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We sought to characterize the incidence of chronic opioid dependence among head and neck cancer survivors treated by radiation, as well as to identify patient and treatment factors associated with persistent use.The medical records of patients with head and neck cancer who received radiation therapy from January 2012 to July 2016 were reviewed. All patients received 60 to 70 Gy with curative intent. Patients who progressed or died within 1 year were intentionally excluded. Opioid doses were calculated in morphine equivalent daily doses in milligrams (mg). Univariate and multivariate regression models were used to identify associations between demographic, medical, disease, and persistent opioid use.Two hundred and sixty-one patients were included. The median follow-up was 39 months (range: 12 to 83 mo). Two hundred and eleven patients (80%) received opioids for pain control during radiation. The median morphine equivalent daily dose during treatment was 73.8 mg (range: 5 to 561 mg). Rates of persistent opioid use at 6 months, 1 year, and 2 years from completion of radiation were 41.8%, 30.1%, and 26.0%, respectively. On multivariate analysis, only preradiation opioid use correlated with persistent opioid use at all 3 time points (P0.05). Smoking history and a Charlson comorbidity index ≥2 predicted for persistent opioid use at some time points, but not all.High rates of persistent opioid use exist in patients with head and neck cancer after radiation therapy. Early interventions to appropriately wean patients should be further investigated.

Introduction: The timely delivery of healthcare is an important quality indicator that has been shown to correlate with outcomes for cancer patients. We present our single-institution experience with the development of a same day access scheduling initiative. Methods and Materials: From March 2021 to August 2022, all patients referred for new consultation to a tertiary care-based radiation oncology department were offered same day appointments as part of a prospective pilot initiative. The timespan of this analysis was categorized into 2 successive periods over 36 months—a 18-month pre-initiative period (September 2019 to February 2021) and another subsequent one (March 2021 to August 2022). Descriptive statistics were used to study the impact of this initiative on access-related benchmarks. Results: A total of 2890 patients were referred. Among the 2107 patients scheduled, three hundred and sixteen (15%) opted for same day appointments. Black, Latino, and Asian patients were significantly more likely to use same day access versus Caucasian patients (p=0.01). The same day access initiative increased the proportion of patients seen within 5 days from referral from 23% to 58% (pConclusions: A significant proportion of patients elected for same day appointments illustrating the high demand for expedient delivery of care. The implementation of this same day access initiative was not only feasible but enhanced operational efficiency and practice performance in the outpatient setting.

Author(s): Margalit, Danielle N; Sacco, Assuntina G; Cooper, Jay S; Ridge, John A; Bakst, Richard L; Beadle, Beth M; Beitler, Jonathan J; Chang, Steven S; Chen, Allen M; Galloway, Tom J; Koyfman, Shlomo A; Mita, Carol; Robbins, Jared R; Tsai, C Jillian; Truong, Minh T; Yom, Sue S; Siddiqui, Farzan | Abstract: BackgroundThe aims of this systematic review are to (a) evaluate the current literature on the impact of postoperative therapy for resected squamous cell carcinoma of the head and neck (SCCHN) on oncologic and non-oncologic outcomes and (b) identify the optimal evidence-based postoperative therapy recommendations for commonly encountered clinical scenarios.MethodsAn analysis of the medical literature from peer-reviewed journals was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. Prospective studies and methodology-based systematic reviews and meta-analyses of postoperative therapy for SCCHN were identified by searching Medline (OVID) and EMBASE (Elsevier) using controlled vocabulary terms (ie, National Library of Medicine Medical Subject Headings [MeSH], EMTREE). Study screening and selection was performed with Covidence software and full-text review. The RAND/UCLA appropriateness method was used by the expert panel to rate the appropriate use of postoperative therapy, and the modified Delphi method was used to come to consensus.ResultsA total of 5660 studies were identified and screened using the title and abstract, leading to 201 studies assessed for relevance using full-text review. After limitation to the eligibility criteria, 101 studies from 1977 to 2020 were identified, including 77 with oncologic endpoints and 24 with function and quality of life endpoints. All studies reported staging prior to the implementation of American Joint Committee on Cancer (AJCC-8).ConclusionsProspective clinical studies and systematic reviews identified through the PRISMA systematic review provided good evidence for consensus statements regarding the appropriate use of postoperative therapy for resected SCCHN. Further research is needed in domains where consensus by the expert panel could not be achieved for the appropriateness of specific postoperative therapeutic interventions.

Individuals respond faster to presentations of bisensory stimuli (e.g. audio-visual targets) than to presentations of either unisensory constituent in isolation (i.e. to the auditory-alone or visual-alone components of an audio-visual stimulus). This well-established multisensory speeding effect, termed the redundant signals effect (RSE), is not predicted by simple linear summation of the unisensory response time probability distributions. Rather, the speeding is typically faster than this prediction, leading researchers to ascribe the RSE to a so-called co-activation account. According to this account, multisensory neural processing occurs whereby the unisensory inputs are integrated to produce more effective sensory-motor activation. However, the typical paradigm used to test for RSE involves random sequencing of unisensory and bisensory inputs in a mixed design, raising the possibility of an alternate attention-switching account. This intermixed design requires participants to switch between sensory modalities on many task trials (e.g. from responding to a visual stimulus to an auditory stimulus). Here we show that much, if not all, of the RSE under this paradigm can be attributed to slowing of reaction times to unisensory stimuli resulting from modality switching, and is not in fact due to speeding of responses to AV stimuli. As such, the present data do not support a co-activation account, but rather suggest that switching and mixing costs akin to those observed during classic task-switching paradigms account for the observed RSE.

Background Small cell lung cancer (SCLC) is a highly invasive and lethal neuroendocrine tumor. Antiangiogenic drugs have been reported in the treatment of SCLC. We aimed to provide a comprehensive evaluation of the impact of angiogenic inhibitors on SCLC survival using network meta‐analysis. Methods The impact of five angiogenesis inhibitors, that is, vandetanib (Van), bevacizumab (Bev), Rh‐endostatin (End), sunitinib (Sun), and thalidomide (Tha), on progression‐free survival (PFS) and overall survival (OS) was evaluated by conducting a network meta‐analysis. RNA sequencing data were downloaded from publicly available databases. Results Nine phase II and III randomized controlled trials (RCTs), that involved 1599 participants, that investigated angiogenesis inhibitors in the treatment of SCLC were included in this meta‐analysis. Sun and Bev achieved better PFS than Tha (Bev VS. Tha, HR = 0.88, 95% CI: 0.79‐0.98, Sun VS. Tha, HR = 0.80, 95% CI: 0.65‐1.00). Moreover, Sun and Bev were superior to placebo in terms of PFS (Bev VS. Placebo, HR = 0.89, 95%CI: 0.81‐0.97, Sun VS. Placebo, HR = 0.81, 95% CI: 0.66‐1.00). Based on this study, we found no significant difference of OS of SCLC. The angiogenesis pathway and expression of target genes were globally deactivated in SCLC tissue. Conclusion Results of this network meta‐analysis indicate that the PFS outcome of SCLC with Sun or Bev drugs is superior to that of Tha. The improved therapeutic impact of angiogenesis inhibitors on SCLC needs more evidence, such as long‐term observation in clinical trials, to be validated., In this manuscript, we performed the up‐to‐date comprehensive network meta‐analysis as well as bioinformatic analysis for the angiogenesis inhibitors on the survival of patients with small cell lung cancer in terms of both PFS and PS. Moreover, we found that the overall expression level of angiogenesis inhibitor targets is low expressed in SCLC tissue compared with matched normal tissue which could be the reason for the unideal response.

Dosimetric constraints of the brachial plexus have not yet been well-established for patients undergoing stereotactic body radiation therapy (SBRT). This study evaluated long-term experience with the treatment of early-stage apical lung tumors with SBRT and reports on dosimetric correlates of outcome.Between 2009 and 2018, a total of 78 consecutive patients with 81 apical lung tumors underwent SBRT for T1-3N0 non-small cell lung cancer. Apical tumors were those with tumor epicenter superior to the aortic arch. The brachial plexus (BP) was anatomically contoured according to the Radiation Therapy Oncology Group atlas. Patient medical records were reviewed retrospectively to determine incidence of brachial plexus injury (BPI) and a normal tissue complication probability model was applied to the dosimetric data.Five patients (6.4%) reported neuropathic symptoms consistent with BPI and occurred a median 11.9 months after treatment (range, 5.2-28.1 months). Most common dose and fractionation in those developing BPI were 50 Gy in 5 fractions (4 patients). Symptoms consisted of pain in 2 patients (40.0%), numbness in the hand or axilla in 4 patients (80.0%), and ipsilateral hand weakness in 1 patient (20.0%). In the overall cohort the median BP Dmax (EQD2Significant variation exists in the dose delivered to the brachial plexus for patients treated by SBRT for apical lung tumors. The incidence of neuropathic symptoms in the post-SBRT setting was appreciable and prospective clinical correlation with dosimetric information should be used to develop evidence-based dose constraints.

BackgroundWe conducted a2-part study to evaluate the incorporation of veliparib, a PARP inhibitor, into chemoradiotherapy (CRT) for stage III non-small-cell lung cancer.Patients and methodsIn the phase I part, patients were treated successivelyat3dose levels of veliparib(40,80, and120mg) twice daily during CRT. In the phase II part, patients were randomized to receive veliparib or placebo during thoracic radiotherapy with concurrent weekly carboplatin andpaclitaxel, followed by 2 cycles of consolidation carboplatin and paclitaxel with veliparib or placebo. The study was prematurely discontinued owing to the emergence of adjuvant immunotherapy as standard of care.ResultsOf 21 patients enrolled in phase I, 2 patients developed dose-limiting toxicities (DLTs): 1 grade 3 esophagitis with dysphagia (at 40 mg) and 1 grade 3 esophagitis with dehydration (at 80 mg). No DLTs were seen at veliparib dose of 120 mg twice daily, which was selected for the phase II part that enrolled 31 eligible patients. Progression-free survival (PFS) was not different between the 2 arms (P=.20). For the veliparib and placebo arms, response rates were 56% and 69%, PFS at 1 year 47% and 46%, and overall survival at 1 year 89% and 54%, respectively.ConclusionVeliparib with CRT was feasible and well tolerated. Efficacy could not accurately be determined because of early study closure. Nonetheless, there is enthusiasm for the evaluation of PARP inhibitors in lung cancer as predictive biomarkers are being developed and combinations with immunotherapy are attractive.

Purpose Despite the proliferation of radiation oncology fellowship training programs over the last decade, limited data exist on their actual details. We present findings from a focused survey aiming to evaluate the experiences of fellowship-trained physicians. Methods and Materials A customized 23-item questionnaire was systematically distributed to 127 board-certified or eligible physicians who had completed a radiation oncology fellowship in the United States between 2005 and 2017 and whose contact information was available. The survey queried motivations for pursuing fellowship and aspects of training pertaining to expertise, mentorship, salary, employment outcome, satisfaction, and regret. Results A total of 92 subjects responded. Five were still in fellowship and 3 failed to complete the survey in its entirety, leaving 84 (56 male; 28 female) eligible for analysis. Graduates of US residencies comprised 62% of respondents. The desire to build a career in a particular treatment modality was most commonly cited as the primary motivation for pursuing fellowship (58%), followed by the desire to secure an academic faculty position (16%) and the desire to secure a job in a specific geographic location (14%). Subspecialty fellowships were most often done in proton therapy (27%) and brachytherapy (24%). Among the 26 people who completed proton fellowships, only 10 were currently practicing using protons (38%). The majority of fellows (52%) were compensated between $50,000 and $75,000 annually. Seventy-eight (93%) and 72 (86%) physicians were satisfied with fellowship training and their job after fellowship, respectively. Six of the 52 US graduates (12%) and 0 of the 32 international graduates (0%) reported that they would not recommend fellowship to others. Conclusions The motivations for pursuing radiation oncology fellowships appear to be complex, and variability exists with respect to multiple aspects of training, including those related to satisfaction and employment outcomes.

BACKGROUND Triweekly high-dose cisplatin (100 mg/m2 ) with concurrent radiation therapy is the current standard of care in the definitive or appropriate postoperative setting in head and neck squamous cell carcinoma (HNSCC). We compared triweekly 100 mg/m2 with alternative weekly 40 mg/m2 and weekly

Purpose To investigate the prognostic value of pre-treatment immune parameters including white blood cell count (WBC) and circulating lymphocyte count (CLC) among patients with oropharyngeal carcinoma treated by radiation therapy. Methods and Materials A total of 136 consecutive patients were treated by radiation therapy for locally advanced (stage III/IV) squamous cell carcinoma of the oropharynx with known human papillomavirus (HPV) status. Medical records were reviewed to identify patients with documented pre-treatment laboratory bloodwork. The Kaplan-Meier method and linear regression models were used to evaluate the association between pre-treatment CBC and CLC values with survival endpoints. Results One hundred and eleven patients satisfied inclusion criteria. Median age was 62 years (range, 22–91). Eighty-four patients were HPV-positive (76%) and 27 (24%) were HPV-negative. There was no difference in WBC and CLC mean values at baseline between HPV-positive and HV-negative (p > 0.05, for both). Trends were detected in the HPV-positive cohort favoring patients with higher CLC, with respect to 2-year local-regional control (93% vs. 82%, p = 0.06) and distant control (88% vs. 82%, p = 0.10) using the median CLC as cut-off. HPV-positive patients with CLC values in the lowest quartile had inferior local-regional control compared to those in the upper 3 quartiles (69% vs. 89%, p = 0.01). Conclusion Low pre-treatment CLC was correlated with local-regional recurrence and distant failure among HPV-positive patients. These associations were not observed in the HPV-negative cohort.

Recently, LOC285194 has shown a potential tumor-suppressor function in several types of human cancers, but its function in non-small cell lung cancer (NSCLC) remains unknown. This study intended to investigate the biological role of LOC285194 and its clinical significance in NSCLC. LOC285194 was detected by qRT-PCR, and its correlation with clinicopathological features of NSCLC was analyzed. The expression of LOC285194 was knocked down or ectopically expressed in lung cancer cells (A549 and H1299) and tumor cell growth, migration and invasion in vitro were investigated. In addition, the interaction of LOC285194 and target proteins was assessed by RNA pulldown and RNA immunoprecipitation in vitro. The results revealed that the expression of LOC285194 was significantly lower in tumor tissues when compared with the corresponding non-tumor tissues (P

Background We conducted the current systemic review to provide up-to-date literature summary and optimal evidence-based recommendations for ipsilateral radiation for squamous cell carcinoma of the tonsil. Methods We performed literature search of peer-reviewed journals through PubMed. The search strategy and subject-specific keywords were developed based on the expert panel's consensus. Articles published from January 2000 to May 2020 with full text available on PubMed and restricted to the English language and human subjects were included. Several prespecified search terms were used to identify relevant publications and additional evidence published since the initial American College of Radiology Appropriateness Criteria Ipsilateral Tonsil Radiation recommendation was finalized in 2012. The full bibliographies of identified articles were reviewed and irrelevant studies were removed. Results The initial search and review returned 46 citations. The authors added three citations from bibliographies, websites, or books not found in the literature search. Of the 49 citations, 30 citations were retained for further detailed review, and 14 of them were added to the evidence table. Articles were removed from the bibliography if they were not relevant or generalizable to the topic, or focused on unknown primary disease. Several commonly encountered clinical case variants were created and panelists anonymously rated each treatment recommendation. The results were reviewed and disagreements discussed. Conclusions The panel provided updated evidence and recommendations for ipsilateral radiation for squamous cell carcinoma of the tonsil in the setting of primary radiation-based therapy and postoperative adjuvant radiotherapy. This committee did not reach agreements for some case variants due to a lack of strong evidence supporting specific treatment decisions, indicating a further need for research in these topics.

Background Medulloblastoma is an aggressive brain tumor mostly found in children, few studies on pathogenic germline mutations predisposing this disease was reported. Case presentation We present an 11-year-old male with medulloblastoma, who harbors a de novo PHOX2B germline mutation as detected by whole exome sequencing (WES). Family history was negative. Sanger sequencing confirmed this mutation in peripheral blood, hair bulbs, urine and saliva. Identification of novel germline mutations is beneficial for childhood cancer screening. Conclusions This case revealed a de novo PHOX2B germline mutation as a potential cause of medulloblastoma in a child and suggests familial germline variant screening is useful when an affected family is considering having a second child.

Introduction: Circulating non-coding RNA is an ideal source to discover novel biomarkers for non-invasive screening. However, studies for the discovery of universal miRNAs in serum and exosomes for breast cancer early diagnosis are limited. Methods: Based on bioinformatic analysis, in vitro and in vivo studies were performed to understand the role of identified hsa-miR-423-5p in cancer proliferation, migration, cancer stem cell properties. Next, global non-coding RNA expression profiles in blood serum and exosome were performed. hsa-miR-423-5p expression from a total of 356 peripheral blood samples was evaluated and the association of hsa-miR-423-5p expression with clinical characteristics, sensitivity and specificity for breast cancer diagnosis were assessed. Results: The expression of serum and exosomal hsa-miR-423-5p is abnormally increased in breast cancer. Suppression of hsa-miR-423-5p inhibited cell proliferation and invasion in both T47D and MDA-MB-231 breast cancer cell lines, and tumor growth in vivo. Compared with 113 healthy women, quantification analysis of hsa-miR-423-5p in 224 breast cancer samples confirmed the abnormal expression. Serum hsa-miR-423-5p was significantly associated with the clinical stage (P=0.001) and Ki-67 level (P=0.004). Conclusions: A translational bioinformatics analysis procedure and validation by in vitro, in vivo, and clinical samples reveal that hsa-miR-423-5p could be used as a non-invasive breast cancer biomarker.

Background Advanced glycation end products (AGEs) are an important risk factor for the development of cognitive decline in aging and late-onset neurodegenerative diseases including Alzheimer's disease. However, whether and how dietary AGEs exacerbate cognitive impairment and brain mitochondrial dysfunction in the aging process remains largely unknown. Objective We investigated the direct effects of dietary AGEs on AGE adducts accumulation, mitochondrial function, and cognitive performance in mice. Methods Mice were fed the AGE+ diet or AGE- diet. We examined levels of AGE adducts in serum and cerebral cortexes by immunodetection and immunohistochemistry, determined levels of reactive oxygen species by biochemical analysis, detected enzyme activity associated with mitochondrial respiratory chain complexes I & IV and ATP levels, and assessed learning and memory ability by Morris Water Maze and nesting behavior. Results Levels of AGE adducts (MG-H1 and CEL) were robustly increased in the serum and brain of AGE+ diet fed mice compared to the AGE- group. Furthermore, greatly elevated levels of reactive oxygen species, decreased activities of mitochondrial respiratory chain complexes I & IV, reduced ATP levels, and impaired learning and memory were evident in AGE+ diet fed mice compared to the AGE- group. Conclusion These results indicate that dietary AGEs are important sources of AGE accumulation in vivo, resulting in mitochondrial dysfunction, impairment of energy metabolism, and subsequent cognitive impairment. Thus, reducing AGEs intake to lower accumulation of AGEs could hold therapeutic potential for the prevention and treatment of AGEs-induced mitochondrial dysfunction linked to cognitive decline.

Background Tumour cells interfere with normal immune functions by affecting the expression of some immune-related genes, which play roles in the prognosis of cancer patients. In recent years, immunotherapy for tumours has been widely studied, but a practical prognostic model based on immune-related genes in lung adenocarcinoma comparable to existing model has not been established and reported. Methods We first obtained publicly accessible lung adenocarcinoma RNA expression data from The Cancer Genome Atlas (TCGA) for differential gene expression analysis and then filtered immune-related genes based on the ImmPort database. By using the lasso algorithm and multivariate Cox Proportional-Hazards (CoxPH) regression analysis, we identified candidate genes for model development and validation. The robustness of the model was further examined by comparing the model with three established gene models. Results Gene expression data from a total of 524 lung adenocarcinoma patients from TCGA were used for model development. We identified four biomarkers (MAP3K8, CCL20, VEGFC, and ANGPTL4) that could predict overall survival in lung adenocarcinoma (HR = 1.98, 95% CI 1.48 to 2.64, P = 4.19e−06) and this model could be used as a classifier for the evaluation of low-risk and high-risk groups. This model was validated with independent microarray data and was highly comparable with previously reported gene expression signatures for lung adenocarcinoma prognosis. Conclusions In this study, we identified a practical and robust four-gene prognostic model based on an immune gene dataset with cross-platform compatibility. This model has potential value in improving TNM staging for survival predictions in patients with lung adenocarcinoma. Impact The study provides a method of immune relevant gene prognosis model and the identification of immune gene classifier for the prediction of lung adenocarcinoma prognosis with RNA sequencing and microarray compatibility.

Xiaoshun Shi,1,2,* Haoming Tan,3 Xiaobing Le,4,5,* Haibing Xian,6,* Xiaoxiang Li,1 Kailing Huang,4,5 Viola Yingjun Luo,4,5 Yanhui Liu,4,5 Zhuolin Wu,7 Haiyun Mo,8 Allen M Chen,4,5,* Ying Liang,9 Jiexia Zhang1 1National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Department of Medicine, Guangzhou Institute of Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou 510120, China; 2Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; 3Department of Thoracic Surgery, Shunde Lecong Affiliated Hospital of Guangzhou Medical University, Guangdong 528315, China; 4Mendel Genes Inc, Guangzhou 510515, China; 5Mendel Genes Inc, Manhattan Beach, CA 90266, USA; 6Department of Head and Neck/Thoracic Medical Oncology, The First People’s Hospital of Foshan, Guangdong 528000, China; 7Department of Biomedical Engineering, University of Minnesota, Twin Cities, MN, USA; 8Department of Public Health, Guangzhou Medical University, Guangzhou 510000, China; 9Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China *These authors contributed equally to this work Background: The current TNM staging system plays a central role in lung adenocarcinoma (LUAD) prognosis. However, it may not adequately stratify the risk of tumor recurrence. With the aid of gene expression profiling, we identified 31 lncRNAs whose expressions in tumor tissues could be used as a risk indicator for the guidance of lung cancer therapy. This exploratory analysis may shed new light on identification of potential prognostic factors. Materials and methods: A survival prediction scoring model was developed from the data that are publicly available in The Cancer Genome Atlas (TCGA) LUAD RNA Sequencing dataset. Multivariate Cox regression analysis and Kaplan–Meier analysis were performed on a cohort of 254 stage I lung carcinoma patients with survival records. Results: Our model indicates that the panels comprising 31 lncRNAs are highly associated with overall survival (OS): 18.9% (95% CI: 10.4%–34.5%) and 89.5% (95% CI: 80.7%–99.2%) for the high- and low-risk group, respectively. The specificity and sensitivity of the model are verified, which show that the area under receiver operating characteristic curve yields 0.881, meaning our model has good accuracy and it is feasible for further applications. Conclusion: The 31-lncRNA model might be able to predict OS in patients with LUAD with high accuracy. Its further applications in biomolecular experiments using clinical samples with independent cohorts of patients are needed to verify the results. Keywords: lung adenocarcinoma, lncRNA, signature, survival analysis, prognosis, RNA-seq

ObjectiveUndifferentiated endometrial carcinoma (UEC) represents a recently recognized and rare diagnosis that is commonly misclassified on histopathologic evaluation. These cancers account for less than 10% of carefully reviewed series of endometrial cancers from academic medical centers. We reviewed a single-institutional experience with the management of UEC focusing on clinicopathologic characteristics and treatment outcomes.MethodsThe medical records of all patients treated for histologically proven endometrial carcinoma between 2007 through 2016 were reviewed. Analysis was limited to 24 consecutive patients with histologically proven endometrial carcinomas that had at least a component of undifferentiated carcinoma on central pathology review. All patients were initially treated by definitive surgical resection. Grade 3 endometrioid carcinomas treated over the same period were used as a control group. The Kaplan-Meier method was used to estimate survival outcomes.ResultsThe median age at diagnosis was 66 years (range, 37–74 years). Ten patients presented with locally advanced or metastatic disease (42%). Fifteen patients (63%) received adjuvant chemotherapy with carboplatin and paclitaxel, 12 patients (50%) received adjuvant pelvic external beam radiation, and 10 patients (42%) received adjuvant vaginal cuff brachytherapy. With a median follow-up of 14 months (range, 0.5–115 months), 4 patients (21%) had developed disease recurrence and/or progression, 2 patients (11%) had died of disease, and 1 patient died of treatment complications. Twelve patients (63%) were alive with no evidence of disease at last contact. Outcomes were comparable to those with grade 3 endometrioid carcinoma.ConclusionsOur data are consistent with prior studies demonstrating that UEC represents a rare clinical entity characterized by high rates of locally advanced disease at presentation. However, survival outcomes appear to be comparable to other high-grade endometrial cancers. Further studies investigating optimal adjuvant therapy in these patients are warranted.

Purpose To evaluate the prognostic significance of human papillomavirus (HPV) status among patients treated by salvage radiation therapy for local-regional recurrences and second primary cancers of the head and neck arising in a previously irradiated field. Methods and materials The medical records of 54 consecutive patients who underwent re-irradiation for squamous cell carcinoma of the head and neck occurring in a previously irradiated field were reviewed. Only patients with biopsy-proven evidence of recurrent disease that had previously been treated with doses of radiation therapy of at least 60 Gy were included. Determination of HPV status at the time of recurrence was performed by p16 immunohistochemistry. The median age at re-irradiation was 58.5 years (range, 27.9 to 81.5 years). Thirty patients (55.5%) were lifelong never-smokers. The Kaplan Meier method was used to calculate overall survival, progression-free survival, and local-regional control, and distant metastasis-free survival with comparisons between groups performed using the log-rank test. Results HPV status among tumors that were re-irradiated was as follows: 16 positive (29.7%); 7 negative (12.9%); 31 unknown (57.4%). The median overall survival in the entire cohort was 11.7 months (range, 8 to 27 months), with the 1-year and 2-year estimates of overall survival being 47.2% and 38.4%, respectively. A statistical trend was identified favoring patients with HPV-positive cancers with respect to the endpoints of overall survival (p = 0.06) and progression-free survival (p = 0.08) after re-irradiation when compared to the HPV-negative/unknown population. There was no significant difference in distant control between the two cohorts (p = 0.40). Conclusions The favorable prognostic significance of HPV seemingly extends to patients treated by re-irradiation suggesting that this biomarker may be useful in risk stratification in this setting.

OBJECTIVE The utility of fluorodeoxyglucose positron emission tomography (FDG-PET) imaging to predict outcome has been well-established for patients undergoing definitive radiation in the initial management of head and neck cancer. However, the usefulness of this modality in the recurrent setting remains uncertain. We sought to evaluate the prognostic value of metabolic tumor parameters measured on FDG-PET in patients treated by reirradiation for recurrent head and neck cancer. METHODS Thirty-four tumors occurring in 29 patients were reirradiated and were evaluable. The most common disease sites were the oropharynx (n = 9), oral cavity (N = 8), and nasopharynx (n = 6). Potential correlations of FDG-PET maximum standardized uptake value (SUV) and metabolic tumor volume (MTV) with survival endpoints were explored. Multivariate analysis was performed using Cox proportional hazard. RESULTS The median MTV, SUV, and gross tumor volume, as delineated using the 50% SUVmax threshold, were 366 cc (range, 0-3,567 cc), 8.1 (range, 0-25), and 48.5 cc (range, 1-190 cc), respectively. On univariate analysis, both MTVs (as measured as a continuous variable and using the median value of 266 cc as cutoff) were predictive of decreased overall survival (P

Purpose To analyze functional outcomes for patients treated on a phase 2 trial of de-escalated chemoradiation therapy for human papillomavirus–positive oropharyngeal cancer. Methods and Materials Patient eligibility included p16-positive, stage III or IV oropharyngeal squamous cell carcinoma and a Zubrod performance status of 0 to 1. Treatment was induction chemotherapy with paclitaxel, 175 mg/m2, and carboplatin, area under the curve (AUC) of 6 mg/ml/min, for 2 cycles every 21 days, followed by concurrent paclitaxel, 30 mg/m2, every 7 days with dose-reduced radiation therapy of 54 or 60 Gy. Trends in body weight and body mass index (BMI) were analyzed with gastrostomy tube and narcotic use rates. Functional outcomes were assessed using the University of Washington Quality of Life Scale and the Functional Assessment of Cancer Therapy–Head and Neck Scale. Results Forty-five patients were registered, of whom 40 were evaluable. Only 1 patient had a BMI deemed unhealthy at the completion of treatment. For the 15 patients (38%) with a normal BMI (18-25 kg/m2) before treatment, recovery back to baseline occurred at approximately 18 months (average BMI, 23.2 kg/m2 vs 22.3 kg/m2; P=.09). In 2 patients (5%), gastrostomy tubes were placed during treatment. No patient was enteral feeding tube-dependent at 6 months after treatment. Ninety-five percent of patients tolerated a normal regular diet at last follow-up. Conclusions De-escalated chemoradiation therapy may improve functional outcomes as indicated by the relatively low incidence of gastrostomy tube placement and long-term dysphagia. In patients with a normal BMI prior to chemoradiation therapy, BMI recovered to baseline levels.

Radiation treatment planning is typically based on the identification of a gross tumor volume (GTV) using computed tomography (CT). The clinical implementation of an integrated MRI-radiation therapy delivery unit allows for a strict comparison of CT- and MRI-derived GTVs for head and neck cancer. Twenty-six consecutive patients with squamous cell carcinoma of the head and neck were selected and planned for intensity-modulated radiotherapy (IMRT) on a novel tri-60Co teletherapy system equipped with a 0.35 T MRI (ViewRay Incorporated, Oakwood Village, OH). All patients had measurable disease. Pre-treatment MRIs were imported into a contouring interface where the primary GTV were assessed and compared to those obtained from a registered CT with the patient in the identical position and immobilization apparatus. The median GTV as derived from the CT and MRI was 27.2 cm3 (range 3.8 to 155.0 cm3) and 34.9 cm3 (range, 5.0 to 189.5 cm3), respectively (p = 0.01). The MRI-derived GTV was larger than the CT-derived GTV in 21 of the 26 cases and was smaller in the remaining 5 cases. Among the 21 cases where the MRI-derived GTV was larger, the median difference in absolute GTV per individual patient was 6.9 cm3 (range 2.1 to 33.4 cm3), representing a 25% difference on average. The median concordance index for patients with de novo versus recurrent disease was 0.83 and 0.66, respectively (p = 0.03). Significant differences in GTV extent were noted between MRI- and CT-derived ViewRay images. The implications for treatment planning are discussed.

Purpose The treatment of apical lung tumors with stereotactic body radiation therapy (SBRT) is challenging due to the proximity of the brachial plexus and the concern for nerve damage. Methods and materials Between June 2009 and February 2017, a total of 75 consecutive patients underwent SBRT for T1-T3N0 non-small cell lung cancer involving the upper lobe of the lung. All patients were treated with 4-dimensional computed tomography (CT)-based image guided SBRT to a dose of 40 to 60 Gy in 3 to 5 fractions. For dosimetric analysis, only apical tumors as defined by the location of the tumor epicenter superior to the aortic arch were included. The anatomical brachial plexus was delineated using the Radiation Therapy Oncology Group atlas. Results Thirty-one patients with 31 apical lung tumors satisfied the anatomical criteria for inclusion. The median age was 73 years (range, 58-89). The median planning target volume was 26.5 cc (range, 8.2-81.4 cc). The median brachial plexus, brachial plexus maximum dose (Dmax), Dmax per fraction, V22 (cc, 3-4 fractions), V30 (cc, 5 fractions), and biologically effective dose 3 Gy were 15.8 Gy (range, 1.7-66.5 Gy), 3.4 Gy (range, 0.6-14.7 Gy), 0.0 cc (range, 0-0.9 cc), 0.06 cc (range, 0-2.5 cc), and 31.5 Gy (range, 3.3-133.1 Gy), respectively. At a median follow-up of 17 months, the observed incidence of brachial plexopathy was 0%. Conclusions There is significant variation in dose to the brachial plexus for patients treated with SBRT for apical lung tumors. Although the incidence of neuropathic symptoms in this series was zero, further attention should be focused on the clinical implications of these findings.

Summary Astrocytes, the most populous glial cell type in the brain, are critical for regulating the brain microenvironment. In various neurodegenerative diseases, astrocytes determine the progression and outcome of the neuropathological process. We have recently revealed the direct involvement of mitochondrial function in human pluripotent stem cell (hiPSC)-derived dopaminergic (DA) neuronal differentiation. Using the astroglial-neuronal co-culture system, we show here that astrocytes effectively rescue defects in neurogenesis of DA neurons with mitochondrial respiratory chain disruption. Co-culture of astrocytes with defective DA neurons completely restored mitochondrial functions and dynamics insulted by mitochondrial toxins. These results suggest the significance of astroglia in maintaining mitochondrial development and bioenergetics during differentiation of hiPSC-derived DA neurons. Our study also provides an active astroglial-neuronal interaction model for future investigation of mitochondrial involvement in neurogenesis and neurodegenerative diseases., Highlights • Role of astrocyte on the development of hiPSC-derived dopaminergic neuron • Astrocyte protects dopaminergic neurogenesis by powering up mitochondrial respiration • Astrocyte restores mitochondrial function and dynamics in dopaminergic neuron • Evidence of astroglial and neuronal interaction during dopaminergic neurogenesis, In this article, Shirley ShiDu Yan and colleagues show that human pluripotent stem cell-derived astrocytes effectively rescue defects in neurogenesis of dopaminergic neurons with mitochondrial respiratory chain disruption. Co-culture with astrocytes restored mitochondrial functions and dynamics in dopaminergic neurons insulted by mitochondrial toxins. These results provide evidence of astroglia in maintaining mitochondrial development and bioenergetics during dopaminergic neuronal differentiation.

Background The purpose of this study was to present our findings on the use of limited-field, oropharynx-directed ipsilateral irradiation for p16-positive squamous cell carcinoma of unknown primary origin. Methods Between April 2011 and January 2016, 25 patients with a histological diagnosis of p16-positive squamous cell carcinoma were selectively irradiated to the ipsilateral oropharynx and cervical neck for tumors of unknown primary origin. The dose to the oropharynx ranged from 54-60 Gy (median 60 Gy) in 30-33 fractions. Concurrent cisplatin-based chemotherapy was administered to 8 patients (32%). Results The actuarial 2-year estimates of locoregional control, progression-free survival, and overall survival were 91%, 87%, and 92%, respectively. One patient failed in the contralateral neck. There was no grade 3 + toxicity in either the acute or late setting. Conclusion Oropharynx-directed, ipsilateral radiation results in disease control that compares favorably with historical controls treated by comprehensive mucosal and bilateral neck radiation.

The purpose of this study was to evaluate the impact of an image-guided adaptive re-planning strategy on patients treated by intensity-modulated radiotherapy (IMRT) for head and neck cancer. Among 198 patients with head and neck cancer comprising the primary study population, 79 (40%) underwent adaptive radiotherapy with modification of the original IMRT midway during treatment. The incidence of grade 3+ acute skin toxicity was 15 and 35% among patients treated with and without adaptive radiotherapy, respectively (p = 0.01). The incidence of grade 3+ oral mucositis was 15 and 29%, respectively (p = 0.03). There was no significant difference in the 2-year rates of local-regional control or overall survival between the two cohorts (p > 0.05, for both). The use of an image-guided adaptive radiotherapy strategy reduced the incidence of high-grade skin toxicity and oral mucositis in the acute setting. Further studies are needed to better define which subset of patients may benefit the most.

Background The current study represents a subset analysis of quality-of-life (QOL) outcomes among patients treated on a phase 2 trial of de-escalated chemoradiation for human papillomavirus (HPV)-associated oropharyngeal cancer. Methods Eligibility included newly diagnosed, (American Joint Committee on Cancer, 7th edition) stage III or IV oropharyngeal squamous cell carcinoma, p16 positivity, age ≥ 18 years, and a Zubrod performance status of 0 to 1. Treatment was induction paclitaxel at a dose of 175 mg/m2 and carboplatin at an area under the curve of 6 for 2 cycles followed by response-adapted, dose-reduced radiation of 54 Gy or 60 Gy with weekly concurrent paclitaxel at a dose of 30 mg/m2 . The University of Washington Quality of Life (UW-QOL) and the Functional Assessment of Cancer Therapy-Head and Neck questionnaires were used to assess patient-reported QOL as a secondary endpoint. Results A total of 45 patients were registered, 40 of whom completed QOL surveys and were evaluable. Nadirs for overall UW-QOL and Functional Assessment of Cancer Therapy-Head and Neck scores were reached at 4 weeks after treatment but returned to baseline at 3 months. Nearly all functional indices returned to baseline levels by 6 to 9 months. The mean overall UW-QOL score was 71.6 at baseline compared with 70.8, 73.0, 83.3, and 81.1, respectively, at 3 months, 6 months, 1 year, and 2 years after therapy. The percentage of patients rating their overall QOL as "very good" or "outstanding" at 6 months, 1 year, and 2 years using the UW-QOL was 50%, 77%, and 84%, respectively. Conclusions This de-escalation regimen achieved QOL outcomes that were favorable compared with historical controls. These results serve as powerful evidence that ongoing de-escalation efforts lead to tangible gains in function and QOL. Cancer 2018;124:521-9. © 2017 American Cancer Society.

Emerging evidence suggests that mitochondrion–endoplasmic reticulum (ER) and mitochondrion–lipid droplet (LD) contact sites are critical in regulating lipid metabolism in cells. It is well established that intracellular organelles communicate with each other continuously through membrane contact sites to maintain organelle function and cellular homeostasis. The accumulation of LDs in hepatocytes is an early indicator of non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD), which may indicate a breakdown in proper inter-organelle communication. In this review, we discuss previous findings in mitochondrion–ER and mitochondrion–LD contact, focusing on their roles in lipid metabolism in hepatocytes. We also present evidence of a unique mitochondrion–LD contact structure in hepatocytes under various physiological and pathological conditions and propose a working hypothesis to speculate about the role of these structures in regulating the functions of mitochondria and LDs and their implications in NAFLD and ALD.

Objectives/Hypothesis To determine the impact of pretreatment psychosocial distress on compliance to radiation therapy (RT) and clinical outcomes for patients with head and neck cancer Study Design Self-reported responses to the mood and anxiety domains of the University of Washington Quality of Life instrument were reviewed among 133 patients with newly diagnosed head and neck cancer prior to initiating RT. Methods Varying definitions were used (total number of unexpectedly missed RT days, >5 days continuous interruption of RT outside of weekends, >10 days continuous interruption of RT, and failure to complete prescribed course of RT) to analyze the effect of psychosocial disruption on compliance. Survival was determined using the Kaplan-Meier method. Results The prevalence of pretreatment depression and anxiety was 23% and 47%, respectively. Continuous RT breaks >5 days occurred in 46%, 33%, 10%, 9%, and 0% of patients whose mood was rated as “extremely depressed,” “somewhat depressed,” “neither in a good mood or depressed,” “generally good,” and “excellent,” respectively (P = .0016). The corresponding proportion of patients who did not complete their planned RT was 23%, 11%, 5%, and 3%, and 0%, respectively (P = .043). The 2-year overall survival of patients who were “extremely depressed” or “somewhat depressed” at baseline was 71% versus 86% for all others (P = .026). Depression was independently associated with decreased overall survival on logistical regression analysis. Conclusions Pretreatment depression predicted for decreased RT compliance and inferior survival for head and neck cancer. Additional research to overcome potential barriers to treatment in this setting may be warranted. Level of Evidence 4. Laryngoscope, 2017

To report a single-institutional experience with the use of magnetic resonance imaging (MRI)-guided radiotherapy for cancers of the head and neck. Between October 2014 and October 2016, 18 patients with newly diagnosed cancers of the head and neck were prospectively enrolled on an institutional registry trial investigating the feasibility and efficacy of external-beam radiotherapy delivered using on-board MRI. All patients had biopsy-proven evidence of malignancy, measurable disease, and the ability to provide consent. None had previously received any treatment. Median dose was 70 Gy (range 54–70 Gy). MRI scans were obtained as part of an image-guided registration protocol for alignment prior to and during each treatment. Concurrent chemotherapy was administered to 14 patients (78%). Patient-reported outcomes were assessed using the University of Washington quality of life instrument. Seventeen of 18 patients completed the planned intensity-modulated radiotherapy (IMRT) treatment of which 15 (83%) had a complete response and 2 (11%) had a partial response based on initial post-therapy positron emission tomography (PET) at 3 months. The 1-year estimates of progression-free survival, overall survival, and local–regional control were 95, 96, and 95%, respectively. There were no treatment-related fatalities. The incidence of grade 3+ acute toxicity was 44%. The proportion of patients rating their health-related quality of life as “very good” or “outstanding” at 6 months and 1 year after completion of radiation therapy was 60 and 70%, respectively. MRI-guided radiotherapy achieves clinical outcomes comparable to contemporary series reporting on IMRT for head and neck cancer.

Purpose To perform a spatial analysis of local–regional recurrences, in relation to quantitative dose distribution, among patients treated by intensity-modulated radiotherapy (IMRT) for human papillomavirus (HPV)-positive oropharyngeal cancer. Methods and materials The records of 107 consecutive patients who presented for consideration of re-irradiation for local–regional recurrent disease occurring in a previously irradiated field were reviewed. The original IMRT plans were retrieved for those with HPV-positive disease originating from the oropharynx, and deformable image registration was used to fuse the magnetic resonance imaging (MRI) and positron emission tomography (PET) scans obtained at recurrence to the pre-treatment planning computed tomography (CT) dataset. The recurrent tumor volume ( V recur ) was subsequently identified on axial imaging, and the dose of radiation received by V recur was then calculated and analyzed using dose–volume histograms. Results A total of 83 recurrent lesions occurring in 50 oropharyngeal cancer patients were HPV-positive and met inclusion criteria. Using PET-defined V recur , thirty-three lesions were classified as in-field recurrences (40%), 35 were marginal misses (41%), and 15 were true misses (18%). Using the MRI-defined V recur , thirty-seven lesions were classified as in-field recurrences (45%), 32 were marginal misses (39%), and 14 were true misses (17%). Conclusion A significant proportion of local–regional recurrences from HPV-positive oropharyngeal cancer represented geographical misses which possibly could have been prevented with more meticulous attention to IMRT planning. This finding has important implications with respect to ongoing attempts to de-escalate radiation dose for this disease. Our data highlight the importance of robust quality assurance with careful review of target volumes prior to the initiation of IMRT.

BACKGROUND: We conducted a phase II multi-center trial of induction chemotherapy followed by response-adapted, dose-reduced radiation therapy with radiosensitizing chemotherapy for patients with locally advanced, human papillomavirus (HPV)-associated squamous cell carcinoma of the oropharynx. The aim of this study was to determine the progression-free survival for patients treated using this de-escalated approach to determine its worthiness for further investigation in a phase III setting. METHODS: Eligible patients presented with newly diagnosed, biopsy-proven stage III or IV squamous cell carcinoma of the oropharynx, p16-positivity, and Zubrod performance status 0 to 1. Smoking history was not used as a criterion for eligibility. Treatment was induction paclitaxel 175 mg/m2 and carboplatin area under the concentration-time curve (AUC) 6 for two cycles every 21 days followed by dose-reduced radiation of 54 Gy or 60 Gy for responders and non-responders, respectively, with weekly paclitaxel 30 mg/m2. Intensity-modulated radiotherapy with daily image-guidance was required. The primary endpoint was 2-year progression-free survival as determined by per protocol analysis. This study is registered with ClinicalTrials.gov, numbers NCT02048020 and NCT01716195. FINDINGS: Between October 4, 2012 and March 3, 2015, forty-five patients (26 tonsil; 19 base of tongue) were registered, of which 44 were analyzable. Median age was 60 years old (IQR, 54 to 67). Sixty-nine percent of the patients were lifelong never smokers. Twenty-four patients (55%) exhibited a complete or partial response to induction chemotherapy; twenty patients (45%) had a less than partial response to induction chemotherapy. With a median follow up of 30 months (IQR, 26 to 37 months), three (7%) of 44 patients developed local-regional recurrence and another distant metastasis, yielding a 2-year progression-free survival of 92%. The most commonly observed grade 3+ toxicity was leukopenia (17 patients) with the most common grade 3+ non-hematologic toxicities being dysphagia (4 patients) and mucositis (4 patients). Seventeen (39%) of 44 patients and nine (20%) of 44 patients developed any grade 3+ and non-hematologic grade 3+ toxicity, respectively, during protocol therapy.. The proportion who were gastrostomy-tube dependent at 3- and 6-months post-therapy was 2% (1 of 44 patients) and 0%, respectively. INTERPRETATION: The rates of disease control demonstrated with this de-escalation regimen for patients with locally advanced, HPV-associated oropharyngeal carcinoma were comparable to those of historical controls treated by standard dose chemoradiotherapy regimens. Additionally, long-term side effects appeared to be reduced. By decreasing toxicity while maintaining cure rates, de-escalation of radiation dose has the potential to improve the therapeutic ratio and optimize long-term function for patients with a disease that is rapidly increasing in incidence.

Purpose To study the tolerance of the brachial plexus to high doses of radiation exceeding historically accepted limits by analyzing human subjects treated with reirradiation for recurrent tumors of the head and neck. Methods and Materials Data from 43 patients who were confirmed to have received overlapping dose to the brachial plexus after review of radiation treatment plans from the initial and reirradiation courses were used to model the tolerance of this normal tissue structure. A standardized instrument for symptoms of neuropathy believed to be related to brachial plexus injury was utilized to screen for toxicity. Cumulative dose was calculated by fusing the initial dose distributions onto the reirradiation plan, thereby creating a composite plan via deformable image registration. The median elapsed time from the initial course of radiation therapy to reirradiation was 24 months (range, 3-144 months). Results The dominant complaints among patients with symptoms were ipsilateral pain (54%), numbness/tingling (31%), and motor weakness and/or difficulty with manual dexterity (15%). The cumulative maximum dose (Dmax) received by the brachial plexus ranged from 60.5 Gy to 150.1 Gy (median, 95.0 Gy). The cumulative mean (Dmean) dose ranged from 20.2 Gy to 111.5 Gy (median, 63.8 Gy). The 1-year freedom from brachial plexus–related neuropathy was 67% and 86% for subjects with a cumulative Dmax greater than and less than 95.0 Gy, respectively (P=.05). The 1-year complication-free rate was 66% and 87%, for those reirradiated within and after 2 years from the initial course, respectively (P=.06). Conclusion The development of brachial plexus–related symptoms was less than expected owing to repair kinetics and to the relatively short survival of the subject population. Time-dose factors were demonstrated to be predictive of complications.

Background and purpose Second malignancies (SM) after external beam radiotherapy (EBRT) or brachytherapy (BT) for prostate cancer (PCa) are rare but serious sequelae. Materials and methods The Surveillance, Epidemiology, and End Results (SEER) database was used to identify men diagnosed with cT1-2N0M0 PCa between 1999 and 2005, who underwent EBRT, BT or radical prostatectomy (RP). Patients with time interval to second malignancy or follow-up shorter than five and two years were excluded for solid and hematopoietic SM analyses respectively. Risks for solid and hematopoietic SM were evaluated via the multivariate Fine and Gray proportional hazards model. Results EBRT and BT resulted in similar increases in solid and hematopoietic SM compared to RP. In subgroup analysis stratified by treatment modality, only the EBRT cohort demonstrated significantly decreased solid and hematopoietic SM in years 2002–2005 compared to years 1999–2001, with adjusted-hazard ratios of 0.752 ( p =0.001) and 0.815 ( p =0.018) respectively. Conclusions EBRT and BT resulted in statistically equivalent increase in both solid and hematopoietic SM compared to RP. EBRT in more recent years resulted in significantly decreased solid and hematopoietic SM, coinciding with increased utilization of IMRT.

Background The purpose of this study was to determine the effect of fraction size on laryngoesophageal dysfunction among patients treated by chemoradiotherapy for laryngeal and hypopharyngeal cancer. Methods Forty patients underwent chemoradiotherapy for stage III/IV squamous cell carcinomas of the larynx and hypopharynx. Median radiation dose was 70 Gy (range, 69.3–70.4 Gy) with daily fractionation ranging from 2 Gy to 2.2 Gy. Results When comparing 2 Gy versus >2 Gy daily fractionation, there was no difference in 2-year overall survival (71% vs 72%; p = .68), locoregional control (79% vs 77%; p = .43), or laryngectomy-free survival (60% vs 61%; p = .72). Use of 2 Gy versus >2 Gy fractionation improved laryngoesophageal dysfunction-free survival (2-year estimates, 49% vs 27%; p = .07). Patient-reported voice and swallowing were improved with the former. Conclusion As the importance of a functional larynx becomes recognized as an endpoint for patients treated by voice preservation, the results of our study help refine treatment guidelines. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1322–1326, 2017