Bootstrapping methods were used to identify optimal time-to-surgery (TTS) thresholds at which overall survival differences were greatest. Cox proportional hazard models with or without restricted cubic splines were used to determine the association between TTS and survival., Results: The study identified TTS as an independent predictor of overall survival (OS). Bootstrapping the data to dichotomize the cohort identified the largest rise in hazard ratio (HR) at day 67, which was used as the optimal TTS cut-point in survival analysis. The patients who underwent surgical treatment longer than 67 days after diagnosis had a significantly increased risk of death (HR, 1.189; 95% confidence interval [CI], 1.122-1.261; P < 0.0001). For every 30-day delay in TTS, the hazard of death increased by 4.6%. Subsite analysis showed that the oropharynx subsite was most affected by surgical delays, followed by the oral cavity., Conclusions: Increasing TTS is an independent predictor of survival for patients with HNSCC and should be performed within 67 days after diagnosis to achieve optimal survival outcomes.

Objectives: This study aimed to assess the effect of definitive or adjuvant concurrent chemoradiation (CRT) among elderly patients with locally advanced head and neck squamous cell carcinoma (LA HNSCC)., Materials and Methods: We retrospectively analyzed 150 elderly LA HNSCC patients (age ≥70) at a single institution. Demographics, disease control outcomes, and toxicities with different chemotherapy regimens were reviewed. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) estimates., Results: Median age at diagnosis was 74 years (range 70-88). Of the cohort, 98 (65.3%) patients received definitive and 52 (34.7%) received adjuvant CRT; 44 (29.3%) patients received weekly carboplatin and paclitaxel, 43 (28.7%) weekly cetuximab, 33 (22%) weekly carboplatin, and 30 (20%) weekly cisplatin. The OS at 2 years was 70% (95% confidence interval [CI]: 63-79%), and PFS at 2 years was 61% (95% CI: 53-70%). There was no significant difference in OS or PFS between definitive and adjuvant CRT (p = 0.867 and p = 0.475, respectively). Type of chemotherapy regimen (single-agent carboplatin vs. others) (95% CI: 1.1-3.9; p = 0.009) was a key prognostic factor in predicting OS in multivariable analysis. Concurrent use of cetuximab was associated with increased risk of PEG tube dependence at 6 months (p < 0.001)., Conclusions: Management of LA HNSCC in the elderly is a challenging scenario. Our study shows that CRT is a feasible treatment modality for elderly patients with LA HNSCC. We recommend CRT with weekly cisplatin or weekly carboplatin and paclitaxel. A chemotherapy regimen should be carefully selected in this difficult to treat population., (© 2021 S. Karger AG, Basel.)

Background: Recent reports have investigated the nascent role of induction chemotherapy for sinonasal undifferentiated carcinoma (SNUC). The goal of this study was to ascertain trends in treatment pattern changes for SNUC at a single institution and design a treatment algorithm utilized at our institution., Methods: Retrospective chart analysis of 21 cases of SNUC from 2010 to 2018., Results: Of 21 patients in this cohort, 18 (85.7%) presented with T4 disease, 7 (33.3%) presented with nodal disease, and 3 (14.3%) presented with distant metastasis. Since 2016, patients have been managed by induction chemotherapy followed by concurrent chemoradiation. To this point, patients treated with TPF induction chemotherapy followed by concurrent chemoradiation show no evidence of disease; however, the average follow up time is 16.8 months., Conclusions: The multimodality treatment for SNUC continues to evolve, as highlighted by this study, toward increased use of induction chemotherapy followed by chemoradiotherapy., (© 2020 Wiley Periodicals LLC.)

Trans-oral robotic surgery (TORS) has emerged as an important surgical treatment option in the management of human papillomavirus (HPV)-positive and -negative oropharynx cancer. However, treatment selection is paramount to ensure that patients will not require multimodality adjuvant therapy. In this study, we determined predictors of adjuvant therapy in TORS-treated patients. The National Cancer Database (NCDB) was used to identify patients with newly diagnosed clinical T1-T4, N0-N3 oropharyngeal squamous cell carcinoma who underwent TORS between 2010-2016. Kaplan-Meier survival analysis was used to estimate overall survival (OS). A total of 2999 patients were studied, and the five-year OS for the entire cohort was 82.5%, and for HPV-positive and -negative cohorts it was 88.3% and 67.9%, respectively ( p < 0.001). Among all patients treated with TORS, 35.1% of patients received no additional treatment, 33.5% received adjuvant radiation alone (RT), and 31.3% received adjuvant chemoradiation. The N stage was pathologically upstaged in 629 (20.9%) patients after TORS. Patients treated at higher-volume centers were more likely to have negative surgical margins (OR: 0.96, 95% CI: 0.94, 0.98, p < 0.001), but this did not influence the receipt of adjuvant therapy. The high rate of adjuvant multimodality treatment after TORS suggests a need for improved patient selection. Limitations of this study, including lack of data on loco-regional control, progression free survival, acute and late toxicities, and utilization of pretreatment PET/CT imaging, should be addressed in future studies.

Background: Positron emission tomography/computed tomography (PET/CT) in staging of advanced oropharyngeal squamous cell carcinoma (OPSCC) and at 3 months posttreatment (PETpost) is often utilized to assess response. The significance of lymph node vs primary site treatment response is incompletely understood., Methods: We reviewed 230 patients treated with radiation therapy. PETpost response was graded at primary and nodal sites and correlated with survival., Results: Median age was 58, and 83% were p16-positive. Median follow-up was 24.3 months. Nodal response at PETpost predicted improved 2-year local recurrence-free survival (LRFS) (93% vs 72%, P =.004), 2-year disease-free survival (DFS) (80% vs 61.3%, P =.021), and 2-year overall survival (OS) (89% vs 83%, P =.051), while primary response only predicted improved 2-year LRFS (91% vs 76% P = .035)., Conclusion: In OPSCC patients, both nodal and primary response at 3 months on PET/CT predicted for improved LRFS, but only nodal response predicted DFS and OS., (© 2020 Wiley Periodicals, Inc.)

Objective Metastatic melanoma patients often receive palliative radiotherapy (RT) and immunotherapy (IT). However, the immunological interplay between RT dose-fractionation and IT is uncertain, and the optimal treatment strategy using RT and IT in metastatic melanoma remains unclear. Our main objective was to examine the effect of RT dose-fractionation on overall survival (OS). Methods Using the National Cancer Database (NCDB), we classified metastatic melanoma patients who received palliative RT into two dose-fractionation groups - conventionally fractionated RT (CFRT; <5 Gy/fraction) and hypofractionated RT (HFRT: ≥5 Gy/fraction) - with or without IT. Survival analysis was performed using the Cox regression model, Kaplan-Meier method, and propensity-score matching (PSM). Results A total of 5,281 metastatic melanoma patients were included, with a median follow-up of 5.9 months. The three-year OS was highest in patients who received HFRT+IT [37.3% (95% CI: 31.1-43.5)] compared to those who received HFRT alone [19.0% (95% CI: 16.2-21.9)], CFRT+IT [17.6 (95%CI: 13.9-21.6)], or CFRT alone [8.6% (95%CI: 7.6-9.7); p<0.0001]. The magnitude of OS benefit with the use of IT was greater in those who received HFRT (18.3%) compared with those who received CFRT (9.0%) (p<0.0001). The addition of IT to HFRT, compared to CFRT, was associated with greater OS benefit in patients treated with RT to the brain and soft tissue/visceral (STV) sites. On PSM analysis, HFRT+IT was associated with improved three-year OS compared to other treatments. Conclusion Metastatic melanoma patients who received HFRT+IT was associated with the greatest OS benefit. Our findings warrant further prospective evaluation as to whether higher RT dose-per-fraction improves clinical outcomes in metastatic melanoma patients receiving IT., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Wang et al.)

Purpose  Olfactory neuroblastoma (ONB) is a rare head and neck cancer believed to be originated from neural crest cells of the olfactory membrane located in the roof of the nasal fossa. This study evaluates clinical outcomes and failure patterns in ONB patients of those patients treated with surgical resection at a high-volume tertiary cancer center. Methods and Materials  Thirty-nine ONB patients who underwent surgical resection at our institution from 1996 to 2017 were retrospectively identified. Univariate, multivariate, and survival analysis were calculated using Cox regression analysis and Kaplan-Meier log-rank. Results  Median follow-up time was 59 months (range: 5.2-236 months). The median overall survival (OS) and disease-free survival (DFS) for the entire cohort were 15 and 7.6 years, respectively. The 5-year cumulative OS and DFS were 83 and 72%, respectively. The 5-year OS for low Hyams grade (LHG) versus high Hyams grade (HHG) was 95 versus 61% ( p  = 0.041). LHG was found in 66% of the early Kadish stage patients compared with 28% in the advanced Kadish stage patients ( p  = 0.057). On multivariate analysis, HHG and positive node status predicted for worse OS and only HHG predicted for worse DFS. Of note, five patients (all Kadish stage A) who received surgical resection alone had no observed deaths or recurrences with a median follow-up of 44 months (range: 5-235 months). Conclusion  In this retrospective cohort, patients with positive nodes or HHG have significantly worse clinical outcomes. Future studies should explore treatment intensification for HHG or positive nodes., Competing Interests: Conflict of Interest None declared., (© Thieme Medical Publishers.)

The purpose of this study was to investigate the dosimetric impact of weight loss in head and neck (H&N) patients and examine the effectiveness of adaptive planning. Data was collected from 22 H&N cancer patients who experienced weight loss during their course of radiotherapy. The robustness of Intensity Modulated Radiation Therapy (IMRT) and Volumetric Modulated Arc Therapy (VMAT) treatment plans were compared including the potential need for replanning. The dosimetric impact of weight loss was evaluated by calculating a verification plan for each patient on an assessment CT scan taken during the course of treatment. Using a regression analysis, significance was tested for the dosimetric change in target volumes and 10 specific organs at risk (OAR) using an anatomical separation difference in the H&N at corresponding levels. For both the IMRT and VMAT plans, a significant correlation was found for the dose to 5% of the high risk Planning Target Volume (PTV) (D 5 ), dose to 95% of the intermediate risk PTV and Clinical Target Volume (CTV) (D 95 ), and the percentage of the pharynx receiving 65 Gy. An independent t-test was also performed for each metric in the VMAT and IMRT plans showing the dose to 95% of the intermediate risk PTV as significant. No quantitative method for finding the threshold of anatomical separation difference requiring a replan was established. Based on the increase in dose to organs at risk and increased target coverage due to separation loss, it was concluded that adaptive radiotherapy may not always be necessary when alignment of bony anatomy and remaining soft tissue is within tolerance. Physician judgment and preference is needed in such situations., (Published by Elsevier Inc.)

Purpose: Oral mucositis (OM) remains a common, debilitating toxicity of radiation therapy (RT) for head and neck cancer. The goal of this phase IIb, multi-institutional, randomized, double-blind trial was to compare the efficacy and safety of GC4419, a superoxide dismutase mimetic, with placebo to reduce the duration, incidence, and severity of severe OM (SOM)., Patients and Methods: A total of 223 patients (from 44 institutions) with locally advanced oral cavity or oropharynx cancer planned to be treated with definitive or postoperative intensity-modulated RT (IMRT; 60 to 72 Gy [≥ 50 Gy to two or more oral sites]) plus cisplatin (weekly or every 3 weeks) were randomly assigned to receive 30 mg (n = 73) or 90 mg (n = 76) of GC4419 or to receive placebo (n = 74) by 60-minute intravenous administration before each IMRT fraction. WHO grade of OM was assessed biweekly during IMRT and then weekly for up to 8 weeks after IMRT. The primary endpoint was duration of SOM tested for each active dose level versus placebo (intent-to-treat population, two-sided α of .05). The National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, was used for adverse event grading., Results: Baseline patient and tumor characteristics as well as treatment delivery were balanced. With 90 mg GC4419 versus placebo, SOM duration was significantly reduced ( P = .024; median, 1.5 v 19 days). SOM incidence (43% v 65%; P = .009) and severity (grade 4 incidence, 16% v 30%; P = .045) also were improved. Intermediate improvements were seen with the 30-mg dose. Safety was comparable across arms, with no significant GC4419-specific toxicity nor increase of known toxicities of IMRT plus cisplatin. The 2-year follow-up for tumor outcomes is ongoing., Conclusion: GC4419 at a dose of 90 mg produced a significant, clinically meaningful reduction of SOM duration, incidence, and severity with acceptable safety. A phase III trial (ROMAN; ClinicalTrials.gov identifier: NCT03689712) has begun.

Background: To report our institutional experience with intraoperative radiotherapy for persistent or recurrent head and neck cancer., Methods: Sixty-one patients were treated with salvage surgery and intraoperative radiation therapy (IORT). Fifty-eight patients (95%) had previously received external beam radiotherapy (EBRT) as a component of their definitive therapy. Forty-four patients (72%) had squamous cell carcinoma (SCC). Surgical margins were positive in 28 patients (46%). IORT was prescribed to a median dose of 12.5 Gy (range, 10-17.5). Twenty-three patients (38%) received a course of postoperative EBRT (median 45 Gy). Clinical outcomes were retrospectively reviewed and univariate analysis was performed using log-rank tests to correlate clinical outcomes with histology, surgical margin, and adjuvant therapy., Results: Median follow-up among surviving patients was 15.9 months. Median progression-free survival (PFS) and overall survival (OS) were 9.8 and 19.1 months, respectively. One- and 2-year rates of locoregional control (LRC) were 59% and 35%, respectively. One- and 2-year rates of PFS were 39% and 19%, respectively. One- and 2-year rates of OS were 62% and 42%, respectively. Overall survival was better for non-SCC histology (P = .03). For SCC patients, negative surgical margin showed a trend toward improved PFS (P = .09) and OS (P = .06). There was one grade-5 toxicity due to carotid rupture., Conclusions: IORT has shown effective LRC and OS with an acceptably low rate of severe toxicity at our institution. OS was significantly better for non-SCC histology. For SCC patients, there is a trend toward improved PFS and OS associated with negative surgical margins., (© 2019 Wiley Periodicals, Inc.)

Targeting inhibitor of apoptosis proteins (IAP) with second mitochondria-derived activator of caspase (SMAC) mimetics may promote cancer cell death. We tested whether cIAP1 predicts poor prognosis in head and neck squamous cell carcinoma (HNSCC) and whether a novel Smac-mimetic, LCL161, could radiosensitize human papillomavirus-positive (HPV + ) and -negative (HPV - ) HNSCC. The association of BIRC2 (encoding cIAP1) mRNA level with HPV status in HNSCC was analyzed using The Cancer Genome Atlas (TCGA) database. cIAP1 was assessed by IHC on an HNSCC tissue microarray (TMA, n = 84) followed by correlation analysis with HPV status and patient outcomes. Human cell culture and animal models of HNSCC were used to analyze the outcome and molecular characteristics following radiotherapy in combination with LCL161. cIAP1 expression is increased in HPV - compared with HPV + HNSCC tumors in the TCGA database. In our TMA, cIAP1 was overexpressed in HNSCC compared with normal tissues ( P = 0.0003) and associated with a poor overall survival ( P = 0.0402). cIAP1 levels were higher in HPV - than that in HPV + HNSCC tumors ( P = 0.004) and patients with cIAP1 + /HPV - HNSCC had the worst survival. LCL161 effectively radiosensitized HPV - HNSCC cells, which was accompanied with enhanced apoptosis, but not HPV + HNSCC cells. Importantly, LCL161 in combination with radiotherapy led to dramatic tumor regression of HPV - HNSCC tumor xenografts, accompanied by cIAP1 degradation and apoptosis activation. These results reveal that cIAP1 is a prognostic and a potential therapeutic biomarker for HNSCC, and targeting cIAP1 with LCL161 preferentially radiosensitizes HPV - HNSCC, providing justification for clinical testing of LCL161 in combination with radiation for patients with HPV - HNSCC., (©2019 American Association for Cancer Research.)

Background: Metastasis from melanoma carries poor prognosis and survival. Average life expectancy is estimated 4 to 6 months after diagnosis of skeletal metastasis. Comprehensive treatment, along with newer immunotherapies, has shown promising results., Case Description: We report a case of long-term survival after metastasis to the brain and spine and discuss associated factors., Conclusions: Our report emphasizes the importance of regular and critical surveillance of the disease and aggressive surgical and medical management in melanoma., (Published by Elsevier Inc.)

The larynx is an organ of the upper aerodigestive tract that is involved in many critical functions such as breathing, speaking, and swallowing. As a result, both larynx cancer and its treatment may significantly affect quality of life. The management of laryngeal cancer has focused on improving survival while preserving the function of the organ. This manuscript focuses on the use of chemotherapy and radiation therapy as a non-surgical approach and potential organ preservation strategy for patients with advanced larynx cancer. We review the key clinical data on the following treatment courses: (1) induction chemotherapy followed by definitive radiation therapy, (2) concurrent chemotherapy and radiation, and (3) induction chemotherapy followed by concurrent chemo-radiation. We also review the clinical data on organ preservation for patients with hypopharynx cancers. Results from phase III studies suggest that patients with advanced T4 cancers have better outcomes with a primary surgical approach, while for patients with T2N+ and T3 tumors, definitive concurrent chemotherapy and radiation or induction chemotherapy followed by definitive radiation therapy are acceptable options. Choosing the optimal treatment strategy depends on patients' desires, tumor extent, and adequate follow-up to detect early recurrences in cases of larynx preservation treatments. To proceed with an organ preservation strategy, the patient should have a good pre-treatment larynx function, and there must be a high level of skill and cooperation among various disciplines., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: Randomized trials evaluating cisplatin versus cetuximab chemoradiation (CRT) for p16+ oropharyngeal cancer (OPC) have yet to report preliminary data. Meanwhile, as a preemptive step toward morbidity reduction, the off-trial use of cetuximab in p16+ patients is increasing, even in those who could potentially tolerate cisplatin. The purpose of this study was to compare the efficacy of cisplatin versus cetuximab CRT in the treatment of p16+ OPC and to identify prognostic factors and predictors of tumor response., Materials and Methods: Cases of p16+ OPC treated with cisplatin or cetuximab CRT at our institution from 2010 to 2014 were identified. Recursive partitioning analysis (RPA) classification was used to determine low-risk (LR-RPA) and intermediate-risk (IR-RPA) groups. Log-rank/Kaplan-Meier and Cox Regression methods were used to compare groups., Results: We identified 205 patients who received cisplatin (n = 137) or cetuximab (n = 68) CRT in the definitive (n = 178) or postoperative (n = 27) setting. Median follow-up was 3 years. Cisplatin improved 3-year locoregional control (LRC) [92.7 vs 65.4%], distant metastasis-free survival (DMFS) [88.3 vs 71.2%], recurrence-free survival (RFS) [86.6 vs 50.6%], and overall survival (OS) [92.6 vs 72.2%] compared to cetuximab [all p < .001]. Concurrent cisplatin improved 3-year OS for LR-RPA (97.1 vs 80.3%, p < .001) and IR-RPA (97.1 vs 80.3%, p < .001) groupings., Conclusion: When treating p16+ OPC with CRT, the threshold for substitution of cisplatin with cetuximab should be maintained appropriately high in order to prolong survival times and optimize locoregional and distant tumor control. When cetuximab is used in cisplatin-ineligible patients, altered fractionation RT should be considered in an effort to improve LRC., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: to examine the impact of radiotherapy center volume on overall survival in patients with oral cavity and oropharyngeal squamous cell carcinoma getting adjuvant radiation therapy after receiving surgery at a high-volume center., Materials and Methods: a retrospective study was conducted on patients with oral cavity squamous cell carcinoma or oropharyngeal squamous cell carcinoma treated surgically at a tertiary institution from 2000 to 2012 who received adjuvant radiotherapy. The outcome variable was overall survival and the independent variable was location of adjuvant radiation therapy: high-volume center (HVC) versus low-volume center (LVC). Cox proportional hazards models were used to assess associations between predictors of death. Variables that were found to be significant at the α = 0.10 were included in a multivariable model., Results: 336 patients met inclusion criteria. One-hundred thirty-nine patients received adjuvant radiation therapy at HVC and 197 patients received adjuvant radiation therapy at LVC. A univariate Cox proportional hazards model identified the variables location, age, marital status, subsite, T stage, extracapsular extension, and smoking status to include in a multivariable model. Age, subsite, T stage, and extracapsular extension were independent predictors of overall survival (p < .05). Location (p = .55), marital status (p = .29), and smoking status (p = .22) were not statistically significant predictors of survival., Conclusion: After surgery at a HVC, the volume of adjuvant radiation therapy center was not significantly associated with overall survival. Significant predictors of survival included age, subsite, T stage, and extracapsular extension., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background and Purpose: Rectal toxicity presents a significant limiting factor in prostate radiotherapy regimens. This study evaluated the safety and efficacy of an implantable and biodegradable balloon specifically designed to protect rectal tissue during radiotherapy by increasing the prostate-rectum interspace., Patients and Methods: Balloons were transperineally implanted, under transrectal ultrasound guidance, into the prostate-rectum interspace in 27 patients with localized prostate cancer scheduled to undergo radiotherapy. Patients underwent two simulations for radiotherapy planning--the first simulation before implant, and the second simulation seven days post implant. The balloon position, the dimensions of the prostate, and the distance between the prostate and rectum were evaluated by CT/US examinations 1 week after the implant, weekly during the radiotherapy period, and at 3 and 6 months post implant. Dose-volume histograms of pre and post implantation were compared. Adverse events were recorded throughout the study period., Results: Four of 27 patients were excluded from the evaluation. One was excluded due to a technical failure during implant, and three patients were excluded because the balloon prematurely deflated. The balloon status was evaluated for the duration of the radiotherapy period in 23 patients. With the balloon implant, the distance between the prostate and rectum increased 10-fold, from a mean 0.22 ± 0.2 cm to 2.47 ± 0.47 cm. During the radiotherapy period the balloon length changed from 4.25 ± 0.49 cm to 3.81 ± 0.84 cm and the balloon height from 1.86 ± 0.24 cm to 1.67 ± 0.22 cm. But the prostate-rectum interspace distance remained constant from beginning to end of radiotherapy: 2.47 ± 0.47 cm and 2.41 ± 0.43 cm, respectively. A significant mean reduction in calculated rectal radiation exposure was achieved. The implant procedure was well tolerated. The adverse events included mild pain at the perineal skin and in the anus. Three patients experienced acute urinary retention which resolved in a few hours following conservative treatment. No infections or thromboembolic events occurred during the implant procedure or during the radiotherapy period., Conclusion: The transperineal implantation of the biodegradable balloon in patients scheduled to receive radiotherapy was safe and achieved a significant and constant gap between the prostate and rectum. This separation resulted in an important reduction in the rectal radiation dose. A prospective study to evaluate the acute and late rectal toxicity is needed.

The catalytic ability of Ricin Toxin A-Chain (RTA) to create an abasic site in a 14-mer stem-tetraloop RNA is exploited for its detection. RTA catalyzes the hydrolysis of the N-glycosidic bond of a specific adenosine in the GAGA tetraloop of stem-loop RNA. Thus, a 14-mer stem-loop RNA substrate containing an intact "GAGA" sequence can be discriminated from the product containing an abasic "GabGA" sequence by hybridization with a 14-mer DNA stem-loop probe sequence and following the fluorescent response of the heteroduplexes. Three DNA beacon probe designs are described. Beacon 1 probe is a stem-loop structure and has a fluorophore and a quencher covalently linked to the 5'- and 3'-ends. In this format the probe-substrate heteroduplex gives a fluorescent signal while the probe-product one remains quenched. Beacon 2 is a modified version of 1 and incorporates a pyrene deoxynucleoside for recognition of the abasic site. In this format both the substrate and product heteroduplexes give a fluorescent response. Beacon 3 utilizes a design where the fluorophore is on the substrate RNA sequence at its 5'-end while the quencher is on the probe DNA sequence at its 3'-end. In this format the fluorescence of the substrate-probe heteroduplex is quenched while that of the product-probe one is enhanced. The lower limit of detection with beacons is 14 ng/mL of RTA.

Molecular dynamics (MD) simulations and free energy component analysis have been performed to evaluate the molecular origins of the 5.5 kcal/mol destabilization of the complex formed between the N-terminal RNP domain of U1A and stem loop 2 of U1 snRNA upon mutation of a conserved aromatic residue, Phe56, to Ala. MD simulations, including counterions and water, have been carried out on the wild type and Phe56Ala peptide-stem loop 2 RNA complexes, the free wild type and Phe56Ala peptides, and the free stem loop 2 RNA. The MD structure of the Phe56Ala-stem loop 2 complex is similar to that of the wild type complex except the stacking interaction between Phe56 and A6 of stem loop 2 is absent and loop 3 of the peptide is more dynamic. However, the MD simulations predict large changes in the structure and dynamics of helix C and increased dynamic range of loop 3 for the free Phe56Ala peptide compared to the wild type peptide. Since helix C and loop 3 are highly variable regions of RNP domains, this indicates that a significant contribution to the reduced affinity of the Phe56Ala peptide for RNA results from cooperation between highly conserved and highly variable regions of the RNP domain of U1A. Surprisingly, these structural effects, which are manifested as cooperative free energy changes, occur in the free peptide, rather than in the complex, and are revealed only by study of both the initial and final states of the complexation process. Free energy component analysis correctly accounts for the destabilization of the Phe56Ala-stem loop 2 complex, and indicates that approximately 80% of the destabilization is due to the loss of the stacking interaction and approximately 20% is due to differences in U1A adaptation.