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Background Psychiatric diagnosis and treatment have historically taken a symptom-based approach, with less attention on identifying underlying symptom-producing mechanisms. Recent efforts have illuminated the extent to which different underlying circuitry can produce phenotypically similar symptomatology (e.g., psychosis in bipolar disorder vs. schizophrenia). Computational modeling makes it possible to identify and mathematically differentiate behaviorally unobservable, specific reinforcement learning differences in patients with schizophrenia versus other disorders, likely owing to a higher reliance on prediction error–driven learning associated with basal ganglia and underreliance on explicit value representations associated with orbitofrontal cortex. Methods We used a well-established probabilistic reinforcement learning task to replicate those findings in individuals with schizophrenia both on (n = 120) and off (n = 44) antipsychotic medications and included a patient comparison group of bipolar patients with psychosis (n = 60) and healthy control subjects (n = 72). Results Using accuracy, there was a main effect of group (F3,279 = 7.87, p Conclusions Both medicated and unmedicated patients showed overreliance on prediction error–driven learning as well as significantly higher noise and value-related memory decay, compared with the healthy control subjects and the patients with bipolar disorder. Additionally, the computational model parameters capturing these processes can significantly improve patient/control classification, potentially providing useful diagnosis insight.

OBJECTIVE The Affordable Care Act mandates that primary preventive services have no out-of-pocket costs but does not exempt secondary prevention from out-of-pocket costs. Most commercially insured patients with diabetes have high-deductible health plans (HDHPs) that subject key microvascular disease–related services to high out-of-pocket costs. Brief treatment delays can significantly worsen microvascular disease outcomes. RESEARCH DESIGN AND METHODS This cohort study used a large national commercial (and Medicare Advantage) health insurance claims data set to examine matched groups before and after an insurance design change. The study group included 50,790 patients with diabetes who were continuously enrolled in low-deductible (≤$500) health plans during a baseline year, followed by up to 4 years in high-deductible (≥$1,000) plans after an employer-mandated switch. HDHPs had low out-of-pocket costs for nephropathy screening but not retinopathy screening. A matched control group included 335,178 patients with diabetes who were contemporaneously enrolled in low-deductible plans. Measures included time to first detected microvascular disease screening, severe microvascular disease diagnosis, vision loss diagnosis/treatment, and renal function loss diagnosis/treatment. RESULTS HDHP enrollment was associated with relative delays in retinopathy screening (0.7 months [95% CI 0.4, 1.0]), severe retinopathy diagnosis (2.9 months [0.5, 5.3]), and vision loss diagnosis/treatment (3.8 months [1.2, 6.3]). Nephropathy-associated measures did not change to a statistically significant degree among HDHP members relative to control subjects at follow-up. CONCLUSIONS People with diabetes in HDHPs experienced delayed retinopathy diagnosis and vision loss diagnosis/treatment of up to 3.8 months compared with low-deductible plan enrollees. Findings raise concerns about visual health among HDHP members and call attention to discrepancies in Affordable Care Act cost sharing exemptions.

INTRODUCTION Integrated quality improvement (QI) and cost reduction strategies can help increase value in cancer care. Time-driven activity-based costing (TDABC) is a bottom-up costing tool that measures resource use over the full care cycle. We applied standard QI and TDABC methods to improve workflow efficiency and reduce costs for MRI-guided prostate brachytherapy. METHODS AND MATERIALS We constructed process maps of the baseline prostate brachytherapy workflow from initial consultation through one year after treatment. Process maps reflected resources and time required at each step. TDABC costs were calculated by multiplying each process time by the cost per min of the resource(s) used at that step. We then used plan-do-study-act methodology to identify workflow inefficiencies and implement solutions to reduce resource consumption. RESULTS The highest cost components at baseline were the operating room (OR) (40%), imaging (8.7%), and consultation (7.6%). Higher-than-expected costs (3%) were incurred during surgery scheduling. After targeted QI initiatives, OR time was reduced from 90 to 70 min, which reduced overall cost by 5%. Personnel task downshifting reduced costs by 10% at consultation and 77% at surgery scheduling. Re-engineering of follow-up protocols reduced costs by 8.4%. Costs under the new workflow decreased by 18.2%. CONCLUSIONS TDABC complements traditional QI initiatives by quantifying the highest cost steps and focusing QI initiatives to reduce costs and improve efficiency. As payment reform evolves toward bundled payments, TDABC and QI initiatives will help providers understand, communicate, and improve the value of cancer care.

Purpose Brachytherapy is an essential technique to deliver radiation therapy and is involved in the treatment of multiple disease sites as monotherapy or as an adjunct to external beam radiation therapy. With a growing focus on the cost and value of cancer treatments as well new payment models, it is essential that standardized quality measures and metrics exist to allow for straightforward assessment of brachytherapy quality and for the development of clinically significant and relevant clinical data elements. We present the American Brachytherapy Society consensus statement on quality measures and metrics for brachytherapy as well as suggested clinical data elements. Methods and Materials Members of the American Brachytherapy Society with expertise in disease site specific brachytherapy created a consensus statement based on a literature review and clinical experience. Results Key quality measures (ex. workup, clinical indications), dosimetric metrics, and clinical data elements for brachytherapy were evaluated for each modality including breast cancer, cervical cancer, endometrial cancer, prostate cancer, keratinocyte carcinoma, soft tissue sarcoma, and uveal melanoma. Conclusions This consensus statement provides standardized quality measures and dosimetric quality metrics as well as clinical data elements for each disease site to allow for standardized assessments of brachytherapy quality. Moving forward, a similar paradigm can be considered for external beam radiation therapy as well, providing comprehensive radiation therapy quality measures, metrics, and clinical data elements that can be incorporated into new payment models.

Highlights • The PIRATES protocol is a novel tumor radiation dose-escalation approach. • PIRATES integrates proton therapy, image guided RT and hybrid hyper-fractionation. • It targets only head and neck cancer patients at high risk of treatment failure. • This Phase I trial aims to test the feasibility and safety of PIRATES., 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.

Background Fine-needle aspiration (FNA) is used to diagnose malignancies, recurrences, and metastases. The procedure is quick and well tolerated and can be facilitated by ultrasound guidance. Methods This article describes the authors' experience in using serial FNA to harvest cellular material during 4 clinical trials of immunotherapy by in situ vaccination in patients with low-grade lymphoma. Results Two hundred ninety-six FNA samples were collected from 44 patients over a span of approximately 6 weeks for each patient. Samples were sufficient in quantity and quality to be analyzed by flow cytometry and/or single-cell messenger RNA sequencing. FNA samples yielded an average of 12 × 106 cells with a mean cellular viability of 86%. Material collected from the tumor lymph nodes differed significantly in the proportions and phenotypes of cellular populations in comparison with matched peripheral blood samples. A comparison of flow cytometry results obtained by FNA directly from the patient and by FNA performed ex vivo and a dissociation of the same lymph node after surgical excision confirmed that FNA sampling of the patient accurately represented the tumor and the microenvironment. An analysis of the FNA samples from immunotherapy-treated target lymph nodes versus nodes from nontreated tumor sites provided insight into the impact of specific immunotherapy regimens. Conclusions This is the largest study describing the use of serial FNA sampling to harvest cellular material during immunotherapy clinical trials. The success of this technique opens the door for FNA sampling to expand significantly future investigations of the dynamic effects of investigational agents, be they immunotherapies or targeted therapies.

BACKGROUND No risk-stratification strategies exist for patients with recurrent oropharyngeal cancer (OPC). METHODS Retrospective analysis using data from prospective NRG Oncology clinical trials RTOG 0129 and 0522. Eligibility criteria included known p16 status and smoking history, and locoregional/distant recurrence. Overall survival (OS) was measured from date of recurrence. Recursive partitioning analysis was performed to produce mutually exclusive risk groups. RESULTS Hundred and fifty-four patients were included with median follow-up after recurrence of 3.9 years (range 0.04-9.0). The most important factors influencing survival were p16 status and type of recurrence, followed by surgical salvage and smoking history (≤20 vs. >20 pack-years). Three significantly different risk groups were identified. Patients in the low-, intermediate-, and high-risk groups had 2-year OS after recurrence of 81.1% (95%CI 68.5-93.7), 50.2% (95%CI 36.0-64.5), and 20.8% (95%CI 10.5-31.1), respectively. CONCLUSION Patient and tumor characteristics may be used to stratify patients into risk groups at the time of OPC recurrence.

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PURPOSE Although the majority of patients with relapsed or refractory large B-cell lymphoma respond to axicabtagene ciloleucel (axi-cel), only a minority of patients have durable remissions. This prospective multicenter study explored the prognostic value of circulating tumor DNA (ctDNA) before and after standard-of-care axi-cel for predicting patient outcomes. METHODS Lymphoma-specific variable, diversity, and joining gene segments (VDJ) clonotype ctDNA sequences were frequently monitored via next-generation sequencing from the time of starting lymphodepleting chemotherapy until progression or 1 year after axi-cel infusion. We assessed the prognostic value of ctDNA to predict outcomes and axi-cel–related toxicity. RESULTS A tumor clonotype was successfully detected in 69 of 72 (96%) enrolled patients. Higher pretreatment ctDNA concentrations were associated with progression after axi-cel infusion and developing cytokine release syndrome and/or immune effector cell–associated neurotoxicity syndrome. Twenty-three of 33 (70%) durably responding patients versus 4 of 31 (13%) progressing patients demonstrated nondetectable ctDNA 1 week after axi-cel infusion ( P < .0001). At day 28, patients with detectable ctDNA compared with those with undetectable ctDNA had a median progression-free survival and OS of 3 months versus not reached ( P < .0001) and 19 months versus not reached ( P = .0080), respectively. In patients with a radiographic partial response or stable disease on day 28, 1 of 10 patients with concurrently undetectable ctDNA relapsed; by contrast, 15 of 17 patients with concurrently detectable ctDNA relapsed ( P = .0001). ctDNA was detected at or before radiographic relapse in 29 of 30 (94%) patients. All durably responding patients had undetectable ctDNA at or before 3 months after axi-cel infusion. CONCLUSION Noninvasive ctDNA assessments can risk stratify and predict outcomes of patients undergoing axi-cel for the treatment of large B-cell lymphoma. These results provide a rationale for designing ctDNA-based risk-adaptive chimeric antigen receptor T-cell clinical trials.

BACKGROUND: Temporal lobe necrosis (TLN) is a potential late effect after radiotherapy for skull base head and neck cancer (HNC). Several photon-derived dose constraints and normal tissue complication probability (NTCP) models have been proposed, however variation in relative biological effectiveness (RBE) may challenge the applicability of these dose constraints and models in proton therapy. The purpose of this study was therefore to investigate the influence of RBE variations on risk estimates of TLN after Intensity Modulated Proton Therapy for HNC. MATERIAL AND METHODS: 75 temporal lobes from 45 previously treated patients were included in the analysis. Sixteen temporal lobes had radiation associated Magnetic Resonance image changes (TLIC) suspected to be early signs of TLN. Fixed (RWD(Fix)) and variable RBE-weighed doses (RWD(Var)) were calculated using RBE=1.1 and two RBE models, respectively. RWD(Fix) and RWD(Var) for temporal lobes were compared using Friedman’s test. Based on RWD(Fix), six NTCP models were fitted and internally validated through bootstrapping. Estimated probabilities from RWD(Fix) and RWD(Var) were compared using paired Wilcoxon test. Seven dose constraints were evaluated separately for RWD(Fix) and RWD(Var) by calculating the observed proportion of TLIC in temporal lobes meeting the specific dose constraints. RESULTS: RWD(Var) were significantly higher than RWD(Fix) (p

Background Immune checkpoint inhibitors (ICIs), such as programmed cell death 1 (PD-1) inhibitors, are used to treat multiple cancers. Limited data exist as to the use of ICIs in patients with coexistent interstitial lung disease (ILD). We conducted a retrospective case series to assess clinical and radiologic outcomes of patients with ILD treated with PD-1 inhibitors. Methods Eligible patients were 18 years of age or older, treated with pembrolizumab or nivolumab for oncologic indications, and had evidence of ILD on chest computed tomography scan not attributable to radiotherapy before initiation of ICI therapy. Outcomes of interest included mortality, hospitalizations for respiratory-related causes, development of pneumonitis, and radiologic change in ILD over a 1-year follow-up period. Results We included 41 patients in the analysis. At 1 year, 17 patients (41.5%) were alive, 23 had died (56.1%), and 1 (2.4%) was lost to follow-up. Of 23 deaths, 16 (69.6%) were due to cancer, 4 (17.4%) to causes excluding cancer and ILD, and 3 (13.0%) to hypoxemic respiratory failure from ILD- or ICI-induced pneumonitis. Three patients (7.3%) required hospitalization owing to ILD, including drug-induced pneumonitis, and 3 (7.3%) developed pneumonitis attributable to anti–PD-1 therapy. On follow-up computed tomography scans, 32 patients (78.0%) had stable or improved ILD and 9 (22.0%) had progression. Conclusion Patients with ILD receiving PD-1 inhibitors more frequently died of cancer-related causes than from ILD. Further research is needed to determine the safety of ICIs in patients with ILD and if ILD subtype may help to refine ICI-associated risks.

Monitoring of measurable residual disease (MRD) is essential to the management of acute lymphoblastic leukemia (ALL) and is typically performed through repeated bone marrow (BM) assessments. Using a next-generation sequencing (NGS) MRD platform, we performed a prospective observational study evaluating the correlation between peripheral blood (PB) and BM MRD in adults with ALL receiving cellular therapies (hematopoietic cell transplantation [HCT] and chimeric antigen receptor T-cell [CAR-T] therapies). Among the study cohort (N = 69 patients; 126 paired PB/BM samples), we found strong correlation between PB and BM MRD (r = 0.87; P < .001), with a sensitivity and specificity of MRD detection in the PB of 87% and 90%, respectively, relative to MRD in the BM. MRD became detectable in the PB in 100% of patients who subsequently relapsed following HCT, with median time from MRD+ to clinical relapse of 90 days, and in 85% of patients who relapsed following CAR T, with median time from MRD+ to clinical relapse of 60 days. In adult patients with ALL undergoing cellular therapies, we demonstrate strong concordance between NGS-based MRD detected in the PB and BM. Monitoring of ALL MRD in the PB appears to be an adequate alternative to frequent invasive BM evaluations in this clinical setting.

Background: Timely evaluation of acute chest pain is necessary, although most evaluations will not find significant coronary disease. With employers increasingly adopting high-deductible health plans (HDHP), how HDHPs impact subsequent care after an emergency department (ED) diagnosis of nonspecific chest pain is unclear. Methods: Using a commercial and Medicare Advantage claims database, we identified members 19 to 63 years old whose employers exclusively offered low-deductible (≤$500) plans in 1 year, then, at an index date, mandated enrollment in HDHPs (≥$1000) for a subsequent year. We matched them with contemporaneous members whose employers only offered low-deductible plans. Primary outcomes included population rates of index ED visits with a principal diagnosis of nonspecific chest pain, admission during index ED visits, and index ED visits followed by noninvasive cardiac testing within 3 and 30 days, coronary revascularization, and acute myocardial infarction hospitalization within 30 days. We performed a cumulative interrupted time-series analysis, comparing changes in annual outcomes between the HDHP and control groups before and after the index date using aggregate-level segmented regression. Members from higher-poverty neighborhoods were a subgroup of interest. Results: After matching, we included 557 501 members in the HDHP group and 5 861 990 in the control group, with mean ages of 42.0 years, 48% to 49% female, and 67% to 68% non-Hispanic White individuals. Employer-mandated HDHP switches were associated with a relative decrease of 4.3% (95% CI, –5.9 to –2.7; absolute change, –4.5 [95% CI, –6.3 to –2.8] per 10 000 person-years) in nonspecific chest pain ED visits and 11.3% (95% CI, –14.0 to –8.6) decrease (absolute change, –1.7 per 10 000 person-years [95% CI, –2.1 to –1.2]) in visits leading to hospitalization. There was no significant decrease in subsequent noninvasive testing or revascularization procedures. An increase in 30-day acute myocardial infarction admissions was not statistically significant (15.9% [95% CI, –1.0 to 32.7]; absolute change, 0.3 per 10 000 person-years [95% CI, –0.01 to 0.5]) but was significant among members from higher-poverty neighborhoods. Conclusions: Employer-mandated HDHP switches were associated with decreased nonspecific chest pain ED visits and hospitalization from these ED visits, but no significant change in post-ED cardiac testing. However, HDHP enrollment was associated with increased 30-day acute myocardial infarction admission after ED diagnosis of nonspecific chest pain among members from higher-poverty neighborhoods.

High-deductible health plans (HDHPs) require substantial out-of-pocket spending for most services, although medications may be subject to traditional copayment arrangements. This study examined effects of HDHPs on medication out-of-pocket spending and use and quality of care among individuals with bipolar disorder.This quasi-experimental study used claims data (2003-2014) for a national sample of 3,532 members with bipolar disorder, ages 12-64, continuously enrolled for 1 year in a low-deductible plan (≤$500) and then for 1 year in an HDHP (≥$1,000) after an employer-mandated switch. HDHP members were matched to 18,923 contemporaneous individuals in low-deductible plans (control group). Outcome measures were out-of-pocket spending and use of bipolar disorder medications, psychotropics for other disorders, and all other medications and appropriate laboratory monitoring for psychotropics.Relative to the control group, annual out-of-pocket spending per person for bipolar disorder medications increased 20.8% among HDHP members (95% confidence interval [CI]=14.9%-26.7%), and the absolute increase was $36 (95% CI=$25.9-$45.2). Specifically, out-of-pocket spending increased for antipsychotics (27.1%; 95% CI=17.4%-36.7%) and anticonvulsants (19.2%; 95% CI=11.9%-26.6%) but remained stable for lithium (-3.7%; 95% CI=-12.2% to 4.8%). No statistically significant changes were detected in use of bipolar disorder medications, other psychotropics, or all other medications or in appropriate laboratory monitoring for bipolar disorder medications.HDHP members with bipolar disorder experienced a moderate increase in out-of-pocket spending for medications but preserved bipolar disorder medication use. Findings may reflect individuals' perceptions of the importance of these medications for their functioning and well-being.

Item does not contain fulltext Dopamine contributes to cognitive control through well-established effects in both the striatum and cortex. Although earlier work suggests that dopamine affects cognitive control capacity, more recent work suggests that striatal dopamine may also impact on cognitive motivation. We consider the emerging perspective that striatal dopamine boosts control by making people more sensitive to the benefits versus the costs of cognitive effort, and we discuss how this sensitivity shapes competition between controlled and prepotent actions. We propose that dopamine signaling in distinct cortico-striatal subregions mediates different types of cost-benefit tradeoffs, and also discuss mechanisms for the local control of dopamine release, enabling selectivity among cortico-striatal circuits. In so doing, we show how this cost-benefit mosaic can reconcile seemingly conflicting findings about the impact of dopamine signaling on cognitive control.

Purpose The prevalence of poor mental health continues to rise among youth; however, large-scale interventions to improve mental and physical health remain a public health challenge. Time spent in nature is associated with improved health among youth. This study aimed to assess youth experiences with nature and the self-perceived impact on their mental and physical health among a nationwide sample of US youth. Methods In September 2020, five open-ended questions that aimed to assess perceptions regarding nature were posed to 1174 MyVoice youth, aged 14–24 years. Qualitative responses were analyzed using thematic analysis, and data were summarized using descriptive statistics. Results The mean (SD) age of the 994 respondents (RR = 84.7%) was 18.9 (2.7) years; 47.4% were female, and 57.4% Non-Hispanic White. Among youth, many felt that spending time in nature positively impacted their mental health, with 51.6% mentioning that it made them “feel calm when I am out in nature”; 22.1% said that it relieved stress or “reduces my anxiety,” and 17.1% felt that being in nature positively impacted their physical health and “makes me feel more active and in shape.” However, 7.0% said it negatively impacted their health, such as “It makes me feel isolated.” Most youth (87.8%) want to spend more time in nature, with 22% mentioning barriers (i.e., busy schedules, built environment, and COVID-19) impeding them from doing so. Conclusions Youth in our sample generally report feeling physically and mentally better when spending time in nature and want to spend more time in nature. Public health policies and practices that eliminate barriers and actively support time spent outside may be a feasible and acceptable practice to promote overall well-being among youth.

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.

Highlights • Head and neck cancers radiotherapy (RT) leads to inevitable injury to parotid glands. • We sought to quantify delta-changes of 18FDG-PET metrics in these parotid glands. • Parotid PET delta-changes and clinical variables could predict xerostomia severity., Purpose Head and neck cancers radiotherapy (RT) is associated with inevitable injury to parotid glands and subsequent xerostomia. We investigated the utility of SUV derived from 18FDG-PET to develop metabolic imaging biomarkers (MIBs) of RT-related parotid injury. Methods Data for oropharyngeal cancer (OPC) patients treated with RT at our institution between 2005 and 2015 with available planning computed tomography (CT), dose grid, pre- & first post-RT 18FDG-PET-CT scans, and physician-reported xerostomia assessment at 3–6 months post-RT (Xero 3–6 ms) per CTCAE, was retrieved, following an IRB approval. A CT-CT deformable image co-registration followed by voxel-by-voxel resampling of pre & post-RT 18FDG activity and dose grid were performed. Ipsilateral (Ipsi) and contralateral (contra) parotid glands were sub-segmented based on the received dose in 5 Gy increments, i.e. 0–5 Gy, 5–10 Gy sub-volumes, etc. Median and dose-weighted SUV were extracted from whole parotid volumes and sub-volumes on pre- & post-RT PET scans, using in-house code that runs on MATLAB. Wilcoxon signed-rank and Kruskal-Wallis tests were used to test differences pre- and post-RT. Results 432 parotid glands, belonging to 108 OPC patients treated with RT, were sub-segmented & analyzed. Xero 3–6 ms was reported as: non-severe (78.7%) and severe (21.3%). SUV- median values were significantly reduced post-RT, irrespective of laterality (p = 0.02). A similar pattern was observed in parotid sub-volumes, especially ipsi parotid gland sub-volumes receiving doses 10–50 Gy (p

OBJECTIVE: To compare acute care utilization and costs following sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). SUMMARY BACKGROUND DATA: Comparing post-bariatric emergency department (ED) and inpatient care use patterns could assist with procedure choice and provide insights about complication risk. METHODS: We used a national insurance claims database to identify adults undergoing SG and RYGB between 2008 and 2016. Patients were matched on age, gender, calendar-time, diabetes, and baseline acute care use. We used adjusted Cox proportional hazards to compare acute care utilization and two-part logistic regression models to compare annual associated costs (odds of any cost, and odds of high costs, defined as ≥80(th) percentile), between SG and RYGB, overall and within several clinical categories. RESULTS: The matched cohort included 4263 SG and 4520 RYGB patients. Up to 4 years after surgery, SG patients had slightly lower risk of ED visits (aHR: 0.90; 95% CI: 0.85,0.96) and inpatient stays (aHR: 0.80; 95% CI: 0.73,0.88), especially for events associated with digestive-system diagnoses (ED aHR: 0.68; 95% CI:0.62,0.75; inpatient aHR: 0.61; 95% CI: 0.53,0.72). SG patients also had lower odds of high ED and high total acute costs (e.g., year-1 acute costs aOR 0.77; 95% CI: 0.66,0.90) in early follow-up. However, observed cost differences decreased by years 3 and 4 (e.g., year-4 acute care costs aOR 1.10; 95% CI: 0.92,1.31). CONCLUSIONS: SG may have fewer complications requiring emergency care and hospitalization, especially as related to digestive system disease. However, any acute care cost advantages of SG may wane over time.

BACKGROUND AND PURPOSE: Sarcopenia is associated with decreased survival in head and neck cancer patients treated with radiotherapy. This study sought to determine whether in-clinic multifrequency bioelectrical impedance analysis (BIA) can identify survival-associated sarcopenia in patients with head and neck cancer. MATERIALS AND METHODS: This prospective observational study enrolled 50 patients with head and neck cancer undergoing radiation therapy. Baseline BIA measures of skeletal muscle (SM) mass, fat-free mass (FFM), and fat mass (FM) were compared to CT-based estimates using linear regression. Sex-specific BIA-derived thresholds for sarcopenia were defined by the maximum Youden Index on receiver operator characteristic (ROC) curves. Patients were stratified by sarcopenia status and OS was compared using the Kaplan-Meier method and log-rank test. RESULTS: Among 48 evaluable patients, BIA measures of body composition were strongly correlated with CT measures: SM mass (r = 0.97; R(2) = 0.94; p < 0.0001), FFM (r = 0.97; R(2) = 0.94; p < 0.0001) and FM (r = 0.95; R(2) = 0.90; p < 0.0001). SM mass index < 9.19 kg/m(2) identified sarcopenia men with high sensitivity (91.7%) and specificity (92.9%), whereas in women SM mass index < 6.53 kg/m(2) was sensitive for sarcopenia (100%), but not specific. Patients with sarcopenia, defined by either CT or BIA, exhibited decreased OS (HR=not estimable; CT p = 0.009; BIA p = 0.03). CONCLUSION: BIA provides accurate estimates of body composition in head and neck cancer patients. Implementation of BIA in clinical practice may identify patients with sarcopenia at risk for poor survival.

Head and neck squamous cell carcinomas (HNSCCs) often present as local-regionally advanced disease at diagnosis, for which a current standard of care is x-ray–based radiation therapy, with or without chemotherapy. This approach provides effective local regional tumor control, but at the cost of acute and late toxicity that can worsen quality of life and contribute to mortality. For patients with human papillomavirus (HPV)–associated oropharyngeal squamous cell carcinoma (SCC) in particular, for whom the prognosis is generally favorable, de-escalation of the radiation dose to surrounding normal tissues without diminishing the radiation dose to tumors is desired to mitigate radiation-related toxic effects. Proton radiation therapy (PRT) may be an excellent de-escalation strategy because of its physical properties (that eliminate unnecessary radiation to surrounding tissues) and because of its biological properties (including tumor-specific variations in relative biological effectiveness [RBE] and linear energy transfer [LET]), in combination with concurrent systemic therapy. Early clinical evidence has shown that compared with x-ray–based radiation therapy, PRT offers comparable disease control with fewer and less severe treatment-related toxicities that can worsen the quality of life for patients with HNSCC. Herein, we review aspects of the biological basis of enhanced HNSCC cell response to proton versus x-ray irradiation in terms of radiation-induced gene and protein expression, DNA damage and repair, cell death, tumor immune responses, and radiosensitization of tumors.

Cancer-related financial toxicity impacts head and neck cancer patients and survivors. With increasing use of proton therapy as a curative treatment for head and neck cancer, the multifaceted financial and economic implications of proton therapy—dimensions of “financial toxicity”—need to be addressed. Herein, we identify knowledge gaps and potential solutions related to the problem of financial toxicity. To date, while cost-effectiveness analysis has been used to assess the value of proton therapy for head and neck cancer, it may not fully incorporate empiric comparisons of patients' and survivors' lost productivity and disability after treatment. A cost-of-illness framework for evaluation could address this gap, thereby more comprehensively identifying the value of proton therapy and distinctly incorporating a measurable aspect of financial toxicity in evaluation. Overall, financial toxicity burdens remain understudied in head and neck cancer patients from a patient-centered perspective. Systematic, validated, and accurate measurement of financial toxicity in patients receiving proton therapy is needed, especially relative to conventional photon-based strategies. This will enrich the evidence base for optimal selection and rationale for payer coverage of available treatment options for head and neck cancer patients. In the setting of cancer care delivery, a combination of conducting proactive screening for financial toxicity in patients selected for proton therapy, initiating early financial navigation in vulnerable patients, engaging stakeholders, improving oncology provider team cost communication, expanding policies to promote price transparency, and expanding insurance coverage for proton therapy are critical practices to mitigate financial toxicity in head and neck cancer patients.

Purpose To report clinical outcomes in terms of disease control and toxicity in patients with major salivary gland cancers (SGCs) treated with proton beam therapy. Materials and Methods Clinical and dosimetric characteristics of patients with SGCs treated from August 2011 to February 2020 on an observational, prospective, single-institution protocol were abstracted. Local control and overall survival were calculated by the Kaplan-Meier method. During radiation, weekly assessments of toxicity were obtained, and for patients with ≥ 90 days of follow-up, late toxicity was assessed. Results Seventy-two patients were identified. Median age was 54 years (range, 23-87 years). Sixty-three patients (88%) received postoperative therapy, and nine patients (12%) were treated definitively. Twenty-six patients (36%) received concurrent chemotherapy. Nine patients (12%) had received prior radiation. All (99%) but one patient received unilateral treatment with a median dose of 64 GyRBE (relative biological effectiveness) (interquartile range [IQR], 60-66), and 53 patients (74%) received intensity-modulated proton therapy with either single-field or multifield optimization. The median follow-up time was 30 months. Two-year local control and overall survival rates were 96% (95% confidence interval [CI] 85%-99%) and 89% (95% CI 76%-95%], respectively. Radiation dermatitis was the predominant grade-3 toxicity (seen in 21% [n = 15] of the patients), and grade ≥ 2 mucositis was rare (14%; n = 10 patients). No late-grade ≥ 3 toxicities were reported. Conclusion Proton beam therapy for treatment of major SGCs manifests in low rates of acute mucosal toxicity. In addition, the current data suggest a high rate of local control and minimal late toxicity.

Purpose To report patient-reported outcomes (PROs) derived from the Functional Assessment of Cancer Therapy-Head and Neck (FACT-HN) tool, in patients with oropharynx cancer (OPC) treated with intensity-modulated proton therapy (IMPT) in the context of first-course irradiation. Materials and Methods Patients with locally advanced OPC treated with radical IMPT between 2011 and 2018 were included in a prospective registry. FACT-HN scores were measured serially during and 24 months following IMPT. PRO changes in the FACT-HN scores over time were assessed with mixed-model analysis. Results Fifty-seven patients met inclusion criteria. Median age was 60 years (range, 41-84), and 91% had human papillomavirus-associated disease. In total, 28% received induction chemotherapy and 68% had concurrent chemotherapy. Compliance to FACT-HN questionnaire completion was 59%, 48%, and 42% at 6, 12, and 24 months after treatment, respectively. The mean FACT-General (G), FACT-Total, and FACT-Trial Outcome Index (TOI) score changes were statistically and clinically significant relative to baseline from week 3 of treatment up to week 2 after treatment. Nadir was reached at week 6 of treatment for all scores, with maximum scores dropping by 15%, 20%, and 39% compared to baseline for FACT-G, FACT-Total, and FACT-TOI, respectively. Subdomain scores of physical well-being, functional well-being, and head and neck additional concerns decreased from baseline during treatment and returned to baseline at week 4 after treatment. Conclusions IMPT was associated with a favorable PRO trajectory, characterized by an acute decline followed by rapid recovery to baseline. This study establishes the expected acute, subacute, and chronic trajectory of PROs for patients undergoing IMPT for OPC.

Background There remains no tool to quantify the total value of comparative processes in health care. Hospital administrative data sets are emerging as valuable sources to evaluate performance. Thus, we use a framework to simultaneously assess multiple domains of value associated with an enhanced recovery initiative using national administrative data. Materials and methods Risk-stratified clinical pathways for patients undergoing pancreatic surgery were implemented in 2016 at our institution. We used a national administrative database to characterize changes in value associated with this initiative. Value metrics assessed included in-hospital mortality, complication rates, length of stay (LOS), 30-day readmission rates, and institutional costs. We compared our performance with other hospitals both before and after implementation of the pathways. Metrics were graphed on radar charts to assess overall value. Results 22,660 cases were assessed. Comparing 75 cases at our institution and 5520 cases at all other hospitals before pathway implementation, mean in-hospital LOS was 9.6 versus 10.8 d, in-hospital mortality was 0.0% versus 1.9%, mean costs were $23,585 versus $21,387, 30-day readmission rates were 1.3% versus 7.4%, and complication rates were 8.0% versus 11.2%, respectively. Comparing 334 cases at our institution and 16,731 cases at all other hospitals after pathway implementation, mean in-hospital LOS was 7.7 versus 10.3 d, in-hospital mortality was 0.3% versus 1.6%, mean costs were $19,428 versus $22,032, 30-day readmission rates were 6.6% versus 7.5%, and complication rates were 6.3% versus 10.3%, respectively. Notably, LOS and institutional costs were reduced at our institution after implementation of the enhanced clinical care pathways. Our costs were higher than comparators before implementation, but lower than comparators after implementation. Conclusions Herein, we used an analytic framework and used national administrative data to assess the value of an enhanced care initiative as benchmarked with data from other hospitals. We thus illustrate how to identify and measure opportunities for targeted improvements in health care delivery. We also recognize the limitations of the use of administrative data in a comprehensive assessment of value in health care.

Purpose We compared work outcomes in patients with oropharyngeal cancer (OPC), randomized to intensity-modulated proton (IMPT) versus intensity-modulated photon therapy (IMRT) for chemoradiation therapy (CRT). Patients and Methods In 147 patients with stage II-IVB squamous cell OPC participating in patient-reported outcomes assessments, a prespecified secondary aim of a randomized phase II/III trial of IMPT (n = 69) versus IMRT (n = 78), we compared absenteeism, presenteeism (i.e., the extent to which an employee is not fully functional at work), and work productivity losses. We used the work productivity and activity impairment questionnaire at baseline (pre-CRT), at the end of CRT, and at 6 months, 1 year, and 2 years. A one-sided Cochran-Armitage test was used to analyze within-arm temporal trends, and a χ2 test was used to compare between-arm differences. Among working patients, at each follow-up point, a 1-sided Wilcoxon rank-sum test was used to compare work-productivity scores. Results Patient characteristics in IMPT versus IMRT arms were similar. In the IMPT arm, within-arm analysis demonstrated that an increasing proportion of patients resumed working after IMPT, from 60% (40 of 67) pre-CRT and 71% (30 of 42) at 1 year to 78% (18 of 23) at 2 years (P = 0.025). In the IMRT arm, the proportion remained stable, with 57% (43 of 76) pre-CRT, 54% (21 of 39) at 1 year, and 52% (13 of 25) working at 2 years (P = 0.47). By 2 years after CRT, the between-arm difference between patients who had IMPT and those who had IMRT trended toward significance (P = 0.06). Regardless of treatment arm, among working patients, the most severe work impairments occurred from treatment initiation to the end of CRT, with significant recovery from absenteeism, presenteeism, and productivity impairments by the 2-year follow-up (P Conclusion In patients with OPC receiving curative CRT, patients randomized to IMPT demonstrated increasing work and productivity recovery trends. Studies are needed to identify mechanisms underlying head and neck CRT treatment causing work disability and impairment.

In most childhood head and neck cancers, radiotherapy is an essential component of treatment; however, it can be associated with problematic long-term complications. Proton beam therapy is accepted as a preferred radiation modality in pediatric cancers to minimize the late radiation side effects. Given that childhood cancers are a rare and heterogeneous disease, the support for proton therapy comes from risk modeling and a limited number of cohort series. Here, we discuss the role of proton radiotherapy in pediatric head and neck cancers with a focus on reducing radiation toxicities. First, we compare the efficacy and expected toxicities in proton and photon radiotherapy for childhood cancers. Second, we review the benefit of proton radiotherapy in reducing acute and late radiation toxicities, including risks for secondary cancers, craniofacial development, vision, and cognition. Finally, we review the cost effectiveness for proton radiotherapy in pediatric head and neck cancers. This review highlights the benefits of particle radiotherapy for pediatric head and neck cancers to improve the quality of life in cancer survivors, to reduce radiation morbidities, and to maximize efficient health care use.

Purpose In value-based health care delivery, radiation oncologists need to compare empiric costs of care delivery with advanced technologies, such as intensity-modulated proton therapy (IMPT) and intensity-modulated radiation therapy (IMRT). We used time-driven activity-based costing (TDABC) to compare the costs of delivering IMPT and IMRT in a case-matched pilot study of patients with newly diagnosed oropharyngeal (OPC) cancer. Materials and Methods We used clinicopathologic factors to match 25 patients with OPC who received IMPT in 2011-12 with 25 patients with OPC treated with IMRT in 2000-09. Process maps were created for each multidisciplinary clinical activity (including chemotherapy and ancillary services) from initial consultation through 1 month of follow-up. Resource costs and times were determined for each activity. Each patient-specific activity was linked with a process map and TDABC over the full cycle of care. All calculated costs were normalized to the lowest-cost IMRT patient. Results TDABC costs for IMRT were 1.00 to 3.33 times that of the lowest-cost IMRT patient (mean ± SD: 1.65 ± 0.56), while costs for IMPT were 1.88 to 4.32 times that of the lowest-cost IMRT patient (2.58 ± 0.39) (P Conclusions In this matched sample, although IMPT was on average more costly than IMRT primarily owing to higher equipment costs, a subset of IMRT patients had similar costs to IMPT patients, owing to greater use of supportive care resources. Multidimensional patient outcomes and TDABC provide vital methodology for defining the value of radiation therapy modalities.

Purpose: Radiation therapy is a standard modality in the treatment for cancers of the head and neck, but is associated with significant short- and long-term side effects. Proton therapy, with its unique physical characteristics, can deliver less dose to normal tissues, resulting in fewer side effects. Proton therapy is currently being used for the treatment of head and neck cancer, with increasing clinical evidence supporting its use. However, barriers to wider adoption include access, cost, and the need for higher-level evidence. Methods: The clinical evidence for the use of proton therapy in the treatment of head and neck cancer are reviewed here, including indications, advantages, and challenges. Results: The Particle Therapy Cooperative Group Head and Neck Subcommittee task group provides consensus guidelines for the use of proton therapy for head and neck cancer. Conclusion: This report can be used as a guide for clinical use, to understand clinical trials, and to inform future research efforts.

Despite advances in surgery, chemotherapy, and radiation, there are limited treatment options for advanced head and neck squamous cell carcinoma (HNSCC) and survival remains very poor. Therefore, effective therapies are desperately needed. Recently, selective exploitation of DNA damage and replication stress responses has become a novel approach for cancer treatment. Wee1 kinase and Rad51 recombinase are two proteins involved in regulating replication stress and homologous recombination repair in cancer cells. In this study, we investigated the combined effect of Rad51 inhibitor (B02) and Wee1 inhibitor (AZD1775) in vitro and in vivo in various HNSCC cell lines. Clonogenic survival assays demonstrated that B02 synergized with AZD1775 in vitro in all HNSCC cell lines tested. The synergy between these drugs was associated with forced CDK1 activation and reduced Chk1 phosphorylation leading to induction of excessive DNA damage and replication stress, culminating in aberrant mitosis and apoptosis. Our results showed that elevated Rad51 mRNA expression correlated with worse survival in HNSCC patients with HPV-positive tumors. The combination of B02 and AZD1775 significantly inhibited tumor growth in vivo in mice bearing HPV-positive HNSCC tumors as compared to HPV-negative HNSCC. This differential sensitivity appears to be linked to HPV-positive tumors having more in vivo endogenous replication stress owing to transformation by E6 and E7 oncogenes. Furthermore, addition of B02 radiosensitized the HPV-negative HNSCC tumors in vitro and in vivo. In conclusion, our data implicate that a novel rational combination with Rad51 and Wee1 inhibitors holds promise as synthetic lethal therapy, particularly in high-risk HPV-positive HNSCC.

Purpose Little is known about the views of U.S. youth on COVID-19 or their use of face coverings. Closing this gap could facilitate messaging to promote COVID-19 risk mitigation behaviors. Methods In July 2020, a five-question text message survey was sent to 1,087 youth aged 14–24 years. Questions assessed youths' perceptions regarding the likelihood of contracting COVID-19, the potential impact of contracting COVID-19 on their lives, the possibility of spreading COVID-19 to others, and their use of face coverings around others with whom they do not live. Coding was conducted to assign responses to discrete categories and to identify common themes. Results Of 1,087 eligible participants, 797 (73.3%) were included in analyses. Of these participants, 27.3% believed they would likely contract COVID-19 in the next few months, 90.3% believed contracting COVID-19 would have a moderate or significant impact on their lives, 86.0% were moderately or very concerned about spreading COVID-19, and 89.2% reported wearing face coverings all or most of the time. Factors affecting face covering use included the desire to avoid contracting and spreading COVID-19, peer influence, and policy mandates. Conclusions Youths' perceptions regarding the risk of contracting COVID-19 varied, but most believed their lives would be adversely impacted if this occurred. Most youth were concerned about spreading COVID-19 and wore face coverings, but many made exceptions to face covering use when around close contacts. Public health campaigns may be most effective if they leverage positive peer influence and appeal to youths' desire not to spread COVID-19 to others.

The prognosis of patients with large B-cell lymphoma (LBCL) that progresses after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first 3 consecutive patients with autologous CAR19-refractory LBCL who were treated with a single infusion of autologous 1 × 106 CAR+ T cells per kilogram targeting CD22 (CAR22) as part of a phase 1 dose-escalation study. CAR22 therapy was relatively well tolerated, without any observed nonhematologic adverse events higher than grade 2. After infusion, all 3 patients achieved complete remission, with all responses continuing at the time of last follow-up (mean, 7.8 months; range, 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range, 85.4-350 cells per microliter), and persisted beyond 3 months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA beyond 6 months after infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients in whom prior CAR T-cell therapies have failed. This trial is registered on clinicaltrials.gov as #NCT04088890.

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.

Background: Cost-sharing disproportionately affects people with chronic illnesses needing more care. Our qualitative study examined lived experiences navigating insurance benefits and treatment for bipolar disorder, which requires ongoing access to behavioral specialists and psychotropic medications. Methods: Forty semi-structured telephone interviews with individuals with bipolar disorder and employer-sponsored health insurance, or their family caregivers, explored health care needs, coverage details, out-of-pocket (OOP) costs, and perspectives on value. An iterative analytic approach identified salient themes. Results: Most individuals in our sample faced an annual insurance deductible, from $350-$10,000. OOP costs for specialist visits ranged from $0-$450 and for monthly psychotropic medications from $0-$1650. Acute episodes and care for comorbidities, including medication side effects, added to cost burdens. Medication nonadherence due to OOP costs was rare; respondents frequently pointed to the necessity of medications: “whatever it takes to get those”; “it's a life or death situation.” Respondents also prioritized visits to psychiatrist prescribers, though visits were maximally spaced because of cost. Psychotherapy was often deemed unaffordable and forgone, despite perceived need. Interviewees cited limited networks and high out-of-network costs as barriers to specialists. Cost-sharing sometimes led to debt, skimping on nonbehavioral care or other necessities, exacerbated or prolonged mood symptoms, and stress at home. Limitations: Volunteer respondents may not fully represent the target population. Conclusions: Many people with bipolar disorder in US employer-sponsored plans experience undertreatment, hardship, and adverse health consequences due to high cost-sharing. More nuanced insurance benefit designs should accommodate the needs of individuals with complex conditions.

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has significantly improved outcomes in the treatment of refractory or relapsed large B-cell lymphoma (LBCL). We evaluated the long-term course of hematologic recovery, immune reconstitution, and infectious complications in 41 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) at a single center. Grade 3+ cytopenias occurred in 97.6% of patients within the first 28 days postinfusion, with most resolved by 6 months. Overall, 63.4% of patients received a red blood cell transfusion, 34.1% of patients received a platelet transfusion, 36.6% of patients received IV immunoglobulin, and 51.2% of patients received growth factor (granulocyte colony-stimulating factor) injections beyond the first 28 days postinfusion. Only 40% of patients had recovered detectable CD19+ B cells by 1 year, and 50% of patients had a CD4+ T-cell count

Highlights • The microbiome of HPV+ oropharynx cancer exhibits reduced alpha diversity during radiotherapy. • The baseline tumor bacterial profiles of smokers vs. non-smokers are inherently different. • Eark High baseline alpha diversity may predict early response to radiation and should be investigated. • Alteration of the tumor microbiome composition occurs as early as in the first week of radiotherapy., Purpose To describe the baseline and serial tumor microbiome in HPV-associated oropharynx cancer (OPC) over the course of radiotherapy (RT). Methods Patients with newly diagnosed HPV-associated OPC treated with definitive radiotherapy +/− concurrent chemotherapy were enrolled in this prospective study. Using 16S rRNA gene sequencing, dynamic changes in the tumor site microbiome during RT were investigated. Surface tumor samples were obtained before RT and at week 1, 3 and 5 of RT. Radiological primary tumor response at mid-treatment was categorized as complete (CR) or partial (PR). Results Ten patients were enrolled, but 9 patients were included in the final analysis. Mean age was 62 years (range: 51–71). As per AJCC 8th Ed, 56%, 22% and 22% of patients had stage I, II and III, respectively. At 4-weeks, 6 patients had CR and 3 patients had PR; at follow-up imaging post treatment, all patients had CR. The baseline diversity of the tumoral versus buccal microbiome was not statistically different. For the entire cohort, alpha diversity was significantly decreased over the course of treatment (p = 0.04). There was a significant alteration in the bacterial community within the first week of radiation. Baseline tumor alpha diversity of patients with CR was significantly higher than those with PR (p = 0.03). While patients with CR had significant reduction in diversity over the course of radiation (p = 0.01), the diversity remained unchanged in patients with PR. Patients with history of smoking had significantly increased abundance of Kingella (0.05) and lower abundance of Stomatobaculum (p = 0.03) compared to never smokers. Conclusions The tumor microbiome of HPV-associated OPC exhibits reduced alpha diversity and altered taxa abundance over the course of radiotherapy. The baseline bacterial profiles of smokers vs. non-smokers were inherently different. Baseline tumor alpha diversity of patients with CR was higher than patients with PR, suggesting that the microbiome deserves further investigation as a biomarker of radiation response.

Purpose To investigate machine segmentation of pelvic anatomy in magnetic resonance imaging (MRI)-assisted radiosurgery (MARS) for prostate cancer using prostate brachytherapy MRIs acquired with different pulse sequences and image contrasts. Methods and Materials Two hundred 3-dimensional (3D) preimplant and postimplant prostate brachytherapy MRI scans were acquired with a T2-weighted sequence, a T2/T1-weighted sequence, or a T1-weighted sequence. One hundred twenty deep machine learning models were trained to segment the prostate, seminal vesicles, external urinary sphincter, rectum, and bladder using the MRI scans acquired with T2-weighted and T2/T1-weighted image contrast. The deep machine learning models consisted of 18 fully convolutional networks (FCNs) with different convolutional encoders. Both 2-dimensional and 3D U-Net FCNs were constructed for comparison. Six objective functions were investigated: cross-entropy, Jaccard distance, focal loss, and 3 variations of Tversky distance. The performance of the models was compared using similarity metrics, including pixel accuracy, Jaccard index, Dice similarity coefficient (DSC), 95% Hausdorff distance, relative volume difference, Matthews correlation coefficient, precision, recall, and average symmetrical surface distance. We selected the highest-performing architecture and investigated how the amount of training data, use of skip connections, and data augmentation affected segmentation performance. In addition, we investigated whether segmentation on T1-weighted MRI was possible with FCNs trained on only T2-weighted and T2/T1-weighted image contrast. Results Overall, an FCN with a DenseNet201 encoder trained via cross-entropy minimization yielded the highest combined segmentation performance. For the 53 3D test MRI scans acquired with T2-weighted or T2/T1-weighted image contrast, the DSCs of the prostate, external urinary sphincter, seminal vesicles, rectum, and bladder were 0.90 ± 0.04, 0.70 ± 0.15, 0.80 ± 0.12, 0.91 ± 0.06, and 0.96 ± 0.04, respectively, after model fine-tuning. For the 5 T1-weighted images, the DSCs of these organs were 0.82 ± 0.07, 0.17 ± 0.15, 0.46 ± 0.21, 0.87 ± 0.06, and 0.88 ± 0.05, respectively. Conclusions Machine segmentation of the prostate and surrounding anatomy on 3D MRIs acquired with different pulse sequences for MARS low-dose-rate prostate brachytherapy is possible with a single FCN.

Despite a preponderance of data demonstrating strong clinical outcomes and cost-effectiveness, prostate brachytherapy use and competency continue to decline. Enhanced resident education may help reverse this trend. We therefore developed and implemented a simulation-based medical education course for low-dose-rate prostate brachytherapy (LDR-PB).A 1-week LDR-PB course comprised four 1-h lectures on clinical outcomes, physics, radiobiology, and anatomy/contouring, followed by a 4.5-h simulation session on ultrasound-guided prostate phantom implantation, was developed for radiation oncology residents at an academic institution. A 10-statement Likert-scale survey and 20-question multiple-choice test were administered 1 week before and 4 weeks after the course.Precourse and postcourse instruments were completed by 24 and 20 residents, respectively. The median number of prior LDR-PB cases after at least one genitourinary rotation was 10.5 (range 5-20). Overall mean test scores were significantly improved (55% before the course vs 68% after the course; p = 0.010). Mean Likert scores significantly increased on nine of 10 survey statements and were significantly increased overall (2.4 before the course vs 3.3 after the course, p0.001). When asked about interest in performing brachytherapy after residency, 37.5% of residents "agreed" or "strongly agreed" before the course vs 50% after the course (p = 0.41). Those with higher postresidency brachytherapy interest (scores of 4-5 vs 1-3) had significantly more LDR-PB cases (11.2 vs 5.3 cases; p = 0.005).A 1-week simulation-based medical education course for LDR-PB can improve didactic performance and self-reported technical competence/confidence, and may increase overall enthusiasm for brachytherapy. Future studies at our institution will incorporate evaluation of implant quality and assessment of procedural competence into this framework. Residency programs should dedicate resources to this essential component of radiation oncology.

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.

Background This study aimed to evaluate the prognostic value of pre-treatment NLR in patients with oropharyngeal cancer. Methods Patients who completed definitive radiotherapy (RT) for oropharyngeal cancer and had blood counts taken pre-RT from 2002 to 2013 were included. NLR was calculated as total neutrophil/lymphocytes. Survival rates were estimated using the Kaplan–Meier method. Univariable and multivariable analyses were conducted with linear and Cox regression methods. NLR was analysed posteriori and dichotomised on the discovered median. Results Eight hundred and forty-eight patients were analysed. The median pre-RT NLR was 3. Patients with NLR of p p = 0.011; HPV-negative p = 0.003). Freedom from any recurrence (FFR), locoregional control (LRC) and freedom of distant recurrence (FDR) were better in those with NLR p = 0.001), FFR (HR = 1.6, p = 0.006) and LRC (HR = 1.8, p = 0.005) remained significant on multivariable analysis. Conclusions Pre-RT NLR is an independent prognostic factor in patients with oropharyngeal cancer regardless of HPV status. Patients with lower NLR had more favourable OS and disease control.

Background and purpose To characterize patterns and outcomes of brain MR image changes after proton therapy (PT) for skull base head and neck cancer (HNC). Material and methods Post-treatment MRIs ≥6 months were reviewed for radiation-associated image changes (RAIC) in 127 patients. All patients had received at least a point dose of 40 Gy(RBE) to the brain. The MRIs were rigidly registered to planning CTs and RAIC lesions were contoured both on T1 weighted (post-contrast) and T2 weighted sequences, and dose–volume parameters extracted. Probability of RAIC was calculated using multistate survival analysis. Univariate/multivariate analyses were performed using Cox Regression. Recursive partitioning analysis was used to investigate dose–volume correlates of RAIC development. Results 17.3% developed RAIC. All RAIC events were asymptomatic and occurred in the temporal lobe (14), frontal lobe (6) and cerebellum (2). The median volume of the contrast enhanced RAIC lesion was 0.5 cc at their maximum size. The RAIC resolved or improved in 45.5% of the patients and were stable or progressed in 36.4%. The 3-year actuarial rate of developing RAIC was 14.3%. RAIC was observed in 63% of patients when V67 Gy(RBE) of the brain ≥0.17 cc. Conclusion Small RAIC lesions after PT occurred in 17.3% of the patients; the majority in nasopharyngeal or sinonasal cancer. The estimated dose–volume correlations confirm the importance of minimizing focal high doses to brain when achievable.

BACKGROUND: Mail order pharmacy (MOP) use has been linked to improved medication adherence and health outcomes among patients with diabetes. However, no large-scale intervention studies have assessed the effect of encouraging MOP use on medication adherence. OBJECTIVE: To assess an intervention to encourage MOP services to increase its use and medication adherence. DESIGN: Randomized encouragement trial. PATIENTS: 63,012 diabetes patients from three health care systems: Kaiser Permanente Northern California (KPNC), Kaiser Permanente Hawaii (KPHI), and Harvard Pilgrim Health Care (HPHC) who were poorly adherent to at least one class of cardiometabolic medications and had not used MOP in the prior 12 months. INTERVENTION: Patients were randomized to receive either usual care (control arm) or outreach encouraging MOP use consisting of a mailed letter, secure email message, and automated telephone call outlining the potential benefits of MOP use (intervention arm). HPHC intervention patients received the letter only. MEASUREMENTS: We compared the percentages of patients that began using MOP and that became adherent to cardiometabolic medication classes during a 12-month follow-up period. We also conducted a race/ethnicity-stratified analysis. RESULTS: During follow-up, 10.6% of intervention patients began using MOP vs. 9.3% of controls (p

Background Supplemental breast cancer screening with breast magnetic resonance imaging (MRI) is recommended for women at high risk of breast cancer. To the authors' knowledge, recent national trends in breast MRI use are unknown. Methods The authors used claims data from a large national insurer to calculate screening breast MRI rates from 2006 to 2016 in a US cohort of 10 million women aged 20 to 64 years. Use was stratified by subgroups of women with a BRCA mutation, family history of breast cancer, and prior breast cancer history and stratified by age. Joinpoint regression evaluated annual changes in trends. Results The total sample included 37,447 screening breast MRI examinations in 25,617 women. Overall screening breast MRI rates were low and increased from 2.9 to 12.1 examinations per 10,000 women from 2006 to 2016. MRI use in women with a BRCA mutation increased by 21% on average annually from 210.8 per 10,000 women to 1562.0 per 10,000 women from 2006 to 2016. By 2016, women aged 50 to 64 years who had a BRCA mutation had the highest use of breast MRI (1669.6 MRI examinations per 10,000 women) compared with younger women (1198.4 MRI examinations per 10,000 women, 1519.1 MRI examinations per 10,000 women, and 1567.2 MRI examinations per 10,000 women, respectively, among women aged 20‐29 years, 30‐39 years, and 40‐49 years). Women with a BRCA mutation comprised

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.

Purpose To determine the clinical outcomes and toxicities of proton beam therapy (PBT) versus 3D-conformal photon radiation therapy (XRT) in patients with testicular seminoma. Materials and Methods This observational study evaluated consecutive patients with testicular seminoma who were treated with inguinal orchiectomy and radiation therapy at a single, tertiary, high-volume center in 2008-19. Acute toxicity was scored with the Common Terminology Criteria for Adverse Events V 4.0. Organs at risk were contoured retrospectively by 2 investigators. Recurrences and secondary malignancies were based on routine follow-up imaging, either computed tomography or magnetic resonance imaging. Results Fifty-five patients were treated with radiation therapy, 11 in the PBT-arm and 44 in the XRT-arm, with a median follow-up interval of 61 months (interquartile range [IQR]: 32-79 months). Acute treatment-related diarrhea, grade 1 to 2, was more common among XRT-treated patients (0% vs 29.5%, P = .039), and dermatitis, grade 1, was more likely among PBT-treated patients (27.3% vs 2.3%, P = .004). Dosimetrically, PBT-treated patients, relative to XRT-treated patients, had lower dose to organs at risk including the kidney, bladder, femoral head, spinal cord, bowel, pancreas, and stomach. The 5-year overall survival rate was 100% and disease-free survival rate was 96.4% for all patients. Two patients, all in the XRT-arm, had disease recurrence: 1 in the pelvis and 1 in the lung. Three patients, all in the XRT-arm, were diagnosed with a secondary malignancy: 1 in-field pancreaticoblastoma, 1 in-field colon adenocarcinoma, and a stage IV T-cell lymphoma. Conclusion Proton beam therapy for testicular seminoma resulted in excellent clinical outcomes and was associated with lower rates of acute diarrhea but higher rates of acute dermatitis. Proton beam therapy resulted in no in-field secondary malignancies and a more favorable dosimetric profile for organs at risk relative to XRT. Reduced dose to organs at risk, such as the kidneys, may result in long-term improvement in function.

Purpose MRI-assisted radiosurgery (MARS) is a modern technique for prostate brachytherapy that provides superior soft tissue contrast. The purpose of this analysis was to evaluate treatment planning factors associated with urinary toxicity, particularly damage to the membranous urethra (MUL) and external urethral sphincter (EUS), after MARS. Material and Methods We retrospectively reviewed 227 patients treated with MARS. Comparisons were made between several factors including preimplantation length of the MUL and EUS dosimetric characteristics after implantation with longitudinal changes in American Urological Association (AUA) urinary symptom score. Results Rates of grade 3 urinary incontinence and obstructive urinary symptoms were 4% and 2%. A piecewise mixed univariate model revealed that MUL and V200, V150, V125, and D5 to the EUS were all associated with increased rates of urinary toxicity over time. On univariate logistic regression, MUL >14.2 mm (odds ratio [OR] 2.03 per cm3, 95% confidence interval [CI] 1.10–3.77, p = 0.025), V125 to the EUS (OR 3.21 cm3, 95% CI 1.18–8.71, p = 0.022), and use of the I-125 isotope (OR 3.45, 95% CI 1.55–7.70, p = 0.001) were associated with subacute urinary toxicity (i.e., that occurring at 4–8 months). Optimal dose-constraint limits to the EUS were determined to be V200 Conclusions MARS brachytherapy provides detailed anatomic information for treatment planning, implantation, and quality assurance. Overall rates of urinary toxicity are low; however, several dosimetric variables associated with the EUS were found to correlate with urinary toxicity.

PURPOSE: Proton therapy is increasingly prescribed, given its potential to improve outcomes; however, prior authorization remains a barrier to access and is associated with frequent denials and treatment delays. We sought to determine whether appropriate access to proton therapy could ensure timely care without overuse or increased costs. METHODS: Our large academic cancer center collaborated with a statewide self-funded employer (n = 186,000 enrollees) on an insurance coverage pilot, incorporating a value-based analysis and ensuring preauthorization for appropriate indications. Coverage was ensured for prospective trials and five evidence-supported anatomic sites. Enrollment initiated in 2016 and continued for 3 years. Primary end points were use, authorization time, and cost of care, with case-matched comparison of total charges at 1 month pretreatment through 6 months posttreatment. RESULTS: Thirty-two patients were approved over 3 years, with only 22 actually receiving proton therapy, versus a predicted use by 120 patients ( P < .01). Median follow-up was 20.1 months, and average authorization time decreased from 17 days to < 1 day ( P < .01), significantly enhancing patient access. During this time, 25 patients who met pilot eligibility were instead treated with photons; and 17 patients with > 6 months of follow-up were case matched by treatment site to 17 patients receiving proton therapy, with no significant differences in sex, age, performance status, stage, histology, indication, prescribed fractions, or chemotherapy. Total medical costs (including radiation therapy [RT] and non-RT charges) for patients treated with PBT were lower than expected (a cost increase initially was expected), with no significant difference in total average charges ( P = .82), in the context of overall ancillary care use. CONCLUSION: This coverage pilot demonstrated that appropriate access to proton therapy does not necessitate overuse or significantly increase comprehensive medical costs. Objective evidence-based coverage polices ensure appropriate patient selection. Stakeholder collaboration can streamline patient access while reducing administrative burden.

We evaluated 79 patients with multiple myeloma (MM) ≥70 years referred to our blood and marrow transplant clinic, within 1 year of diagnosis from 2010 to 2019, for consideration of autologous stem cell transplant (ASCT). Thirty-eight (48%) of 79 patients underwent ASCT. ASCT was not pursued in 41 (52%) patients due to: patient or physician preference in 80% (n = 33) or ineligibility in 20% (n = 8). Baseline characteristics of patients in the two groups were similar. Median PFS from treatment start amongst patients undergoing ASCT (n = 38) vs. not (n = 41) was 41 months vs. 33 months, p = 0.03. There was no difference in OS, with estimated 5-year OS of 73% vs. 83%, respectively (p = 0.86). Day +100 transplant-related mortality (TRM) was 0%. ASCT was an independent favorable prognostic factor for PFS in multivariate analysis, after accounting for HCT-CI score, performance status, hematologic response, and maintenance. Finally, patients ≥70 years undergoing ASCT had similar PFS compared to a contemporaneous institutional cohort of patients

Patients with prostate cancer presenting with advanced T stage, mainly T4, might have a unique pattern of nodal failure and disease involvement that is not typically covered when local therapy is offered. We attempted to identify common sites of nodal disease presentation and failure for patients presenting with cT4 prostate cancer.All patients with treatment-naïve cT4 prostate cancer were retrospectively identified. All patients were required to have a confirmed diagnosis reviewed by our genitourinary pathologist and completed baseline staging. Lymph node (LN) involvement and location at diagnosis were reviewed by a genitourinary radiologist. All patients' follow-up scans were also reviewed; based on LN size, imaging characteristics, and progression/regression characteristics on systemic therapy, the locations of sites of LN failure were recorded. For patients who underwent surgery, any pathologically involved LNs and their anatomic locations were recorded. A total of 103 patients met these criteria, with a median follow-up of 8 years (range, 0.5-14 years).Rectal involvement by the primary disease was associated with a higher risk of perirectal and mesorectal LN involvement (45%) relative to no rectal involvement (26%) (P.05). These echelons are typically not covered with conventional pelvic external beam radiation therapy and are not routinely part of pelvic LN dissection in patients treated surgically. Conversely, bladder or pelvic side wall invasion did not correlate with increased frequency of involvement of perirectal/mesorectal LNs (P.05).When offering local therapy, target modification to include the perirectal and mesorectal LNs should be considered for patients presenting with T4 prostate cancer with rectal involvement.