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Clinical informatics is a young, diverse and rapidly growing field. We asked eight clinical informaticians from a variety of oncology specialties, training pathways and careers for personal narratives to illustrate the wide spectrum of clinical informatics careers. Primary clinical specialties included radiation oncology, medical/haematology oncology and palliative care. Training pathways included fellowship, non-fellowship formal training and informal training. Careers included clinical care, research, operations and industry. We summarised common themes and advice for trainees. We hope to raise awareness of clinical informatics among trainees and oncologists to reveal new career opportunities and to avoid inadvertently taking clinical informatics and informaticians for granted., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Multiple factors influence the time elapsed between diagnosis of breast cancer and surgical extirpation of the primary tumor. The disease-free interval between resection of primary breast cancer and first evidence of recurrence is predictive of mortality. We aimed to determine patient, disease, and treatment factors associated with a delay in time to surgery (TTS) and identify the point when prolonged TTS negatively impacts disease-free survival., Patients and Methods: Cancer registry and electronic medical record data for patients with breast cancer who underwent surgery as first course of treatment during 2006-2016 were retrospectively reviewed. Patients undergoing surgery in ≤30 vs. 31-60 vs. >60 days of initial diagnosis were compared. Kaplan-Meier survival analyses with Cox proportional hazards were performed to evaluate impact of time from breast cancer diagnosis to definitive therapeutic surgery on breast cancer recurrence or death (all-cause)., Results: Overall, 4462 patients were analyzed, 43.4% of whom underwent surgery beyond 30 days. The following factors were associated with TTS >30 days: age <50, non-Hispanic White race/ethnicity, commercial or health exchange/Medicaid insurance, diagnosis of noninvasive disease (i.e., ductal carcinoma in situ), had breast magnetic resonance imaging before definitive surgery, underwent total mastectomy (especially if immediate reconstruction, particularly if autologous, was performed), and did not receive adjuvant therapies (P < .001 for all). After adjusting for relevant variables, significant predictors of recurrence/death included a TTS >60 days, increased patient age, higher breast cancer stage, and triple-negative biomarker expression., Conclusion: Risk of recurrence or death is not compromised until TTS exceeds 60 days after initial breast cancer diagnosis., (Copyright © 2021. Published by Elsevier Inc.)

Background: The survival benefit of elective neck dissection (END) for patients with cutaneous squamous cell carcinoma (cSCC) of the head and neck and no evidence of regional metastasis (cN0) has never been reported. The aim of this study was to determine the effect of END on patient survival., Methods: The authors included patients with head and neck cSCC who had undergone primary surgery from 1995 to 2017. The primary end point was survival, and the secondary end points were the incidence of occult regional disease and regional disease control. To assess the impact of END on survival, the authors used multivariable Cox proportional hazards models with propensity score and matching techniques for internal validation., Results: A total of 1111 patients presented with no evidence of nodal disease; 173 had END, and 938 were observed. Adjuvant radiotherapy to the neck was administered to 101 patients (9%). END resulted in a 5-year overall survival rate of 52%, whereas the rate was 63% in the observation group (P = .003 [log-rank]). The 5-year disease-free survival rate for patients undergoing END was similar to that for the observation group (73% vs 75%; P = .429). A multivariate regression model showed that the performance of END was not associated with improved rates of overall, disease-specific, or disease-free survival; similarly, among patients with advanced disease (T3-4), those who underwent END did not have improved survival rates., Conclusions: Among patients with cSCC of the head and neck, observation of the neck nodes resulted in noninferior survival rates in comparison with END at the time of primary surgery. Further studies are required to elucidate the role of END in patients with advanced disease., (© 2021 American Cancer Society.)

Aim: To investigate the effect of resistance training (RT) on hepatocardiovascular and muscle mitochondrial parameters in rats that were fed a high-calorie diet for 12 weeks., Main Methods: The animals were divided into four groups: control (C), exercise (E), obese (O), and obese plus exercise (OE). Group E and OE rats performed resistance training by climbing on a vertical ladder with load attached to the end of the tail (1×/day, 3×/week, for 12 weeks). Group O and OE rats were fed a high-calorie diet containing chow and a cafeteria diet for 12 weeks. Under anesthesia, the heart and liver were removed for histopathological analysis, and the gastrocnemius muscle was removed for Western blotting., Key Findings: Group O rats were heavier, with increased fat mass, elevated fasting glycemia, and total triglycerides, and exhibited a significant number of Kupffer cells and diffuse steatosis in the liver. Group O rats also showed increased thickness of the right ventricle, septum, and pulmonary artery. All of these parameters were attenuated by RT. PGC1-α protein levels were increased in both exercise groups. The protein levels of OXPHOS complexes III, IV, and V were reduced in Group O, while RT prevented this alteration., Significance: RT exerts a protective effect against hepato-cardiac alterations and prevents changes in the muscle mitochondrial protein profile induced by a high-calorie diet., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s).)

Introduction: Radiation dose-escalation for head and neck cancer (HNC) patients aiming to improve cure rates is challenging due to the increased risk of unacceptable treatment-induced toxicities. With "Proton Image-guided Radiation Assignment for Therapeutic Escalation via Selection of locally advanced head and neck cancer patients" (PIRATES), we present a novel treatment approach that is designed to facilitate dose-escalation while minimizing the risk of dose-limiting toxicities for locally advanced HPV-negative HNC patients. The aim of this Phase I trial is to assess the safety & feasibility of PIRATES approach., Methods: The PIRATES protocol employs a multi-faceted dose-escalation approach to minimize the risk of dose-limiting toxicities (DLTs): 1) sparing surrounding normal tissue from extraneous dose with intensity-modulated proton therapy, 2) mid-treatment hybrid hyper-fractionation for radiobiologic normal tissue sparing; 3) Magnetic Resonance Imaging (MRI) guided mid-treatment boost volume adaptation, and 4) iso-effective restricted organ-at-risk dosing to mucosa and bone tissues.The time-to-event Bayesian optimal interval (TITE-BOIN) design is employed to address the challenge of the long DLT window of 6 months and find the maximum tolerated dose. The primary endpoint is unacceptable radiation-induced toxicities (Grade 4, mucositis, dermatitis, or Grade 3 myelopathy, osteoradionecrosis) occurring within 6 months following radiotherapy. The second endpoint is any grade 3 toxicity occurring in 3-6 months after radiation., Discussion: The PIRATES dose-escalation approach is designed to provide a safe avenue to intensify local treatment for HNC patients for whom therapy with conventional radiation dose levels is likely to fail. PIRATES aims to minimize the radiation damage to the tissue surrounding the tumor volume with the combination of proton therapy and adaptive radiotherapy and within the high dose tumor volume with hybrid hyper-fractionation and not boosting mucosal and bone tissues. Ultimately, if successful, PIRATES has the potential to safety increase local control rates in HNC patients with high loco-regional failure risk.Trial registration: ClinicalTrials.gov ID: NCT04870840; Registration date: May 4, 2021.Netherlands Trial Register ID: NL9603; Registration date: July 15, 2021., (© 2021 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Objectives/hypothesis: To report the largest single-institution review of temporal bone osteoradionecrosis (TBORN), and characterize the disease's natural history, prognostic factors, management, and outcomes., Study Design: Retrospective chart review., Methods: Retrospective review was conducted to identify patients with TBORN. Pertinent data were extracted. Descriptive statistics were used to summarize patient, tumor, and treatment characteristics. Multivariable analyses were conducted to explore associations between these characteristics and time to TBORN diagnosis and risk of developing diffuse disease., Results: TBORN was identified in 145 temporal bones from 128 patients. Mean age at diagnosis was 62 years, and mean time to diagnosis after radiotherapy was 10 years. Age greater than 50 years was associated with earlier diagnosis. According to the Ramsden criteria, 76% of TBs had localized and 24% had diffuse disease at initial diagnosis; 37% had diffuse disease at last follow-up. On multivariable analysis, diabetes, three-dimensional conformal radiotherapy (3D-CRT), and periauricular skin malignancy were significant risk factors for developing diffuse disease. Localized disease was successfully managed with conservative measures, whereas surgery was often necessary for diffuse disease. When TBORN spread outside the mastoid or infratemporal fossa, conservative measures were always unsuccessful., Conclusions: TBORN occurs earlier in older patients. While diffuse disease is less common than localized disease, it occurs more frequently in patients with diabetes, history of 3D-CRT, and periauricular skin malignancies. Conservative management is appropriate for localized disease, while surgery is often necessary for diffuse disease. The prognostic factors identified helped propose a TBORN staging system and treatment guidelines which may improve patient risk stratification and disease management., Level of Evidence: 4 Laryngoscope, 131:2578-2585, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Recurrent head and neck cancer has poor prognosis. Stereotactic body radiotherapy (SBRT) may improve outcomes by delivering ablative radiation doses., Methods: We reviewed patients who received definitive-intent SBRT reirradiation at our institution from 2013 to 2020. Patterns of failure, overall survival (OS), and toxicities were analyzed., Results: One hundred and thirty-seven patients were evaluated. The median OS was 44.3 months. The median SBRT dose was 45 Gy and median target volume 16.9 cc. The 1-year local, regional, and distant control was 78%, 66%, and 83%, respectively. Systemic therapy improved regional (p = 0.004) and distant control (p = 0.04) in nonmetastatic patients. Grade 3+ toxicities were more common at mucosal sites (p = 0.001) and with concurrent systemic therapy (p = 0.02)., Conclusions: In a large cohort of SBRT reirradiation for recurrent, small volume head and neck cancers, a median OS of 44.3 months was observed. Systemic therapy improved regional and distant control. Toxicities were modulated by anatomic site and systemic therapy., (© 2021 Wiley Periodicals LLC.)

Introduction: It has become increasingly important to include patient preference information in decision-making processes for drug development. As neuromuscular disorders represent multisystem, debilitating, and progressive rare diseases with few treatment options, this study aimed to explore unmet health care needs and patient treatment preferences for two neuromuscular disorders, myotonic dystrophy type 1 (DM1) and mitochondrial myopathies (MM) to inform early stages of drug development., Methods: Fifteen semi-structured interviews and five focus group discussions (FGDs) were held with DM1 and MM adult patients and caregivers. Topics discussed included (1) reasons for study participation; (2) disease signs/symptoms and their impact on daily lives; (3) top desired benefits; and (4) acceptability of risks and tolerance levels for a hypothetical new treatment. Data were analyzed following a thematic 'code' approach., Results: A total of 52 participants representing a wide range of disease severities participated. 'Muscle strength' and 'energy and endurance' were the disease-related unmet needs most often mentioned. Additionally, improved 'balance', 'cognition' and 'gut function' were the top desired treatment benefits, while 'damage to the liver, kidneys or eyes' was the most concerning risk. Factors influencing their tolerance to risks related to previously having experienced the risk and differentiation between permanent and temporary risks. A few differences were elicited between patients and caregivers., Conclusions: This qualitative study provided an open forum to elicit treatment-desired benefits and acceptable risks to be established by patients themselves. These findings can inform decisions for developing new treatments and the design of clinical trials for DM1 and MM., (© 2021. The Author(s).)

Background: Induction chemotherapy (IC) has been associated with a decreased risk of distant metastasis in locally advanced head and neck squamous cell carcinoma. However, its role in the treatment of oropharyngeal squamous cell carcinoma (OPSCC) is not well established., Methods: The outcomes of patients with OPSCC treated with IC followed by concurrent chemoradiation (CRT) were compared with the outcomes of those treated with CRT alone. The primary outcome was overall survival (OS), and the secondary end points were the times to locoregional and distant recurrence., Results: In an existing database, 585 patients met the inclusion criteria: 137 received IC plus CRT, and 448 received CRT. Most patients were positive for human papillomavirus (HPV; 90.9%). Patients receiving IC were more likely to present with a higher T stage, a higher N stage, and low neck disease. The 3-year OS rate was significantly lower in patients receiving IC (75.7%) versus CRT alone (92.9%). In a multicovariate analysis, receipt of IC (adjusted hazard ratio [aHR], 3.4; P < .001), HPV tumor status (aHR, 0.36; P = .002), and receipt of concurrent cetuximab (aHR, 2.7; P = .002) were independently associated with OS. The risk of distant metastasis was also significantly higher in IC patients (aHR, 2.8; P = .001), whereas an HPV-positive tumor status (aHR, 0.44; P = .032) and completion of therapy (aHR, 0.51; P = .034) were associated with a lower risk of distant metastasis. In HPV-positive patients, IC remained associated with distant metastatic progression (aHR, 2.6; P = .004) but not OS., Conclusions: In contrast to prior studies, IC was independently associated with worse OS and a higher risk of distant metastasis in patients with OPSCC. Future studies are needed to validate these findings., (© 2021 American Cancer Society.)

Although active immunotherapies are effective strategies to induce activation of CD8 + T cells, advanced stage tumors require further improvements for efficient control. Concerning the burden of cancer-related to Human papillomavirus (HPV), particularly the high incidence and mortality of cervical cancer, our group developed an approach based on a DNA vaccine targeting the HPV-16 E7 oncoprotein (pgDE7h). This immunotherapy is capable of inducing an antitumour CD8 + T cell response but show only partial control of tumors in more advanced growth stages. Here, we combined a chemotherapeutic agent (gemcitabine- Gem) with pgDE7h to overcome immunosuppression and improve antitumour responses in a preclinical mouse tumor model. Our results demonstrated that administration of Gem had synergistic antitumor effects when combined with pgDE7h leading to eradication of both early-stages and established tumors. Overall, the antiproliferative effects of Gem observed in vitro and in vivo provided an optimal window for immunotherapy. In addition, the enhanced antitumour responses induced by the combined therapeutic regimen included enhanced frequencies of antigen-presenting cells (APCs), E7-specific IFN-γ-producing CD8 + T cells, and cytotoxic CD8 + T cells and, concomitantly, less pronounced accumulation of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). These findings demonstrated that the combination of Gem and an active immunotherapy strategy show increased effectiveness, leading to a reduced need for multiple drug doses and, therefore, decreased deleterious side effects avoiding resistance and tumor relapses. Altogether, our results provide evidence for a new and feasible chemoimmunotherapeutic strategy that supports future clinical translation., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

This project sought to evaluate if business card distribution improved the utility of Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) surveys by serving as a feedback mechanism for trainees. Between fall 2018 and spring 2019, patient encounters for 6 cardiovascular disease fellows were tracked over two 60-day periods. Six weeks were allowed for HCAHPS surveys to be returned. Business cards were subsequently deployed and encounters similarly tracked. During the control-group monitoring period, 721 patient encounters were logged and 80 (11.1%) surveys were returned. Qualitative feedback, in the form of free-response comments, was provided in 41 (51.3%) surveys. Business cards were then deployed and encounters similarly tracked. During the business card period, 508 patient encounters occurred and 97 (19.1%) surveys were returned. Qualitative feedback was provided in 52 (53.6%) surveys. No fellow-specific feedback was returned in either group. Business card use by trainees was associated with an improved rate of survey return, from 11.1% to 19.1%, but no effect on feedback to fellows or patient satisfaction scores was found. HCAHPS surveys were not useful in providing trainees with feedback. Immediate verbal feedback from patients via ancillary staff was observed. A method of relaying communication from patients to ancillary staff and medical education programs is needed., Competing Interests: Conflict of interest None., (© 2021 Aurora Health Care, Inc.)

Integrated, data-driven criteria are necessary to evaluate delivery outcomes in pregnancies affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the ongoing COVID-19 pandemic. This study analyzed maternal demographics, clinical characteristics, treatments, and delivery outcomes of 85 ethnically diverse, adult pregnant women who tested positive for SARS-CoV-2 at the time of delivery. Median maternal and gestational ages were 27 years (interquartile range [IQR]: 23-31) and 39 weeks (IQR: 37.3-40.0), respectively. Of the 85 SARS-CoV-2-positive participants, 67 (79%) had no COVID-19 symptoms at the time of routine COVID-19 admission testing, 14 (16%) reported mild COVID-19 symptoms, and 4 (5%) presented severe COVID-19 symptoms that required hospitalization. Patients in the severe COVID-19 group had significantly longer hospitalizations than those with nonsevere COVID-19 (7 [IQR: 4.5-9.5] vs 2 [IQR: 2-3] days; P<0.01). Neonatal outcomes included 100% live births with a median 1-minute Apgar score of 8 and 15% preterm births. No neonatal deaths or vertical transmissions were reported, and all neonatal intensive care unit admissions were related to prematurity. Overall, maternal symptom prevalence and peripartum complication rates were low, suggesting a generally good prognosis for pregnant women with SARS-CoV-2 infections at the time of delivery., Competing Interests: Conflict of interest None., (© 2021 Aurora Health Care, Inc.)

Background: The goal of this study was to comprehensively investigate the association of chemotherapy with trajectories of acute symptom development and late symptom recovery in patients with oropharyngeal cancer (OPC) by comparing symptom burden between induction chemotherapy followed by concurrent chemoradiotherapy (ICRT), concurrent chemo-radiotherapy (CRT), or radiotherapy (RT) alone., Methods: Among a registry of 717 patients with OPC, the 28-item patient-reported MD Anderson Symptom Inventory-Head and Neck Module (MDASI-HN) symptoms were collected prospectively at baseline, weekly during RT, and 1.5, 3 to 6, 12, and 18 to 24 months after RT. The effect of the treatment regimen (ICRT, CRT, and RT alone) was examined with mixed-model analyses for the acute and late period. In the CRT cohort, the chemotherapy agent relationship with symptoms was investigated., Results: Chemoradiation (ICRT/CRT) compared with RT alone resulted in significantly higher acute symptom scores in the majority of MDASI-HN symptoms (ie, 21 out of 28). No late symptom differences between treatment with or without chemotherapy were observed that were not attributable to ICRT. Nausea was lower for CRT with carboplatin than for CRT with cisplatin; cetuximab was associated with particularly higher scores for acute and late skin, mucositis, and 6 other symptoms. The addition of ICRT compared with CRT or RT alone was associated with a significant increase in numbness and shortness of breath., Conclusion: The addition of chemotherapy to definitive RT for OPC patients was associated with significantly worse acute symptom outcomes compared with RT alone, which seems to attenuate in the late posttreatment period. Moreover, induction chemotherapy was specifically associated with worse numbness and shortness of breath during and after treatment., Lay Summary: Chemotherapy is frequently used in addition to radiotherapy cancer treatment, yet the (added) effect on treatment-induced over time is not comprehensively investigated This study shows that chemotherapy adds to the symptom severity reported by patients, especially during treatment., (© 2021 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Purpose: To characterize our experience and the disease control and toxicity of proton therapy (PT) for patients with head and neck cancer (HNC)., Patients and Methods: Clinical outcomes for patients with HNC treated with PT at our institution were prospectively collected in 2 institutional review board-approved prospective studies. Descriptive statistics were used to summarize patient characteristics and outcomes. Overall survival, local-regional control, and disease-free survival were estimated by the Kaplan-Meier method. Treatment-related toxicities were recorded according to the Common Terminology Criteria for Adverse Events (version 4.03) scale., Results: The cohort consisted of 573 patients treated from February 2006 to June 2018. Median patient age was 61 years. Oropharynx (33.3%; n = 191), paranasal sinus (11%; n = 63), and periorbital tissues (11%; n = 62) were the most common primary sites. Patients with T3/T4 or recurrent disease comprised 46% (n = 262) of the cohort. The intent of PT was definitive in 53% (n = 303), postoperative in 37% (n = 211), and reirradiation in 10% (n = 59). Median dose was 66 Gy (radiobiological equivalent). Regarding systemic therapy, 43% had received concurrent (n = 244), 3% induction (n = 19), and 15% (n = 86) had both. At a median follow-up of 2.4 years, 88 patients (15%) had died and 127 (22%) developed disease recurrence. The overall survival, local-regional control, and disease-free survival at 2 and 5 years were, respectively, 87% and 75%, 87% and 78%, and 74% and 63%. Maximum toxicity (acute or late) was grade 3 in 293 patients (51%), grade 2 in 234 patients (41%), and grade 1 in 31 patients (5%). There were 381 acute grade 3 and 190 late grade 3 unique toxicities across 212 (37%) and 150 (26%) patients, respectively. There were 3 late-grade 4 events across 2 patients (0.3%), 2 (0.3%) acute-grade 5, and no (0%) late-grade 5 events., Conclusions: The overall results from this prospective study of our initial decade of experience with PT for HNC show favorable disease control and toxicity outcomes in a multidisease-site cohort and provide a reference benchmark for future comparison and study., Competing Interests: Conflicts of Interest: Steven J. Frank, MD, is an Associate Editor of the International Journal of Particle Therapy. Dr Frank is a scientific advisory board member of Breakthrough Chronic Care; he has received research grants from C4 Imaging, Eli Lilly, Elekta, and Hitachi, and he has reported personal fees from Varian Medical Systems, Inc (consultant/advisory board), C4 Imaging (founder and director), Hitachi (honoraria/advisory board), Augmenix (honoraria), and National Comprehensive Cancer Center (board member). Stephen G. Chun, MD, is a consultant for AstraZeneca, PLC. The authors report no other conflicts of interest., (©Copyright 2021 The Author(s).)

Aims: Myocardial work (MW) is a novel parameter that can be used in a clinical setting to assess left ventricular (LV) pressures and deformation. We sought to distinguish patterns of global MW index in hypertensive vs. non-hypertensive patients and to look at differences between categories of hypertension., Methods and Results: Sixty-five hypertensive patients (mean age 65 ± 13 years; 30 male) and 15 controls (mean age 38 ± 12 years; 7 male) underwent transthoracic echocardiography at rest. Hypertensive patients were subdivided into Stage 1 (n = 32) and Stage 2 (n = 33) hypertension based on 2017 American College of Cardiology guidelines. Exclusion criteria were suboptimal image quality for myocardial deformation analysis, reduced ejection fraction, valvular heart disease, intracardiac shunt, and arrhythmia. Global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency were estimated from LV pressure-strain loops utilizing proprietary software from speckle-tracking echocardiography. LV systolic and diastolic pressures were estimated using non-invasive brachial artery cuff pressure. Global longitudinal strain and LV ejection fraction were preserved between the groups with no statistically significant difference, whereas there was a statically significant difference between the control and two hypertension groups in GWI (P = 0.01), GCW (P < 0.001), and GWW (P < 0.001)., Conclusion: Non-invasive MW analysis allows better understanding of LV response under conditions of increased afterload. MW is an advanced assessment of LV systolic function in hypertension patients, giving a closer look at the relationship between LV pressure and contractility in settings of increased load dependency than LV ejection fraction and global longitudinal strain., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Opinion Statement: The rise in the incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPC), the relatively young age at which it is diagnosed, and its favorable prognosis necessitate the use of treatment techniques that reduce the likelihood of side effects during and after curative treatment. Intensity-modulated proton therapy (IMPT) is a form of radiotherapy that de-intensifies treatment through dose de-escalation to normal tissues without compromising dose to the primary tumor and involved, regional lymph nodes. Preclinical studies have demonstrated that HPV-positive squamous cell carcinoma is more sensitive to proton radiation than is HPV-negative squamous cell carcinoma. Retrospective studies comparing intensity-modulated photon (X-ray) radiotherapy to IMPT for OPC suggest comparable rates of disease control and lower rates of pain, xerostomia, dysphagia, dysgeusia, gastrostomy tube dependence, and osteoradionecrosis with IMPT-all of which meaningfully affect the quality of life of patients treated for HPV-associated OPC. Two phase III trials currently underway-the "Randomized Trial of IMPT versus IMRT for the Treatment of Oropharyngeal Cancer of the Head and Neck" and the "TOxicity Reduction using Proton bEam therapy for Oropharyngeal cancer (TORPEdO)" trial-are expected to provide prospective, level I evidence regarding the effectiveness of IMPT for such patients.

Aims: Myocardial work is a novel echocardiographic algorithm that corrects speckle-tracking-derived global longitudinal strain (GLS) for afterload using non-invasive systolic blood pressure as a surrogate for left ventricular systolic pressure (LVSP). Yet, in patients with severe aortic stenosis, non-invasive systolic blood pressure does not equal LVSP., Methods and Results: We evaluated 35 patients with severe aortic stenosis who underwent transcatheter aortic valve replacement (TAVR). Transthoracic echocardiography, including myocardial mechanics, was performed pre- and post-TAVR. We performed simultaneous echocardiographic and cardiac catheterization measurements in 23 of the 35 patients at the time of TAVR. Peak and mean aortic gradients were calculated from echocardiographic and cardiac catheterization data. Peak-to-peak LV-aortic gradient correlated highly with mean LV-aortic gradient (r = 0.96); measured LVSP correlated highly with our novel method of non-invasively estimated LVSP (non-invasive systolic blood pressure cuff + Doppler-derived mean aortic gradient, r = 0.92). GLS improved from pre- to post-TAVR (-14.2% ± 4.3 vs. -15.1% ± 3.2), and myocardial work reduced from corrected pre-TAVR to post-TAVR (global work index: 1856.2 mmHg% ± 704.6 vs. 1534.8 ± 385.0)., Conclusion: We propose that non-invasive assessment of myocardial work can be reliably performed in aortic stenosis by the addition of mean aortic gradient to non-invasive systolic blood pressure. From this analysis, we note the novel and unique finding that GLS can improve as myocardial work reduces post-TAVR in patients with severe aortic stenosis. Both GLS and myocardial work post-TAVR remain below normal values, requiring further studies., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Objective: There is limited research comparing demographic and clinical characteristics between patients who present with atrial fibrillation (AF) and new-onset cardiomyopathy (CM) to patients with new-onset CM without dysrhythmia. We aimed to evaluate clinical characteristics and outcomes in patients with new-onset CM with and without AF and to report their real-world treatment., Methods and Results: The study population was identified using patient records from our healthcare system from January 1, 2012 to September 30, 2016. Patients with a left ventricular ejection fraction ≤40% without a prior history of CM were divided into two groups; those with an antecedent or concomitant diagnosis of AF (AF-CM group) and those with no history of dysrhythmia (CM group). Patients in the AF-CM group (n=196) were older, more likely to be male, had a higher burden of comorbidities but lower levels of cardiac biomarkers, and had lower voltage on surface electrocardiogram than the CM group (n=197). In AF-CM, symptom onset was insidious, leading to a higher likelihood of outpatient diagnosis; 88.3% of AF-CM patients presented with atypical symptoms of AF. The AF-CM group had higher mortality on follow-up. Only 8.7% of patients in this group underwent an ablation procedure. Women, those with a history of coronary artery disease, and older patients were less likely to receive a cardioversion or ablation procedure., Conclusions: Patients presenting with new-onset CM associated with AF have a markedly different risk factor and demographic profile, clinical presentation, and outcomes. In real-world practice, a minority of patients undergo a rhythm control strategy.

The COVID-19 pandemic led to a nationwide shutdown of elective medical procedures. Upon resumption of services, preprocedure nasopharyngeal swab testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was introduced for all patients requiring surgical or other aerosol-generating procedures. We investigated preprocedure COVID-19 testing in one of the largest U.S. health systems. Patients included in this retrospective, observational study were asymptomatic and scheduled for a procedure or surgery. All patients underwent a nasopharyngeal swab test for SARS-CoV-2 performed 24-72 hours prior to a planned procedure. Clinical demographics, type of procedure, test results, and subsequent procedure status were evaluated. Of 38,608 total patients, there were 277 COVID-19-positive patients (positivity rate: 0.72%). Of those 277, 244 (88%) had procedural delays or cancellations. Of the COVID-19-negative patients, 50 (0.13%) required later hospitalization for COVID-19. Median time from preprocedure negative test to admission was 46.3 ± 27.2 days. In the largest series published on preprocedure COVID-19 testing in the early phase of the pandemic, preprocedure COVID-19 positivity was low. Preprocedure COVID-19 testing had a significant impact on clinical management. Rate of COVID-19 cases requiring hospitalization in the months following the procedure was negligible, suggesting health system policies adequately protected patient safety., Competing Interests: Conflicts of Interest None., (© 2021 Aurora Health Care, Inc.)

Background: The prognostic performance of the recently updated American Joint Committee on Cancer lymph node classification of cutaneous head and neck squamous cell carcinoma (HNSCC) has not been validated. The objective of this study was to assess the prognostic role of extranodal extension (ENE) in cutaneous HNSCC., Methods: This was a retrospective analysis of 1258 patients with cutaneous HNSCC who underwent surgery with or without adjuvant therapy between 1995 and 2019 at The University of Texas MD Anderson Cancer Center. The primary outcome was disease-specific survival (DSS). Local, regional, and distant metastases-free survival were secondary outcomes. Recursive partitioning analysis (RPA) and a Cox proportional hazards regression model were used to assess the fitness of staging models., Results: No significant differences in 5-year DSS were observed between patients with pathologic lymph node-negative (pN0) disease (67.4%) and those with pN-positive/ENE-negative disease (68.2%; hazard ratio, 1.02; 95% CI, 0.61-1.79) or between patients with pN-positive/ENE-negative disease and those with pN-positive/ENE-positive disease (52.7%; hazard ratio, 0.57; 95% CI, 0.31-1.01). The RPA-derived model achieved better stratification between high-risk patients (category III, ENE-positive with >2 positive lymph nodes) and low-risk patients (category I, pN0; category II, ENE-positive/pN1 and ENE-negative with >2 positive lymph nodes). The performance of the RPA-derived model was better than that of the pathologic TNM classification (Akaike information criterion score, 1167 compared with 1176; Bayesian information criterion score, 1175 compared with 1195)., Conclusions: The number of metastatic lymph nodes and the presence of ENE are independent prognostic factors for DSS in cutaneous HNSCC, and incorporation of these factors in staging systems improves the performance of the American Joint Committee on Cancer lymph node classification., (© 2020 American Cancer Society.)

Objective: To assess the association between variant repeat (VR) interruptions in patients with myotonic dystrophy type 1 (DM1) and clinical symptoms and outcome measures after cognitive behavioral therapy (CBT) intervention., Methods: Adult patients with DM1 were recruited within the OPTIMISTIC trial (NCT02118779). Disease-related history, current clinical symptoms and comorbidities, functional assessments, and disease- and health-related questionnaires were obtained at baseline and after 5 and 10 months. After genetic analysis, we assessed the association between the presence of VR interruptions and clinical symptoms' long-term outcomes and compared the effects of CBT in patients with and without VR interruptions. Core trial outcome measures analyzed were: 6-minute walking test, DM1-Activ-C, Checklist Individual Strength Fatigue Score, Myotonic Dystrophy Health Index, McGill-Pain questionnaire, and Beck Depression inventory-fast screen. Blood samples for DNA testing were obtained at the baseline visit for determining CTG length and detection of VR interruptions., Results: VR interruptions were detectable in 21/250 patients (8.4%)-12 were assigned to the standard-of-care group (control group) and 9 to the CBT group. Patients with VR interruptions were significantly older when the first medical problem occurred and had a significantly shorter disease duration at baseline. We found a tendency toward a milder disease severity in patients with VR interruptions, especially in ventilation status, mobility, and cardiac symptoms. Changes in clinical outcome measures after CBT were not associated with the presence of VR interruptions., Conclusions: The presence of VR interruptions is associated with a later onset of the disease and a milder phenotype. However, based on the OPTIMISTIC trial data, the presence of VR interruptions was not associated with significant changes on outcome measures after CBT intervention., Trial Registration Information: ClinicalTrials.gov NCT02118779., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Patients who are surgically treated for stage I to III non-small cell lung cancer (NSCLC) have dismal prognosis after incomplete (R1-R2) resection. Our study aimed to develop a prediction model to estimate the chance of incomplete resection based on preoperative patient-, tumor-, and treatment-related factors., Methods: From a Dutch national cancer database, NSCLC patients who had surgical treatment without neoadjuvant therapy were selected. Thirteen possible predictors were analyzed. Multivariable logistic regression was used to create a prediction model. External validation was applied in the American National Cancer Database, whereupon the model was adjusted. Discriminatory ability and calibration of the model was determined after internal and external validation. The prediction model was presented as nomogram., Results: Of 7156 patients, 511 had an incomplete resection (7.1%). Independent predictors were histology, cT stage, cN stage, extent of surgery, and open vs thoracoscopic approach. After internal validation, the corrected C statistic of the resulting nomogram was 0.72. Application of the nomogram to an external data set of 85,235 patients with incomplete resection in 2485 patients (2.9%) resulted in a C statistic of 0.71. Calibration revealed good overall fit of the nomogram in both cohorts., Conclusions: An internationally validated nomogram is presented providing the ability to predict the individual chance of incomplete resection in patients with stage I to III NSCLC planned for resection. In case of a high predicted risk of incomplete resection, alternative treatment strategies could be considered, whereas a low risk further supports the use of surgical procedures., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) carries a favorable prognosis for patients, yet nearly 30% of patients will experience disease relapse. We sought to detail patterns of failure, associated salvage therapy, and outcomes for patients with recurrent HPV-positive OPSCC., Methods and Materials: This is a single institution retrospective study of patients with recurrent HPV-positive OPSCC irradiated from 2002 to 2014. The primary study outcome was overall survival (OS, calculated using the Kaplan-Meier method). Secondary aims included patterns of first failure with descriptive details of salvage therapy. Solitary recurrences were defined as initial presentation of recurrence in a single site (primary, neck or oligometastatic), and multi-site was defined as local and regional and/or multiple sites of distant recurrence. Survival outcomes were compared using the log-rank test., Results: The cohort consisted of 132 patients. The median follow-up was 59 months for surviving patients. Estimated 2-year and 5-year OS rates were 47% and 32%, respectively. Comparative 2-year and 5-year OS rates were 65% and 46% versus 19% and 9% for the solitary group and multi-site group, respectively (p < .001)., Conclusions: Patients with recurrent HPV-positive OPSCC experience 5-year survival of approximately 32%. However, patients with a "solitary" recurrence including disease at the primary site, neck or oligometastatic site have more favorable long-term outcomes., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The last revision of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual included a specific system for cutaneous squamous cell carcinoma (CSCC) of the head and neck. Here, we assessed the prognostic performance of six candidate modified T-classification models in head and neck CSCC patients., Methods: Analysis of 916 patients with head and neck CSCC given treatment with curative intent at The University of Texas MD Anderson Cancer Center between 1995 and 2019 was performed. The main outcome was disease-specific survival (DSS), and the impact of depth of invasion (DOI) was analyzed using multivariable regression models. Candidate models were developed using the optimal DOI cut points for each AJCC T classification based on goodness of fit of the model and the simplicity of the model. Staging systems were compared using Harrell's concordance index., Results: Median age was 70 years (range, 19-97years) and median follow-up time of 22 months (range, 1-250months). The median DOI was 6.0 mm (range, 0.1-70.0 mm). The five-year DSS rate was 80.7% (95%CI, 77.4-83.7%). We found significant association between DOI (hazard ratio, 1.21 [95%CI: 1.01-1.43]) and DSS on multivariable analysis. Based on a low Akaike information criterion score, improvement in the concordance index, and Kaplan-Meier curves, model 6 surpassed the AJCC staging system., Conclusions: Incorporation of DOI in the current AJCC staging system improves discrimination of T classifications in head and neck CSCC patients., Lay Summary: The current staging system for head and neck cutaneous squamous cell carcinoma demonstrates wide prognostic variability and provides suboptimal risk stratification. Incorporation of depth of invasion in the T-classification system improves risk prediction and patient counseling., Precis: We propose improved head and neck cutaneous squamous cell carcinoma T staging that will include depth of invasion and should be considered in future versions of the American Joint Committee on Cancer after external validation., Competing Interests: Conflict of interest statement The authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Approximately 70% of adults in Mexico are overweight or obese. Unhealthy lifestyle behaviors are also prevalent. We examined the association of three lifestyle behaviors with body mass index (BMI) categories in adults from Mexico., Methods: We used publicly available data from the ENSANUT 2016 survey (n = 6419). BMI was used to categorize participants. Differences in sleep duration, suffering from symptoms of insomnia, TV watching time, time in front of any screen, vigorous physical activity (yes vs no), moderate physical activity (> 30 min/day-yes vs. no) and walking (> 60 min/day-yes vs. no) were compared across BMI groups using adjusted linear and logistic regression analyses., Results: Thirty-nine percent of participants were overweight and 37% obese. Time in front of TV, in front of any screen, sleep duration and physical activity were significantly associated with overweight and obesity. Compared to normal weight participants, participants in the obese II category spend on average 0.60 h/day (95% CI 0.36-0.84, p = 0.001) and participants in the obese III category 0.54 h/day (95% CI 0.19-0.89, p < 0.001) more in front of any screen; participants in the obese II category reported 0.55 h/day less sleep (95% CI - 0.67 to - 0.43, p < 0.001); participants in the obese III category were less likely to engage in vigorous activity (OR = 0.60, 95% CI 0.43-0.84, p ≤ 0.003), or walking (OR = 0.65, 95% CI 0.49-0.88, p = 0.005)., Conclusion: Screen time, sleeping hours, and physical activity were associated with overweight and obesity. However, these associations were not consistent across all BMI categories. Assuming established causal connections, overweight individuals and individuals with obesity would benefit from reduced screen time and engaging in moderate/vigorous physical activity., Level of Evidence: Level III: observational case-control analytic study.

Purpose: Coronavirus disease 2019 (COVID-19) presents with a spectrum of disease severity, the most serious cases requiring intensive care. Echocardiography is a front-line tool in evaluating cardiovascular complications of COVID-19 in the intensive care unit (ICU); we analyzed transthoracic echocardiograms obtained from this patient population with state-of-the-art ultrasound technology., Methods: All patients with COVID-19 requiring ICU admission on whom a transthoracic echocardiogram was obtained were included in the study. Focused transthoracic protocols were performed by experienced sonographers. Echocardiographic variables, including speckle-tracking echocardiography, were collected and analyzed. Clinical information was obtained from the electronic medical record. Patients were followed until discharge., Results: Of 52 total patients (mean age: 59.9 ± 11.6 years), 59.6% were male and 15 (29%) had known prior cardiac disease. Cardiac complications identified on echocardiography were prevalent, occurring in 55.7% of patients. Patients with known prior cardiac disease were more likely to have new or worsening left ventricular dysfunction. Right ventricular dysfunction was the most common abnormality (assessed qualitatively in 18 cases and with advanced echocardiographic methods in 34 cases). Known prior cardiac disease, right ventricular enlargement, and pulmonary hypertension were significantly associated with morbidity and mortality., Conclusions: Patients requiring intensive care for COVID-19 face significant morbidity and mortality, and cardiac complications occur in the majority of patients admitted to the ICU with COVID-19. Those with known prior cardiac disease fare worse, and other echocardiographic findings (right ventricular enlargement, pulmonary hypertension) are also associated with worse outcomes. State-of-the-art echocardiography performed by experienced sonographers can be critical to identifying cardiac complications and guiding ICU strategy., Competing Interests: Conflicts of Interest None., (© 2021 Aurora Health Care, Inc.)

Purpose: To determine the optimal dose-volume constraint for laryngeal sparing using three commonly employed intensity modulated radiation therapy (IMRT) approaches in patients with oropharyngeal cancer treated to the bilateral neck., Materials and Methods: Thirty patients with stage II-IVA oropharynx cancers received definitive radiotherapy with split-field IMRT (SF-IMRT) to the bilateral neck between 2008 and 2013. Each case was re-planned using whole-field IMRT (WF-IMRT) and volumetric modulated arc therapy (VMAT) and plan quality metrics and dose to laryngeal structures was evaluated. Two larynx volumes were defined and compared on the current study: the Radiation Therapy Oncology Group (RTOG) larynx as defined per the RTOG 1016 protocol and the MDACC larynx defined as the components of the larynx bounded by the superior and inferior extent of the thyroid cartilage., Results: Target coverage, conformity, and heterogeneity indices were similar in all techniques. The RTOG larynx mean dose was lower with WF-IMRT than SF-IMRT (22.1 vs 25.8 Gy; P < 0.01). The MDACC larynx mean dose was 17.5 Gy ± 5.4 Gy with no differences between the 3 techniques. WF-IMRT and VMAT plans were associated with lower mean doses to the supraglottic larynx (42.1 vs 41.2 vs 54.8 Gy; P < 0.01) and esophagus (18.1 vs 18.2 vs 36 Gy; P < 0.01)., Conclusions: Modern whole field techniques can provide effective laryngeal sparing in patients receiving radiotherapy to the bilateral neck for advanced oropharyngeal cancers., Summary: We evaluated laryngeal dose in patients with locally advanced oropharyngeal cancer treated to the bilateral neck using split-field IMRT (SF-IMRT), whole-field IMRT (WF-IMRT) and volumetric arc therapy (VMAT). All three techniques provided good sparing of laryngeal structures and were able to achieve a mean larynx dose < 33 Gy. There were no significant differences in dose to target structures or non-laryngeal organs at risk among techniques., (© 2020 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

CT-guided treatment delivery can improve target localization in mediastinal lymphoma patients treated with "butterfly" intensity-modulated radiotherapy and deep-inspiration breath hold. Although daily CT imaging adds additional radiation exposure, its use may be justified given the greater normal tissue sparing enabled by PTV margin reduction., (Copyright © 2020. Published by Elsevier B.V.)

Background: Reirradiation of head and neck cancer is associated with high rates of locoregional failure and potentially severe treatment-related toxicity. We report our institutional experience of reirradiation using modern highly conformal radiotherapy approaches in patients with prior oropharyngeal radiation., Methods: We reviewed patients receiving curative-intent reirradiation with intensity-modulated radiation therapy, stereotactic body radiation therapy, and proton beam radiotherapy at our institution from 1999 to 2019. Disease control, survival, and toxicity rates following reirradiation were determined., Results: Sixty-nine patients were evaluated. Local control (LC), progression-free survival, and overall survival at 2 years following reirradiation were 77%, 35%, and 51%, respectively. Grade 3 or greater (G3+) late toxicities occurred in 46% of patients and 41% required feeding tube placement during or after reirradiation., Conclusions: In select patients with prior oropharyngeal radiation, highly conformal reirradiation offers acceptable LC, but G3+ toxicity and out-of-field failure rates remain high. These findings warrant continued evaluation of new multimodality approaches to improve oncologic outcomes., (© 2020 Wiley Periodicals LLC.)

Objectives: Patient preference studies are increasingly used to inform decision-making during the medical product lifecycle but are rarely used to inform early stages of drug development.  The primary aim of this study is to quantify treatment preferences of patients with neuromuscular disorders, which represent serious and debilitating conditions with limited or no treatment options available. Methods: This quantitative patient preferences study was designed as an online survey, with a cross-over design.  This study will target two different diseases from the neuromuscular disorders disease group, myotonic dystrophy type 1 (DM1) and mitochondrial myopathies (MM). Despite having different physio-pathological pathways both DM1 and MM manifest in a clinically similar manner and may benefit from similar treatment options.  The sample will be stratified into three subgroups: two patient groups differentiated by age of symptom onset and one caregivers group.   Each subgroup will be randomly assigned to complete two of three different preference elicitation methods at two different time points: Q-methodology survey, discrete choice experiment, and best-worst scaling type 2, allowing cross-comparisons of the results across each study time within participants and within elicitation methods. Additional variables such as sociodemographic, clinical and health literacy will be collected to enable analysis of potential heterogeneity. Ethics and Dissemination: This study protocol has undergone ethical review and approval by the Newcastle University R&D Ethics Committee (Ref: 15169/2018). All participants will be invited to give electronic informed consent to take part in the study prior accessing the online survey. All electronic data will be anonymised prior analysis. This study is part of the Patient Preferences in Benefit-Risk Assessments during the Drug Life Cycle (IMI-PREFER) project, a public-private collaborative research project aiming to develop expert and evidence-based recommendations on how and when patient preferences can be assessed and used to inform medical product decision making., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Jimenez-Moreno AC et al.)

Purpose: Here we provide an analysis of the set-up and positioning accuracy of SABR for skull base malignancies to evaluate the use of site- or axis-specific margins to reduce field size., Methods and Materials: Data were prospectively collected on 63 patients who received 304 fractions of SABR for recurrent/previously irradiated skull base tumors. Using our custom cushion-mask-bite-block immobilization system combined with ExacTrac x-ray and cone beam computed tomography (CBCT), set-up, residual, CBCT-positioning agreement, and intrafractional errors were measured. The resulting planning target volume (PTV) margins were estimated across 4 skull base subsites: anterior (group 1), central (group 2), posterolateral (group 3), and skull base-associated sites (eg, nasopharynx/retropharyngeal, cervical vertebrae 1-2, occiput) (group 4)., Results: On initial set-up, 66% of treatment courses required shifts of >2 mm or >2°, necessitating 4.9 mm PTV margins without image guidance. After correction, only 6 of 304 treatment sessions had residual errors >1 mm. CBCT-ExacTrac agreement was ≤1 mm in 89.1% of treatments and ≤1.5 mm in all but 1 session. Group 4 showed a higher rate of >1 mm or >1° CBCT-positioning differences compared with other groups (24.5% vs 7.8%; P = .0001), and the greatest variations occurred in the craniocaudal translational and the pitch rotational axes. Overall calculated PTV margins (based on intrafractional error) were 1.5 mm across subsites except for group 4, which required 2.0 mm margins., Conclusions: The use of 2.0 mm PTV margins for skull base SABR appears feasible using ExacTrac x-ray as the sole imaging modality for most subsites. However, PTVs were not uniformly equal, and the use of a site-specific nonuniform margin reduction to optimize critical-organ dose sparing may be feasible for select cases. These findings warrant clinical investigation., (Copyright © 2020. Published by Elsevier Inc.)

Objectives: Cancer treatment can present its own physical and mental challenges resulting in symptoms such as fatigue, stress, pain, nausea, and vomiting. Aurora Health Care is a large health system with 19 cancer centers. Integrative therapies such as acupuncture and massage have demonstrated success in reducing cancer-related symptoms and side effects to conventional cancer treatment and improving patient outcomes. In 2018, 15 of the 19 Aurora Cancer Clinics embedded a replicable Integrative Cancer Care closed model to provide adjuvant therapies for the best patient outcomes. This quality improvement study aimed to explore if the replicable integrative care model could demonstrate consistent outcomes for massage and acupuncture therapies aimed at symptom reduction across multiple oncology clinics. Design: Aurora Cancer Care and Aurora Integrative Medicine designed a reproducible integrative therapy service model to be embedded into the Aurora Cancer Centers. Integrative therapies within the cancer centers allow patients easy access to care before, during, or after their cancer treatment. In 2018, 15 of the 19 cancer clinics had integrative therapies available to patients with cancer. This model required unified operations, onboarding, training, competency, and clinical oversight to achieve consistent processes for consistent outcomes. Furthermore, these innovative models prioritized the following: patient access (easy and affordable); service delivery (consistent and operationalized); clinical outcomes (effective and meaningful); and caliber of clinician (competent and confident). Aurora Health Care employs massage therapists (Mts) and acupuncturists (Ats). This employment model allows for standards and program model adherence. To achieve competent and confident clinician's, MT or AT must complete a cancer treatment-focused competency training program relative to their respective profession and adherence to practice standards outlined. The training program is built on evidence-based practice, observation, direct demonstration, return demonstration, mentorship, and ongoing quality review by clinical leaders. Aurora's Integrative Cancer Care closed model of care is accessible to patients through philanthropic funds secured to underwrite the free service of MT provided during infusion treatments. Funds also provided three free AT sessions. Ongoing acupuncture therapies were provided at a low-cost group acupuncture fee at $25.00 per treatment. Acupuncture is available in group format and provided either before or after chemotherapy treatment. The free services were intended to introduce the concept of integrative therapies as a viable adjuvant option with conventional cancer care. As this model incorporates a mix of philanthropic funding and low-cost fees to offset the cost of the therapy provider, it is referred to as a "closed model" or accessible only to those patients under the care of an Aurora Cancer specialist. In 2018, 15 Aurora Cancer Clinics offered massage and 11 Aurora Cancer Clinics offered acupuncture. Patients who self-selected integrative therapies via system-employed Mts and Ats were surveyed pre/post acupuncture and MT treatments using a visual analog scale about their perceived levels of pain, stress, nausea, and neuropathy. The staff integrative clinicians collected data from patients, and post-treatment data were compiled by the Department of Integrative Medicine. Settings/Location: Aurora Cancer Centers are embedded within Aurora hospitals or free-standing clinics located throughout Wisconsin. In 2018, 15 cancer clinic locations embedded Mts, and 11 cancer clinic locations embedded Ats. Subjects: Oncology patients. Interventions: Clinical competencies were developed and applied to address indications, contraindications, and oncology-specific procedures to ensure that consistent quality of therapies was provided across sites. In 2018, Ats delivered 4367 Ats across 11 locations and Mts delivered 4197 Mts across 15 locations. During this study, the number of treatments provided was tracked versus episodic care. Outcome Measures: Pre/post AT and MT pain, stress, nausea, and neuropathy scores were recorded (0 [least] to 10 [worst]) and compared using paired t -tests. Results: Pre/post AT scores for pain, neuropathy, stress, and nausea were all significantly different ( p  < 0.001). For AT, there was a reported decrease in pain, stress, and neuropathy of 61.7%, 68.8%, and 47.9%, respectively. Pre/post MT scores for pain, neuropathy, nausea, and stress were also significantly different ( p  < 0.001). MT was greater at reducing stress and pain, 42.5% and 34.4%, respectively. Conclusions: Across 15 cancer clinics, both AT and MT treatments consistently and significantly reduced cancer-related side effects. These findings highlight the value of conducting a larger randomized-controlled trial to further assess the impact of Oncological Multisite Massage and Acupuncture Therapy on cancer-related symptoms across multiple oncologic clinics.

Importance: Malignant arrhythmic mitral valve prolapse (MVP) phenotype poses a substantial risk of sudden cardiac death (SCD), and an estimated 26 000 individuals in the United States are at risk of SCD per year. Thus, identifying risk-stratification strategies for SCD is imperative., Observations: Patients with MVP have a heterogenous clinical spectrum, ranging from a benign course to a devastating complication such as SCD. Some of the high-risk markers of MVP, which are identified electrocardiographically, include inverted or biphasic T waves, QT dispersion, QT prolongation, and premature ventricular contractions originating from the left ventricular outflow tract and papillary muscles. Morphofunctional characteristics of SCD are leaflet thickness of 5 mm or greater, mitral annulus disjunction, paradoxical systolic increase of the mitral annulus diameter, increased tissue Doppler velocity of the mitral annulus, and higher mechanical dispersion on echocardiography and fibrosis identified by late gadolinium enhancement on cardiac magnetic resonance imaging., Conclusions and Relevance: Findings from this review suggest that SCD can occur earlier in the course of MVP from complex arrhythmias that are triggered by the repeated tugging and traction of the chordopapillary muscle unit and basal mid-myocardium, even before macrofibrosis can be identified in these regions by late gadolinium enhancement on cardiac magnetic resonance imaging. Some of the newer markers identified by speckle-tracking Doppler, such as mechanical dispersion, myocardial work index, and postsystolic shortening, need further validation in a larger population.

Purpose: Intensity modulated radiation therapy delivered with deep-inspiration breath hold (IMRT-BH) provides favorable normal tissue dosimetric profiles when treating patients with mediastinal lymphoma. However, it is unclear if IMRT-BH plans are comparable to free breathing (FB) proton plans. We performed a retrospective, comparative dosimetric study between IMRT-BH and FB passive scatter proton therapy (P-FB) or intensity modulated proton therapy (IMPT-FB). Hypothesizing that BH would provide superior normal tissue sparing when added to proton therapy, we also compared plans to passive scatter BH (P-BH)., Methods and Materials: For 15 patients who received involved-site RT with "butterfly" IMRT-BH, 3 additional proton plans (P-FB, IMPT-FB, P-BH) were optimized to deliver 30.6 Gy/Gy relative biological effectiveness. Dosimetric variables (mean dose, V30, V25, V15, and V5) for organs at risk (OARs) were calculated and compared using nonparametric Wilcoxon signed-rank tests., Results: Of 57 studied OAR parameters, IMRT-BH plans were comparable in 37 (65%) parameters with P-FB plans, 32 (56%) of IMPT-FB parameters, and 30 (53%) of P-BH parameters. Doses to breasts were generally equivalent among plans while esophageal dosing was worse with IMRT-BH. Mean doses and V5 of the total lung and heart were the highest with IMRT-BH; however, IMRT-BH resulted in comparable coronary and superior lung V30 relative to proton plans. The addition of BH with proton therapy resulted in the greatest lung sparing, with mean lung dose reductions of 11% to 38%., Conclusions: The use of BH with IMRT reduces the disparity in OAR doses with equivalence achieved in nearly two-thirds of OAR metrics compared with P-FB and 50% compared with IMPT-BH. Because each modality exhibited unique benefits, personalization of modality selection is recommended. Proton therapy via BH provides additional benefits in heart and lung sparing., (© 2020 The Author(s).)

Introduction: Tongue-deviating oral stents (TDOS) are commonly used during unilateral neck radiation therapy to reduce unnecessary dose to nontarget oral structures. Their benefit in the setting of highly conformal treatment techniques, however, is not defined. The goal of this study was to investigate the potential benefit of TDOS use on dosimetric parameters in unilateral intensity modulated radiation therapy (IMRT) and intensity modulated proton therapy (IMPT)., Methods: A total of 16 patients with T1-2 tonsil cancer treated at a single institution were selected, of which 8 were simulated/treated with a TDOS and 8 without a TDOS. All received definitive unilateral IMRT to a dose of 66 Gy in 30 fx. IMPT plans were generated for each patient for study purposes and optimized according to standard institutional practice., Results: For IMRT plans, the presence of a TDOS (vs without) was associated with a significantly lower oral mucosa mean dose (31.4 vs 35.3 Gy; P = .020) and V30 (42.7% vs 57.1%; P = .025). For IMPT plans, the presence of TDOS (vs without) was not associated with any improvement in oral mucosa mean dose (18.3 vs 19.9 Gy; P = .274) or V30 (25.0% vs 26.2%; P = .655). IMPT plans without TDOS compared with IMRT plans with TDOS demonstrated reduced oral mucosa mean dose ( P < .001) and V30 ( P < .001)., Conclusion: The use of a TDOS for the unilateral treatment of well-lateralized tonsil cancers was associated with oral mucosa sparing for IMRT, but not for IMPT. Moreover, mucosa sparing was improved for IMPT plans without a TDOS compared to IMRT plans with a TDOS., (© 2020 The Author(s).)

Background and Purpose: With an enlarging population of long-term oropharyngeal cancer survivors, dysphagia is an increasingly important toxicity following oropharynx cancer treatment. While lower doses to normal surrounding structures may be achieved with intensity modulated proton therapy (IMPT) compared to photon-based radiation, the clinical benefit is uncertain., Methods and Materials: Seventy-one patients with stage III/IV oropharyngeal cancer (AJCC 7th edition) undergoing definitive IMPT on a longitudinal prospective cohort study who had completed the MD Anderson Dysphagia Inventory (MDADI) at pre-specified time points were included., Results: The majority of patients had HPV-positive tumors (85.9%) and received bilateral neck radiation (81.4%) with concurrent systemic therapy (61.8%). Mean composite MDADI scores decreased from 88.2 at baseline to 59.6 at treatment week 6, and then increased to 74.4 by follow up week 10, 77.0 by 6 months follow up, 80.5 by 12 months follow up, and 80.1 by 24 months follow up. At baseline, only 5.6% of patients recording a poor composite score (lower than 60), compared to 61.2% at treatment week 6, 19.1% at follow up week 10, 13.0% at 6 months follow up, 13.5% at 1 year follow up, and 11.1% at 2 years follow up., Conclusions: Patient reported outcomes following IMPT for oropharyngeal cancer demonstrates decreased swallowing function at completion of treatment with relatively rapid recovery by 10 weeks follow up and steady improvement through 2 years. The results are comparable to similar longitudinal studies of photon-based radiotherapy for oropharynx cancer, and suggest that IMPT confers no additional excess toxicity related to swallowing., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In treatment planning, multiple imaging modalities can be employed to improve the accuracy of tumor delineation but this can be costly. This study aimed to compare the interobserver consistency of using dual energy computed tomography (DECT) versus magnetic resonance imaging (MRI) for delineating tumors in the head and neck cancer (HNC) re-irradiation scenario. Twenty-three patients with recurrent HNC and had planning DECT and MRI were identified. Contoured tumor volumes by seven radiation oncologists were compared. Overall, T1c MRI performed the best with median DSC of 0.58 (0-0.91) for T1c. T1c MRI provided higher interobserver agreement for skull base sites and 60 kV DECT provided higher interobserver agreement for non-skull base sites., 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., (© 2020 Published by Elsevier B.V. on behalf of European Society of Radiotherapy & Oncology.)

In efforts to better characterize incidence and predictors of 30- and 90-day mortality following operative versus nonoperative approaches for locally advanced esophageal cancer (EC), we conducted a novel investigation of a large, contemporary US database. The National Cancer Database was queried for newly-diagnosed T1-3N0-1 squamous cell or adenocarcinoma receiving surgical-based therapy (esophagectomy alone or preceded by chemotherapy and/or radiotherapy) versus definitive chemoradiotherapy (dCRT). Statistics included graphing cumulative incidences of mortality before and following propensity score matching (PSM), based on age-based intervals. Cox regression determined factors independently predictive of 30- and 90-day mortality. Of 15,585 patients, 9,278 (59.5%) received surgical-based therapy and 6,307 (40.5%) underwent dCRT. In the unadjusted population, despite nonsignificant differences at 30 days (3.3% dCRT, 3.6% surgical-based), the dCRT cohort experienced higher 90-day mortality (11.0% vs. 7.5%, P < 0.001). Following PSM, however, dCRT patients experienced significantly lower 30-day mortality (P < 0.001), with nonsignificant differences at 90 days (P = 0.092). Surgical-based management yielded similar (or better) mortality as dCRT in ≤70-year-old patients; however, dCRT was associated with reduced mortality in subjects > 70 years old. In addition to the intervention group, factors predictive for 30- and 90-day mortality included age, gender, insurance status, facility type, comorbidity index, tumor location, histology, and T/N classification. In summary, surgical-based therapy for EC is associated with higher 30-day mortality, which becomes statistically similar to dCRT by 90 days. Differences between surgery and dCRT were most pronounced in patients > 70 years of age. These data may better inform shared decision-making between multidisciplinary providers and patients., (© The Author(s) 2019. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: A factor contributing to the value of patient preference studies is patient centricity. This study aimed to explore how patients want to be involved in the design and conduct of patient preference studies. In addition, we investigated patients' expectations regarding the communication of study results back to patients. Methods: Semi-structured interviews were conducted with patient representatives within three different disease areas: rheumatic diseases, cancer, and neuromuscular disorders. For each disease area, interviews were conducted with interviewees from Belgium, the Netherlands and the United Kingdom. Interviews followed a predefined interview guide covering topics relating to timing, level, and requirements for patient involvement in patient preference studies, as well as communication of results. Interviews were audio-recorded, transcribed and analyzed using framework analysis in NVivo 12. Results: A total of 14 interviews were conducted. Some interviewees believed that patients should be involved in all steps of a patient preference study. Patient involvement seemed most valuable during the design phase to support defining research questions and instrument design. During analysis, patients can be involved for optimal interpretation of results. Most interviewees mentioned that patient involvement should be on the level of advice or collaboration, not control. Interviewees expressed requirements for patient involvement relating to the knowledge of the involved patient, time investment, compensation and other incentives. Regarding communication of results, most interviewees wished to receive a brief and lay summary of the results, followed by a detailed explanation of both individual and average results accompanied by visuals. Conclusions: Patient involvement in patient preference studies could increase question comprehension by study participants and ensure correct interpretation of results by researchers. Patients want to be involved as advisors or collaborators, and considering their personal situation as well as establishing agreements on roles, time involvement and compensation early on will result in a most optimal partnership., (Copyright © 2020 van Overbeeke, Vanbinst, Jimenez-Moreno and Huys.)

Introduction: Stereotactic body radiotherapy (SBRT) results in excellent local control of stage I NSCLC. Radiobiology models predict greater tumor response when higher biologically effective doses (BED 10 ) are given. Prior studies support a BED 10 greater than or equal to 100 Gy with SBRT; however, data are limited comparing outcomes after various SBRT regimens. We therefore sought to evaluate national trends and the effect of using "low" versus "high" BED 10 SBRT courses on overall survival (OS)., Methods: This retrospective study used the National Cancer Data Base to identify patients diagnosed with clinical stage I (cT1-2aN0M0) NSCLC from 2004 to 2014 treated with SBRT. Patients were categorized into LowBED (100-129 Gy) or HighBED (≥130 Gy) groups. A 1:1 matched analysis based on patient and tumor characteristics was used to compare OS by BED 10 group. Tumor centrality was not assessed., Results: O 25,039 patients treated with LowBED (n = 14,756; 59%) or HighBED (n = 10,283; 41%) SBRT, 20,542 were matched. Shifts in HighBED to LowBED SBRT regimen use correlated with key publications in the literature. In the matched cohort, 5-year OS rates were 26% for LowBED and 34% for HighBED groups (p = 0.039). On multivariate analysis, receipt of LowBED was associated with significantly worse survival (hazard ratio = 1.046, 95% confidence interval: 1.004-1.090, p = 0.032)., Conclusions: LowBED SBRT for treating stage I NSCLC is becoming more common. However, our findings suggest SBRT regimens with BED 10 greater than or equal to 130 Gy may confer an additional survival benefit. Additional studies are required to evaluate the dose-response relationship and toxicities associated with modern HighBED SBRT., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Recurrent or previously irradiated head and neck cancers (HNC) are therapeutically challenging and may benefit from high-dose, highly accurate radiation techniques, such as stereotactic ablative radiation therapy (SABR). Here, we compare set-up and positioning accuracy across HNC subsites to further optimize the treatment process and planning target volume (PTV) margin recommendations for head and neck SABR., Methods and Materials: We prospectively collected data on 405 treatment fractions across 79 patients treated with SABR for recurrent/previously irradiated HNC. First, interfractional error was determined by comparing ExacTrac x-ray to the treatment plan. Patients were then shifted and residual error was measured with repeat x-ray. Next, cone beam computed tomography (CBCT) was compared with ExacTrac for positioning agreement, and final shifts were applied. Lastly, intrafractional error was measured with x-ray before each arc. Results were stratified by treatment site into skull base, neck/parotid, and mucosal., Results: Most patients (66.7%) were treated to 45 Gy in 5 fractions (range, 21-47.5 Gy in 3-5 fractions). The initial mean ± standard deviation interfractional errors were -0.2 ± 1.4 mm (anteroposterior), 0.2 ± 1.8 mm (craniocaudal), and -0.1 ± 1.7 mm (left-right). Interfractional 3-dimensional vector error was 2.48 ± 1.44, with skull base significantly lower than other sites (2.22 vs 2.77; P = .0016). All interfractional errors were corrected to within 1.3 mm and 1.8°. CBCT agreed with ExacTrac to within 3.6 mm and 3.4°. CBCT disagreements and intrafractional errors of >1 mm or >1° occurred at significantly lower rates in skull base sites (CBCT: 16.4% vs 50.0% neck, 52.0% mucosal, P < .0001; intrafractional: 22.0% vs 48.7% all others, P < .0001). Final PTVs were 1.5 mm (skull base), 2.0 mm (neck/parotid), and 1.8 mm (mucosal)., Conclusions: Head and neck SABR PTV margins should be optimized by target site. PTV margins of 1.5 to 2 mm may be sufficient in the skull base, whereas 2 to 2.5 mm may be necessary for neck and mucosal targets. When using ExacTrac, skull base sites show significantly fewer uncertainties throughout the treatment process, but neck/mucosal targets may require the addition of CBCT to account for positioning errors and internal organ motion., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose : Metaplastic breast cancer (BC) is an uncommon yet aggressive histologic subtype of BC. We sought to identify factors associated with its diagnosis and compare the management and outcomes of metaplastic BC with those of other BCs and triple negative invasive ductal carcinoma in particular given how often it has a triple negative phenotype. Patients and Methods : We identified women diagnosed with invasive BC in 2010-2014 in the National Cancer Data Base, and used univariate analysis to compare baseline patient and tumor characteristics by BC subtype. Overall survival (OS) was estimated with the Kaplan-Meier method, and multivariate Cox proportional hazards models were used to identify independent predictors of OS. Results : Of 247,355 cases, 2,084 (0.8%) were metaplastic BC, 55,998 (23%) triple negative BC, and 77% other BC. Relative to non-metaplastic BC, women with metaplastic BC were more likely to be older at diagnosis (median age, 62 vs. 59 years), have ≥1 comorbid conditions (22% vs. 18%), and be on Medicare (41% vs. 33%; P <0.001). Metaplastic BCs tended to be basal-like (77%), and relative to triple-negative or other BC, metaplastic BC was associated with higher clinical T status (cT3-4, 18% vs. 11%, 8%), no clinical nodal involvement (cN0, 86%, 77%, 80%), no lymphovascular invasion (72%, 65%, 62%), and high-grade tumors (71%, 77%, 35%) ( P <0.001). Most metaplastic BCs were treated with mastectomy (58%), sentinel lymph node dissection (65%), chest wall or breast irradiation (74%), and chemotherapy (75%) as adjuvant therapy (60%). At a median follow-up time of 44.5 months, OS rates were lower for metaplastic BC than for triple-negative or other BC across all clinical stages at 5 years (stage I, 85%, 87%, 91%; II, 73%, 77%, 87%; III, 43%, 53%, 75%) and at 3 years (Stage IV, 15%, 22%, 64%; P <0 . 001). On multivariate analysis, increasing age, advanced clinical stage, lymphovascular invasion, axillary (vs. sentinel) node dissection, and no radiation or chemotherapy were associated with worse outcomes in metaplastic BC. Extent of surgery affected survival for triple-negative and other BC but not for metaplastic BC. Conclusion : Outcomes for metaplastic BC continue to be worse than those for other BC subtypes despite modern treatments. Optimizing systemic therapy options, which was a significant predictor of survival, should be a priority in managing metaplastic BC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Accelerometers are accurate tools to assess movement and physical activity. However, interpreting standardly used outputs is not straightforward for populations with impaired mobility. Methods: The applicability of GENEActiv was explored in a group of 30 participants with myotonic dystrophy and compared to a group of 14 healthy-controls. All participants performed a set of tests while wearing four different accelerometers (wrists and ankles): [1] standing still; [2] ten-meters walk test; [3] six-minutes walking test; and, [4] ten-meters walk/run test. Results: Relevant findings were: [1] high intra-accelerometer reliability (i.e. 0.97 to 0.99; p  < 0.001); [2] each test acceleration values differ significantly between each other; [3] no inter-accelerometer reliability between wrist-worn devices and ankle-worn; and [4] a significant difference between the myotonic dystrophy group and the healthy-controls detectable at each test (i.e. Left-ankle values at six-minutes walking test: 48±17 for the myotonic dystrophy group, vs, 74±16 for the healthy-controls; p  < 0.001). Conclusions: GENEActiv demonstrated to be valid and reliable, capable of detecting walking periods and discriminating different speeds. However, inter-accelerometer reliability only applied when comparing opposite sides of the same limb. Specific movement characteristics of the myotonic dystrophy group were identified and muscle strength showed not to be a full determinant of limb acceleration.Implications for rehabilitationRehabilitation professionals in the field of neuromuscular disorders should be aware of the potential use of objective monitoring tools such as accelerometers whilst acknowledging the implications of assessing populations with altered movement patterns.Researchers should be cautious when translating accelerometry outputs previously validated in healthy populations to functionally impaired cohorts like myotonic dystrophy.Accelerometers can objectively expose movement disturbances allowing further investigations for the source of these disturbances.