Radiation and immune checkpoint inhibitor-mediated pneumonitis risk stratification in patients with locally advanced non-small cell lung cancer: role of functional lung radiomics?

BACKGROUND: Patients undergoing chemoradiation and immune checkpoint inhibitor (ICI) therapy for locally advanced non-small cell lung cancer (NSCLC) experience pulmonary toxicity at higher rates than historical reports. Identifying biomarkers beyond conventional clinical factors and radiation dosimetry is especially relevant in the modern cancer immunotherapy era. We investigated the role of novel functional lung radiomics, relative to functional lung dosimetry and clinical characteristics, for pneumonitis risk stratification in locally advanced NSCLC. METHODS: Patients with locally advanced NSCLC were prospectively enrolled on the FLARE-RT trial (NCT02773238). All received concurrent chemoradiation using functional lung avoidance planning, while approximately half received consolidation durvalumab ICI. Within tumour-subtracted lung regions, 110 radiomics features (size, shape, intensity, texture) were extracted on pre-treatment [99mTc]MAA SPECT/CT perfusion images using fixed-bin-width discretization. The performance of functional lung radiomics for pneumonitis (CTCAE v4 grade 2 or higher) risk stratification was benchmarked against previously reported lung dosimetric parameters and clinical risk factors. Multivariate least absolute shrinkage and selection operator Cox models of time-varying pneumonitis risk were constructed, and prediction performance was evaluated using optimism-adjusted concordance index (c-index) with 95% confidence interval reporting throughout. RESULTS: Thirty-nine patients were included in the study and pneumonitis occurred in 16/39 (41%) patients. Among clinical characteristics and anatomic/functional lung dosimetry variables, only the presence of baseline chronic obstructive pulmonary disease (COPD) was significantly associated with the development of pneumonitis (HR 4.59 [1.69-12.49]) and served as the primary prediction benchmark model (c-index 0.69 [0.59-0.80]). Discrimination of time-varying pneumonitis risk was numerically higher when combining COPD with perfused lung radiomics size (c-index 0.77 [0.65-0.88]) or shape feature classes (c-index 0.79 [0.66-0.91]) but did not reach statistical significance compared to benchmark models (p > 0.26). COPD was associated with perfused lung radiomics size features, including patients with larger lung volumes (AUC 0.75 [0.59-0.91]). Perfused lung radiomic texture features were correlated with lung volume (adj R2 = 0.84-1.00), representing surrogates rather than independent predictors of pneumonitis risk. CONCLUSIONS: In patients undergoing chemoradiation with functional lung avoidance therapy and optional consolidative immune checkpoint inhibitor therapy for locally advanced NSCLC, the strongest predictor of pneumonitis was the presence of baseline chronic obstructive pulmonary disease. Results from this novel functional lung radiomics exploratory study can inform future validation studies to refine pneumonitis risk models following combinations of radiation and immunotherapy. Our results support functional lung radiomics as surrogates of COPD for non-invasive monitoring during and after treatment. Further study of clinical, dosimetric, and radiomic feature combinations for radiation and immune-mediated pneumonitis risk stratification in a larger patient population is warranted.

Reliability of Quantitative 18F-FDG PET/CT Imaging Biomarkers for Classifying Early Response to Chemoradiotherapy in Patients With Locally Advanced Non-Small Cell Lung Cancer.

PURPOSE OF THE REPORT: We evaluated the reliability of 18F-FDG PET imaging biomarkers to classify early response status across observers, scanners, and reconstruction algorithms in support of biologically adaptive radiation therapy for locally advanced non-small cell lung cancer. PATIENTS AND METHODS: Thirty-one patients with unresectable locally advanced non-small cell lung cancer were prospectively enrolled on a phase 2 trial (NCT02773238) and underwent 18F-FDG PET on GE Discovery STE (DSTE) or GE Discovery MI (DMI) PET/CT systems at baseline and during the third week external beam radiation therapy regimens. All PET scans were reconstructed using OSEM; GE-DMI scans were also reconstructed with BSREM-TOF (block sequential regularized expectation maximization reconstruction algorithm incorporating time of flight). Primary tumors were contoured by 3 observers using semiautomatic gradient-based segmentation. SUVmax, SUVmean, SUVpeak, MTV (metabolic tumor volume), and total lesion glycolysis were correlated with midtherapy multidisciplinary clinical response assessment. Dice similarity of contours and response classification areas under the curve were evaluated across observers, scanners, and reconstruction algorithms. LASSO logistic regression models were trained on DSTE PET patient data and independently tested on DMI PET patient data. RESULTS: Interobserver variability of PET contours was low for both OSEM and BSREM-TOF reconstructions; intraobserver variability between reconstructions was slightly higher. ΔSUVpeak was the most robust response predictor across observers and image reconstructions. LASSO models consistently selected ΔSUVpeak and ΔMTV as response predictors. Response classification models achieved high cross-validated performance on the DSTE cohort and more variable testing performance on the DMI cohort. CONCLUSIONS: The variability FDG PET lesion contours and imaging biomarkers was relatively low across observers, scanners, and reconstructions. Objective midtreatment PET response assessment may lead to improved precision of biologically adaptive radiation therapy.

Scanning Beam Proton Therapy versus Photon IMRT for Stage III Lung Cancer: Comparison of Dosimetry, Toxicity, and Outcomes.

PURPOSE: There are limited clinical data on scanning-beam proton therapy (SPT) in treating locally advanced lung cancer, as most published studies have used passive-scatter technology. There is increasing interest in whether the dosimetric advantages of SPT compared with photon therapy can translate into superior clinical outcomes. We present our experience of SPT and photon intensity modulated radiation therapy (IMRT) with clinical dosimetry and outcomes in patients with stage III lung cancer. METHODS AND MATERIALS: Patients with stage III lung cancer treated at our center between 2013 and May 2018 were identified in compliance with our institutional review board (64 patients = 34 SPT + 30 IMRT). Most proton patients were treated with pencil beam scanning (28 of 34), and 6 of 34 were treated with uniform scanning. Fisher exact test, χ2 test, and Mann-Whitney test were used to compare groups. All tests were 2-sided. RESULTS: Patient characteristics were similar between the IMRT and SPT patients, except for worse lung function in the IMRT group. Mean dose to lung, heart, and esophagus was lower in the SPT group, with most benefit in the low-dose region (lungs, 9.7 Gy vs 15.7 Gy for SPT vs IMRT, respectively [P = .004]; heart, 7 Gy vs 14 Gy [P = .001]; esophagus, 28.2 Gy vs 30.9 Gy [P = .023]). Esophagitis and dermatitis grades were not different between the 2 groups. Grade 2+ pneumonitis was 21% in the SPT group and 40% in the IMRT group (P = .107). Changes in blood counts were not different between the 2 groups. Overall survival and progression-free survival were not different between SPT and IMRT (median overall survival, 41.6 vs 30.7 months, respectively [P = .52]; median progression-free survival, 19.5 vs 14.6 months [P = .50]). CONCLUSIONS: We report our experience with SPT and IMRT in stage III lung cancer. Our cohort of patients treated with SPT had lower doses to normal organs (lungs, heart, esophagus) than our IMRT cohort. There was no statistically significant difference in toxicity rates or survival, although there may have been a trend toward lower rates of pneumonitis.

A highly efficient preparative-scale generic immunoaffinity chromatography method for the purification of antibodies to hydrophobic haptens: purification procedure and monitoring tests.

A generic affinity chromatography purification protocol for the isolation of preparative quantities of pure and stable polyclonal antibodies to hydrophobic haptenic analytes is described together with a panel of tests to monitor the purification process and assess the functional and structural purity of isolated antibodies. The purification method is based on the use of a mixture of acetonitrile and propionic acid to elute bound antibodies from Sepharose 4B-based immunoabsorbent gels. Highly specific and pure antibodies to steroid estrogens, pentachlorophenol and Irgarol 1051 were isolated in 50-150 mg quantities per preparation in a batch-wise method using appropriate ligands linked to the solid phase via a hydrophilic chemical arm, tetraethylene pentamine. The panel of ELISA tests together with SDS-PAGE enabled the monitoring of the absorption and elution steps and provided data relevant to the assessment of the degree of structural and functional purity of the isolated antibody preparations. The study demonstrates that the affinity purification procedure is practical, simple, generic for antibodies to hydrophobic haptens and suitable for scaling up. In addition, the study showed that the functional properties of the affinity-purified antibodies indicated improvements on the operational properties (specificity and assay detection limits) of the source antisera. The isolated IgG antibodies showed near 100% functional and structural purity and no deterioration of activity on storage for long periods. The method provides critical reagents for labelled-antibody immunoassays and immunosensors and antibody-dependent sample purification techniques.

Generation of antiserum to Irgarol 1051 and development of a sensitive enzyme immunoassay using a new heterologous hapten derivative.

A polyclonal antiserum to Irgarol 1051 was developed in sheep and used to construct an enzyme immunoassay method for the measurement of the antifouling compound in river and seawater samples. The antiserum was generated by a hapten derivative, 2-(tert-butylamino)-4-(cyclopropylamino)-6-(thiopropionic acid)-1,3,5-triazine, coupled to a mixture of keyhole limpet hemocyanin and bovine serum albumin, and the competitive enzyme immunoassay was constructed using a plate-coating antigen made of a heterologous new hapten derivative, 2-(tert-butylamino)-4-(cyclopropylamino)-6-(phenoxybenzoic acid)-1,3,5-triazine, linked to gelatine. The assay showed a sensitivity of about 5 ng L(-1) in river and seawater matrices with reasonable specificity with respect to commonly used triazines such as atrazine (3%), simazine (>0.1%) and desethylatrazine (>0.01%). However, high cross-reactivity levels were found with ametryn (56%) and prometryn (60%). Tests on the effects of organic solvents on assay performance indicated a high tolerance to methanol but much less so to acetonitrile. The assay was found to be highly reproducible and robust owing to the stability of the sheep antibody and the highly optimised competitive assay reagents which included the use of the new triazine-O-phenoxybenzoic acid derivative.

Evaluation of a polyclonal antiserum to pentachlorothiophenol-acetic acid-KLH immunogen: binding properties and use with heterologous PCP derivatives in ELISA for pentachlorophenol.

A polyclonal antiserum to pentachlorothiophenol-acetic acid-KLH was generated in sheep and assessed by solid phase ELISA. The assessment procedure included use of double checkerboard analysis in the absence and in the presence of analyte loads, estimation of cross reactivities of chlorophenol pesticides, assessment of the effect of pH, Tween 20, and Thames water matrix. The antiserum was highly specific for pentachlorophenol and enabled minimum detection limits of less than 0.2 ng mL(-1) in river water matrix. Particularly important was the significant improvement of assay performance in the absence of Tween 20 and at pH 4 and the very low cross reactivity (less than 0.01%) for other commonly used chlorophenols-2,4,5-trichlorophenol and 2,4,6-trichlorophenol, 2-methyl-4-chlorophenoxyacetic acid, and 2,4-dichlorophenoxy acetic acid. The study re-affirms the importance of the judicious choice of hapten derivatives in the synthesis of immunogens and assay reagents for pentachlorophenol analysis by competitive immunoassays.

An empirical typology of seriously and persistently mentally ill patients using symptom and social functioning factors.

This study generated an empirical, statistically based typology that used both symptom data and social functioning dimensions to define subtypes of seriously mentally ill patients. The intent of using social functioning information was to explore the degree to which it improves clinicians' understanding of and treatment planning for diverse subgroups of patients. Social functioning dimensions and symptom data collected on a group of SPMI (seriously and persistently mentally ill) patients were factor analyzed and then submitted to a cluster analysis that yielded five meaningful patient subtypes. Demonstrations of the usefulness of this classification included significant subgroup differences on clinically important external variables, including needs for specific types of treatment and service consumption. For comparison purposes, the failure of the DSM-III diagnostic classification to distinguish patients on the clinically relevant criteria also was demonstrated.

Client-treatment interaction in the study of differential change processes.

Research that combines correlational and experimental approaches in a search for aptitude-treatment interactions (ATI) is both inescapable and of potential benefit to the field. A number of epistemological and methodological issues regarding ATI research are discussed, ranging from the meaning of interaction to questions regarding the number of aptitudes and their types and the nature of interacting treatments. Despite the less than encouraging record of ATI research, it should not be abandoned, rather its purposes should be expanded. Instead of focusing on the pragmatic but hard-to-achieve goal of finding an optimal match between individual clients and specific therapies. ATI research should serve heuristic purposes. Theoretically derived and empirically tested interactions can clarify the change processes and mechanisms that make therapies differentially effective. Exploration of another type of interaction is recommended also: aptitude-outcome interaction (AOI), in which ostensibly identical therapies yield different outcomes through different mechanisms for different clients. The emphasis of AOI research is also more heuristic than pragmatic.

The seriously mentally ill: another perspective on treatment resistance.

There is a subpopulation of the seriously mentally ill who remain acute care recidivists, rarely becoming engaged in follow-up treatment. It has been argued that these individuals are system, rather than treatment resisters. The perceptions they have of their problems are often in conflict with staff evaluations, or with what the system has to offer. In the present study, patients who dropped out of residential care against staff's advice were compared to patients who remained in treatment. The results suggest that the greater the difference between the perceptions a patient and therapist have concerning the patient's problem, the greater the likelihood of the patient dropping out of treatment.

Measuring effective functioning in the elderly: an application of Erikson's theory.

This study seeks to assess effective functioning within Erikson's epigenetic theory of development, in a sample of 143 Elderhostel participants who were administered the Inventory of Psychosocial Balance (IPB) and the California Psychological Inventory (CPI) Self-Realization (Sr) scale. A correlational analysis indicated no major systematic sex differences, but significant intercorrelations between the IPB scales and the Self-Realization scale. Multiple regression analyses indicated that in men, Trust is the most important variable, with Generativity and Intimacy yielding negative weights, whereas for women, Identity is the major component, with Industry, Autonomy, Generativity, and Trust yielding negative weights. The results support the utility of the IPB as a vehicle to study psychosocial development in the elderly.

The homeless mentally ill in Tucson: implications of early findings.

Homeless persons who received emergency psychiatric screening in a public general hospital exhibited patterns of gross geographic mobility. They did not uniformly avail themselves of community services, such as soup kitchens, and there were marked sex differences within the sample.