PURPOSE The immunogenicity and reactogenicity of SARS-CoV-2 vaccines in patients with cancer are poorly understood. METHODS We performed a prospective cohort study of adults with solid-organ or hematologic cancers to evaluate anti–SARS-CoV-2 immunoglobulin A/M/G spike antibodies, neutralization, and reactogenicity ≥ 7 days following two doses of mRNA-1273, BNT162b2, or one dose of Ad26.COV2.S. We analyzed responses by multivariate regression and included data from 1,638 healthy controls, previously reported, for comparison. RESULTS Between April and July 2021, we enrolled 1,001 patients; 762 were eligible for analysis (656 had neutralization measured). mRNA-1273 was the most immunogenic (log10 geometric mean concentration [GMC] 2.9, log10 geometric mean neutralization titer [GMT] 2.3), followed by BNT162b2 (GMC 2.4; GMT 1.9) and Ad26.COV2.S (GMC 1.5; GMT 1.4; P < .001). The proportion of low neutralization (< 20% of convalescent titers) among Ad26.COV2.S recipients was 69.9%. Prior COVID-19 infection (in 7.1% of the cohort) was associated with higher responses ( P < .001). Antibody titers and neutralization were quantitatively lower in patients with cancer than in comparable healthy controls, regardless of vaccine type ( P < .001). Receipt of chemotherapy in the prior year or current steroids were associated with lower antibody levels and immune checkpoint blockade with higher neutralization. Systemic reactogenicity varied by vaccine and correlated with immune responses ( P = .002 for concentration, P = .016 for neutralization). In 32 patients who received an additional vaccine dose, side effects were similar to prior doses, and 30 of 32 demonstrated increased antibody titers (GMC 1.05 before additional dose, 3.17 after dose). CONCLUSION Immune responses to SARS-CoV-2 vaccines are modestly impaired in patients with cancer. These data suggest utility of antibody testing to identify patients for whom additional vaccine doses may be effective and appropriate, although larger prospective studies are needed.

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IMPORTANCESevere acute esophagitis occurs in up to 20% of patients with locally advanced lung cancer treated with chemoradiation therapy to at least 60 Gy once daily and represents a dose-limiting toxic event associated with poor outcomes. OBJECTIVE To assess whether formalized sparing of the contralateral esophagus (CE) is associated with reduced risk of severe acute esophagitis. DESIGN, SETTING, AND PARTICIPANTSThis single-center phase 1 nonrandomized clinical trial assessing an empirical CE-sparing technique enrolled patients from July 2015 to January 2019. In total, 27 patients with locally advanced non-small cell lung carcinoma (with or without solitary brain metastasis) or limited-stage small cell lung carcinoma with gross tumor within 1 cm of the esophagus were eligible.INTERVENTIONS Intensity-modulated radiation therapy to 70 Gy at 2 Gy/fraction concurrent with standard chemotherapy with or without adjuvant durvalumab. The esophageal wall contralateral to gross tumor was contoured as an avoidance structure to guide a steep dose falloff gradient. Target coverage was prioritized over CE sparing, and 99% of internal and planning target volumes had to be covered by 70 Gy and at least 63 Gy, respectively. MAIN OUTCOMES AND MEASURESThe primary end point was the rate of at least grade 3 acute esophagitis as assessed by Common Terminology Criteria for Adverse Events, version 4. RESULTSOf 27 patients enrolled, 25 completed chemoradiation therapy. Nineteen patients had non-small cell lung carcinoma, and 6 had small cell lung carcinoma. The median age at diagnosis was 67 years (range, 51-81 years), and 15 patients (60%) were men. Thirteen patients (52%) had stage IIIA cancer, 10 (40%) had stage IIIB cancer, and 2 (8%) had stage IV cancer. The median CE maximum dose was 66 Gy (range, 44-71 Gy); the median volume of CE receiving at least 55 Gy was 1.4 cm 3 (range, 0-5.3 cm 3 ), and the median volume of CE receiving at least 45 Gy was 2.7 cm 3 (range, 0-9.2 cm 3 ). The median combined percentage of lung receiving at least 20 Gy was 25% (range, 11%-37%). The median follow-up was 33.3 months (range, 11.1-52.2 months). Among the 20 patients who had treatment breaks of 0 to 3 days and were thus evaluable for the primary end point, the rate of at least grade 3 esophagitis was 0%. Other toxic events observed among all 25 patients included 7 (28%) with grade 2 esophagitis, 3 (12%) with at least grade 2 pneumonitis (including 1 with grade 5), and 2 (8%) with at least grade 3 cardiac toxic event (including 1 with grade 5). There was no isolated local tumor failure. The 2-year progression-free survival rate was 57% (95% CI, 33%-75%), and the 2-year overall survival rate was 67% (95% CI, 45%-82%). CONCLUSIONS AND RELEVANCEThis phase 1 nonrandomized clinical trial found that the CE-sparing technique was associated with reduced risk of esophagitis among patients treated uniformly with chemoradiation therapy (to 70 Gy), with no grade 3 or higher esophagitis despite tumor within 1 cm of the esophagus. This technique may be translated...

A model of the pulmonary airways was used to study three single-breath indices of gas mixing, dead space (VD), slope of the alveolar plateau, and alveolar mixing inefficiency (AMI). In the model, discrete elements of airway volume were represented by nodes. Using a finite difference technique the differential equation for simultaneous convection and diffusion was solved for the nodal network. Conducting airways and respiratory bronchioles were modeled symmetrically, but alveolar ducts asymmetrically, permitting interaction between convection and diffusion. VD, alveolar slope, and AMI increased with increasing flow. Similar trends were seen with inspired volume, although slope decreased at high inspired volumes with constant flow. VD was affected most by inspiratory flow and AMI and alveolar slope by expiratory time. VD fell approximately exponentially with time of breath holding. Eight different breathing patterns were compared. They had a small effect on alveolar slope and AMI and a greater effect on VD. The model shows how series and parallel inhomogeneity occur together and interact in asymmetrical systems: the old argument as to which is the more important should be abandoned.

An asymmetrical model of the human pulmonary acinus is described, in which elements of volume are represented by nodes joined by conductors permitting convective flow and molecular diffusion. The method of analysis permits simultaneous convection, diffusion, and dimensional change in any direction and requires only simple boundary conditions. Inspiration of O2 into a resident gas of 79% N2 followed by expiration was simulated at two flows. On expiration the slope of the alveolar plateau was 1.7%, and the alveolar N2 mixing efficiency was 97.0%. A symmetrical but otherwise similar model gave a slope of zero and a mixing efficiency of 99.9%. The patterns of gas concentration within the asymmetrical acinus during the respiratory cycle confirm and extend previous observations on the interactions between simultaneous convection and diffusion in asymmetrical structures (16, 21, 22). Even though these in combination within alveolar duct asymmetry can account for the slope of the alveolar plateau, they are insufficient to account for the failure of complete gas mixing found in normal subjects.

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Purpose/Objective(s): Patients receiving concurrent chemo/radiation therapy (CRT) for non-small cell (NSCLC) or small cell (SCLC) lung carcinoma are at risk for severe acute esophagitis (AE) (≥ grade (G) 3). We sought to compare AE in a cohort of patients treated with an empiricallyderived contralateral esophagus sparing technique (CEST) to historical patients treated without this technique. This data will inform nurses and nurse practitioners when anticipating and managing CRT side effects in lung cancer patients. Materials/Methods: In this retrospective IRB-approved study, we reviewed the records of patients with locally advanced (stage III by AJCC 7th ed +/-solitary brain metastasis) NSCLC or limited-stage SCLC who had gross tumor within 1 cm of the esophagus. All patients were planned with intensity-modulated radiation therapy (IMRT) to a prescription dose of at least 60 Gy with concurrent chemotherapy. Cohort A represents a secondary analysis of an institutional phase I trial that enrolled patients during 7/2015-2/2019. Cohort B consists of consecutive patients treated with standard of care IMRT during 7/2008-12/2012, before the implementation of CEST at our institution. We tabulated patient, tumor, and treatment characteristics and graded AE using CTCAEv4 from baseline to 3-month posttreatment follow-up appointments. Results: We identified a total of 52 CRT patients (A, n = 26; B, n = 26). Median ages for cohorts A and B were 67 and 69.5 years, respectively. In each cohort there were 10 females and 16 males. Stage distribution was: IIIA 50%, IIIB 42%, IV 8% for cohort A and IIIA 65%, IIIB 35% for cohort B. In cohorts A and B, median radiation dose was 70 Gy (range 68-70 Gy) and 68.7 Gy (range 45-74 Gy), respectively. Overall rates of G2+ AE in cohorts A and B were 31% (n = 8) and 58% (n = 15) (P = 0.03), respectively. This difference was evident by week 4 of CRT when for cohorts A and B the rates were 15% and 35%, respectively. By 3 months post-treatment, each cohort had 1 patient with G2+ AE. There were no G4/ 5 events, and the only G3 AE was in cohort B leading to early termination of treatment at 52.2 Gy. Twelve percent (n = 3) of patients in cohort A and 27% (n = 7) of patients in cohort B required IV fluids. Forty six percent (n = 12) patients in cohort A and 62% (n = 16) of patients in cohort B required diet adjustments, while 27% (n = 7) of patients in cohort A and 73% (n = 19) of patients in cohort B required pain medications. Overall, CEST allowed patients to maintain a more normal diet, spend less time receiving IV fluids, and take fewer pain medications. Conclusion: Advances in IMRT-based treatment techniques have enabled a considerable reduction in G2-3 AE rates. Reduced AE is expected to lead to improved quality of life and treatment adherence. Nurses and nurse practitioners can use this data to perform a more focused assessment, create patient-specific interventions, and streamline patient education.

response heterogeneity between the primary and metastasis tumor increased significantly as H r1 (13.3%) ＜ H r2 (25.6%)＜ H r3 (46.1%)＜ H r4 (53.5%) ＜H r5 (56.9%). We identified EGFR T790M as the most common mechanism of acquired resistance (63.6%). No pre-EGFR-TKI tumor had a preexisting T790M mutation. The capability of response heterogeneity parameter to predict T790M was shown by the ROC. Hr4 and Hr3 predicted T790M mutation (AUCZ0.826and 0.783, respectively) more accurately than other parameters did. PFS and OS was significantly shorter in patients with higher response heterogeneity between primary and metastasis (P Z 0.006). Compared to T790M-positive tumors, T790Mnegative tumors showed relatively higher response heterogeneity between the primary and metastasis tumor and shorter survival, suggesting T790Mnegative patients as a potential candidate for early topical therapy. Conclusion: The therapeutic response of TKI showed significance difference between primary and metastasis tumors in advanced NSCLC. The gap increased month-by-month. Higher intra-tumor response heterogeneity showed correlation with T790M-negative and poor outcome. Dynamic radiogenomics analysis will provide a systems-level understanding of underlying heterogeneous cellular and molecular processes of acquired resistance molecular mechanisms.