M.F. Gensheimer

Chalcone isomerase family and fold: No longer unique to plants

Chalcone isomerase, an enzyme in the isoflavonoid pathway in plants, catalyzes the cyclization of chalcone into (2S)‐naringenin. Chalcone isomerase sequence family and three‐dimensional fold appeared to be unique to plants and has been proposed as a plant‐specific gene marker. Using sensitive methods of sequence comparison and fold recognition, we have identified genes homologous to chalcone isomerase in all completely sequenced fungi, in slime molds, and in many gammaproteobacteria. The residues directly involved in the enzymes catalytic function are among the best conserved across species, indicating that the newly discovered homologs are enzymatically active. At the same time, fungal and bacterial species that have chalcone isomerase‐like genes tend to lack the orthologs of the upstream enzyme chalcone synthase, suggesting a novel variation of the pathway in these species.

Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling

Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here, we apply cancer personalized profiling by deep sequencing (CAPP-seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first posttreatment blood sample, indicating reliable identification of MRD. Posttreatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months, and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in patients with lung cancer can be accurately detected using CAPP-seq and may allow personalized adjuvant treatment while disease burden is lowest.Significance: This study shows that ctDNA analysis can robustly identify posttreatment MRD in patients with localized lung cancer, identifying residual/recurrent disease earlier than standard-of-care radiologic imaging, and thus could facilitate personalized adjuvant treatment at early time points when disease burden is lowest. Cancer Discov; 7(12); 1394-403. ©2017 AACR.See related commentary by Comino-Mendez and Turner, p. 1368This article is highlighted in the In This Issue feature, p. 1355.

IN VIVO PROTON BEAM RANGE VERIFICATION USING SPINE MRI CHANGES

PURPOSE In proton therapy, uncertainty in the location of the distal dose edge can lead to cautious treatment plans that reduce the dosimetric advantage of protons. After radiation exposure, vertebral bone marrow undergoes fatty replacement that is visible on magnetic resonance imaging (MRI). This presents an exciting opportunity to observe radiation dose distribution in vivo. We used quantitative spine MRI changes to precisely detect the distal dose edge in proton radiation patients. METHODS AND MATERIALS We registered follow-up T1-weighted MRI images to planning computed tomography scans from 10 patients who received proton spine irradiation. A radiation dose-MRI signal intensity curve was created using the lateral beam penumbra in the sacrum. This curve was then used to measure range errors in the lumbar spine. RESULTS In the lateral penumbra, there was an increase in signal intensity with higher dose throughout the full range of 0-37.5 Gy (RBE). In the distal fall-off region, the beam sometimes appeared to penetrate farther than planned. The mean overshoot in 10 patients was 1.9 mm (95% confidence interval, 0.8-3.1 mm), on the order of the uncertainties inherent to our range verification method. CONCLUSIONS We have demonstrated in vivo proton range verification using posttreatment spine MRI changes. Our analysis suggests the presence of a systematic overshoot of a few millimeters in some proton spine treatments, but the range error does not exceed the uncertainty incorporated into the treatment planning margin. It may be possible to extend our technique to MRI sequences that show early bone marrow changes, enabling adaptive treatment modification.

Challenges and opportunities in patient-specific, motion-managed and PET/CT-guided radiation therapy of lung cancer: review and perspective

The increasing interest in combined positron emission tomography (PET) and computed tomography (CT) to guide lung cancer radiation therapy planning has been well documented. Motion management strategies during treatment simulation PET/CT imaging and treatment delivery have been proposed to improve the precision and accuracy of radiotherapy. In light of these research advances, why has translation of motion-managed PET/CT to clinical radiotherapy been slow and infrequent? Solutions to this problem are as complex as they are numerous, driven by large inter-patient variability in tumor motion trajectories across a highly heterogeneous population. Such variation dictates a comprehensive and patient-specific incorporation of motion management strategies into PET/CT-guided radiotherapy rather than a one-size-fits-all tactic. This review summarizes challenges and opportunities for clinical translation of advances in PET/CT-guided radiotherapy, as well as in respiratory motion-managed radiotherapy of lung cancer. These two concepts are then integrated into proposed patient-specific workflows that span classification schemes, PET/CT image formation, treatment planning, and adaptive image-guided radiotherapy delivery techniques.

Neutron radiotherapy for adenoid cystic carcinoma of the lacrimal gland

Purpose:Lacrimal gland adenoid cystic carcinomas are rare, aggressive orbital tumors that share histopathologic similarities with salivary gland malignancies. Neutron radiotherapy may be useful for treatment due to its high biological effectiveness for salivary malignancies. Methods:The authors retrospectively reviewed the outcomes for 11 lacrimal gland adenoid cystic carcinoma patients treated with neutrons from 1988 to 2011. Most had undergone surgery prior to radiation therapy. However, gross residual disease was present in 8 patients. The most common American Joint Committee on Cancer stage was T4cN0M0. Four patients with skull base involvement received a radiosurgery boost and 1 received a proton therapy boost. Results:Median follow up was 6.2 years. Median overall survival was 11.1 years and median disease-free survival was 6.3 years. Five-year local control was estimated by the Kaplan–Meier method as 80%. Three patients had a local recurrence; 4 developed distant metastases. Six patients died. Seven patients had intact vision in the affected eye before neutron radiation. Two required enucleation for a painful dry eye. Of the 5 who avoided an enucleation, 3 had either severe visual impairment (20/400) or only light perception and 2 were without known vision compromise or complications at the time of their death. One patient developed asymptomatic frontal lobe radionecrosis after 2 courses of radiation therapy. Conclusions:Neutron radiation therapy achieved excellent 5-year local control in this series of high-risk patients, with most cases having gross residual disease. Late recurrences and distant metastases remain a challenge. Meaningful ipsilateral vision preservation was not possible in most cases in the long term, although only 2 patients required an enucleation for treatment effects.

Mentorship Programs in Radiation Oncology Residency Training Programs: A Critical Unmet Need

PURPOSE To conduct a nationwide survey to evaluate the current status of resident mentorship in radiation oncology. METHODS AND MATERIALS An anonymous electronic questionnaire was sent to all residents and recent graduates at US Accreditation Council for Graduate Medical Education-accredited radiation oncology residency programs, identified in the member directory of the Association of Residents in Radiation Oncology. Factors predictive of having a mentor and satisfaction with the mentorship experience were identified using univariate and multivariate analyses. RESULTS The survey response rate was 25%, with 85% of respondents reporting that mentorship plays a critical role in residency training, whereas only 53% had a current mentor. Larger programs (≥ 10 faculty, P=.004; and ≥ 10 residents, P<.001) were more likely to offer a formal mentorship program, which makes it more likely for residents to have an active mentor (88% vs 44%). Residents in a formal mentoring program reported being more satisfied with the overall mentorship experience (univariate odds ratio 8.77, P<.001; multivariate odds ratio 5, P<.001). On multivariate analysis, women were less likely to be satisfied with the mentorship experience. CONCLUSIONS This is the first survey focusing on the status of residency mentorship in radiation oncology. Our survey highlights the unmet need for mentorship in residency programs.

Influence of planning time and treatment complexity on radiation therapy errors

PURPOSE Radiation treatment planning is a complex process with potential for error. We hypothesized that shorter time from simulation to treatment would result in rushed work and higher incidence of errors. We examined treatment planning factors predictive for near-miss events. METHODS AND MATERIALS Treatments delivered from March 2012 through October 2014 were analyzed. Near-miss events were prospectively recorded and coded for severity on a 0 to 4 scale; only grade 3-4 (potentially severe/critical) events were studied in this report. For 4 treatment types (3-dimensional conformal, intensity modulated radiation therapy, stereotactic body radiation therapy [SBRT], neutron), logistic regression was performed to test influence of treatment planning time and clinical variables on near-miss events. RESULTS There were 2257 treatment courses during the study period, with 322 grade 3-4 near-miss events. SBRT treatments had more frequent events than the other 3 treatment types (18% vs 11%, P = .04). For the 3-dimensional conformal group (1354 treatments), univariate analysis showed several factors predictive of near-miss events: longer time from simulation to first treatment (P = .01), treatment of primary site versus metastasis (P < .001), longer treatment course (P < .001), and pediatric versus adult patient (P = .002). However, on multivariate regression only pediatric versus adult patient remained predictive of events (P = 0.02). For the intensity modulated radiation therapy, SBRT, and neutron groups, time between simulation and first treatment was not found to be predictive of near-miss events on univariate or multivariate regression. CONCLUSIONS When controlling for treatment technique and other clinical factors, there was no relationship between time spent in radiation treatment planning and near-miss events. SBRT and pediatric treatments were more error-prone, indicating that clinical and technical complexity of treatments should be taken into account when targeting safety interventions.

Prognostic value and molecular correlates of a CT image-based quantitative pleural contact index in early stage NSCLC

PurposeTo evaluate the prognostic value and molecular basis of a CT-derived pleural contact index (PCI) in early stage non-small cell lung cancer (NSCLC).Experimental designWe retrospectively analysed seven NSCLC cohorts. A quantitative PCI was defined on CT as the length of tumour-pleura interface normalised by tumour diameter. We evaluated the prognostic value of PCI in a discovery cohort (n = 117) and tested in an external cohort (n = 88) of stage I NSCLC. Additionally, we identified the molecular correlates and built a gene expression-based surrogate of PCI using another cohort of 89 patients. To further evaluate the prognostic relevance, we used four datasets totalling 775 stage I patients with publically available gene expression data and linked survival information.ResultsAt a cutoff of 0.8, PCI stratified patients for overall survival in both imaging cohorts (log-rank p = 0.0076, 0.0304). Extracellular matrix (ECM) remodelling was enriched among genes associated with PCI (p = 0.0003). The genomic surrogate of PCI remained an independent predictor of overall survival in the gene expression cohorts (hazard ratio: 1.46, p = 0.0007) adjusting for age, gender, and tumour stage.ConclusionsCT-derived pleural contact index is associated with ECM remodelling and may serve as a noninvasive prognostic marker in early stage NSCLC.Key points• A quantitative pleural contact index (PCI) predicts survival in early stage NSCLC.• PCI is associated with extracellular matrix organisation and collagen catabolic process.• A multi-gene surrogate of PCI is an independent predictor of survival.• PCI can be used to noninvasively identify patients with poor prognosis.

Mid-radiotherapy PET/CT for prognostication and detection of early progression in patients with stage III non-small cell lung cancer

BACKGROUND AND PURPOSE Pre- and mid-radiotherapy FDG-PET metrics have been proposed as biomarkers of recurrence and survival in patients treated for stage III non-small cell lung cancer. We evaluated these metrics in patients treated with definitive radiation therapy (RT). We also evaluated outcomes after progression on mid-radiotherapy PET/CT. MATERIAL AND METHODS Seventy-seven patients treated with RT with or without chemotherapy were included in this retrospective study. Primary tumor and involved nodes were delineated. PET metrics included metabolic tumor volume (MTV), total lesion glycolysis (TLG), and SUVmax. For mid-radiotherapy PET, both absolute value of these metrics and percentage decrease were analyzed. The influence of PET metrics on time to death, local recurrence, and regional/distant recurrence was assessed using Cox regression. RESULTS 91% of patients had concurrent chemotherapy. Median follow-up was 14months. None of the PET metrics were associated with overall survival. Several were positively associated with local recurrence: pre-radiotherapy MTV, and mid-radiotherapy MTV and TLG (p=0.03-0.05). Ratio of mid- to pre-treatment SUVmax was associated with regional/distant recurrence (p=0.02). 5/77 mid-radiotherapy scans showed early out-of-field progression. All of these patients died. CONCLUSIONS Several PET metrics were associated with risk of recurrence. Progression on mid-radiotherapy PET/CT was a poor prognostic factor.

Trimodality Treatment of Malignant Pleural Mesothelioma: An Institutional Review.

Objective: Malignant pleural mesothelioma (MPM) is a deadly disease with varying treatment options. This study retrospectively describes treatment practices at the University of Washington Medical System from 1980 to 2011, and evaluates the impact of trimodality therapy and radiation (photon and neutron) on survival. Methods: A retrospective study was conducted on patients treated for MPM. Univariate and multivariate methods were utilized to evaluate potential factors associated with survival. Treatments received and baseline characteristics were included. Survival analysis of trimodality therapy was performed using a propensity score method to control for baseline characteristics. Results: Among 78 eligible patients, the median age at diagnosis was 59 years and the median survival was 13.7 months. On multivariate analysis, the significant predictors of improved survival were age, smoking history, location, and receipt of radiation therapy or chemotherapy. In the 48 patients receiving radiation therapy, the difference in survival between neutron therapy and non-neutron therapy patients was not statistically significant: hazard ratio, 1.20 (95% confidence interval, 0.68-2.13), P=0.52. Patients receiving trimodality therapy were more likely to have early-stage disease (60% vs. 30%) and epithelioid histology (86% vs. 58%). In a propensity score-weighted Cox proportional hazards model, trimodality therapy patients had improved overall survival, hazard ratio 0.45, P=0.004, median 14.6 versus 8.6 months. Conclusions: Trimodality therapy was significantly associated with prolonged survival in patients with MPM, even when adjusting for baseline patient factors. Radiation therapy was associated with improved survival, but the modality of radiation therapy used was not associated with outcome.