Radiographic Extranodal Extension in Human Papillomavirus-Associated Oropharyngeal Carcinoma: Can it Help Tailor Treatment?
International journal of radiation oncology, biology, physics
2019; 104 (5): 1028?29
Automated Survival Prediction in Metastatic Cancer Patients Using High-Dimensional Electronic Medical Record Data
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
2019; 111 (6): 568?74
Adverse Radiation Effect and Disease Control in Patients Undergoing Stereotactic Radiosurgery and Immune Checkpoint Inhibitor Therapy for Brain Metastases
2019; 126: E1399?E1411
Increases in Serial Pretreatment 18F-FDG PET-CT Metrics Predict Survival in Early Stage Non-Small Cell Lung Cancer Treated With Stereotactic Ablative Radiation Therapy.
Advances in radiation oncology
2019; 4 (2): 429?37
Adverse Radiation Effect and Disease Control in Patients Undergoing Stereotactic Radiosurgery and Immune Checkpoint Inhibitor Therapy for Brain Metastases.
Purpose: Quantitative changes in positron emission tomography with computed tomography imaging metrics over serial scans may be predictive biomarkers. We evaluated the relationship of pretreatment metabolic tumor growth rate (MTGR) and standardized uptake value velocity (SUVV) with disease recurrence or death in patients with early-stage non-small cell lung cancer treated with stereotactic ablative radiation therapy (SABR).Methods and Materials: Under institutional review board approval, we retrospectively identified patients who underwent positron emission tomography with computed tomography at diagnosis and staging and simulation for SABR. Two cohorts underwent SABR between November 2005 to October 2012 (discovery) and January 2012 to April 2016 (validation). MTGR and SUVV were calculated as the daily change in metabolic tumor volume and maximum standardized uptake value, respectively. Cox proportional hazard models identified predictors of local, regional, and distant recurrence and death for the combined cohort. MTGR and SUVV thresholds dichotomizing risk of death in the discovery cohort were applied to the validation cohort.Results: A total of 152 lesions were identified in 143 patients (92 lesions in 83 discovery cohort patients). In multivariable models, increasing MTGR trended toward increased hazard of distant recurrence (hazard ratio, 6.98; 95% confidence interval, 0.67-72.61; P=.10). In univariable models, SUVV trended toward risk of death (hazard ratio, 11.8, 95% confidence interval, 0.85-165.1, P=.07). MTGR greater than 0.04mL/d was prognostic of decreased survival in discovery (P=.048) and validation cohorts (P<.01).Conclusions: MTGR greater than 0.04mL/d is prognostic of death in patients with non-small cell lung cancer treated with SABR. Increasing SUVV trends, nonsignificantly, toward increased risk of recurrence and death. MTGR and SUVV may be candidate imaging biomarkers to study in trials evaluating systemic therapy with SABR for patients at high risk of out-of-field recurrence.
View details for PubMedID 31011689
Impact of Accuracy of Survival Predictions on Quality of End-of-Life Care Among Patients With Metastatic Cancer Who Receive Radiation Therapy.
Journal of oncology practice
BACKGROUND: Immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS) are increasingly used together to manage brain metastases (BMs). We assessed adverse radiation effect, disease control, and overall survival in patients with BMs who received SRS with anti-CTLA-4 and/or anti-PD-1/PD-L1 therapies.METHODS: We retrospectively reviewed the records of patients with intact or resected BMs treated with SRS and ICIs within 5 months of SRS between 2010 and 2018. Patients were defined as receiving 'concurrent' SRS and ICI if a dose of ICI was given within 4 weeks of SRS. Local failure (LF), distant intracranial failure (DIF), extracranial failure (EF), and adverse radiation effect (ARE) were assessed using cumulative incidence rates and competing risk regressions with death as a competing risk. Overall survival was assessed using the Kaplan-Meier method and Cox proportional hazards models.RESULTS: A total of 97 patients with 580 BMs were included in our analysis. Competing risk analyses demonstrated that concurrent SRS-ICI therapy is associated with higher rates of ARE (6.4% vs 2.0% at 1 year; multivariable HR 4.47; 95% CI, 1.57-12.73; p=0.005), lower rates of EF (69.7% vs 80.8% at 1 year; multivariable HR 0.60; 95% CI, 0.42-0.87; p=0.007), and better overall survival (48.6% vs 25.4% at 1 year; multivariable HR 0.57; 95% CI, 0.33-0.99; p=0.044) as compared to non-concurrent therapy. SRS-ICI timing was not associated with LF or DIF.CONCLUSIONS: Concurrent SRS-ICI therapy has a tolerable adverse event profile and may improve extracranial disease control and overall survival, supporting concurrent use in the management of BMs.
View details for PubMedID 30902777
A scalable discrete-time survival model for neural networks.
2019; 7: e6257
PURPOSE:: For patients treated with palliative radiation, we examined the association between life expectancy predictions by radiation oncologists and aggressive end-of-life care.MATERIALS AND METHODS:: We included decedents from a study that assessed the ability of oncologists to predict survival of patients with metastatic cancer who received radiation. We identified patients who died within 12 months of study enrollment to assess accuracy of predictions. Aggressive end-of-life care was defined by the National Quality Forum, ASCO Quality Oncology Practice Initiative metrics, and advanced radiation modalities in the last month of life. Survival predictions were categorized as follows: correct (< 12 months), 12 to 18 months, 18 to 24 months, and more than 24 months. We assessed association between prediction and aggressive end-of-life care using a generalized estimation equation.RESULTS:: Of 489 decedents, we identified 467 encounters with survival estimates. Overall, 156 decedents (32%) met at least one metric of aggressive end-of-life care. Factors associated with aggressive end-of-life care included younger age, female sex, primary cancer diagnosis, no brain metastases, and private insurance. In each encounter when an oncologist predicted survival, 363 predictions (78%) were correct (< 12 months), 54 (11%) incorrectly predicted 12 to 18 months, 27 (6%) predicted 18 to 24 months, and 23 (5%) predicted more than 24 months. Compared with patients who had encounters that had correct survival predictions, patients predicted to live more than 24 months were more likely to meet at least one metric of aggressive end-of-life care (odds ratio, 2.55; 95% CI, 1.09 to 5.99; P = .03).CONCLUSION:: Inaccurate survival predictions by oncologists are associated with more aggressive end-of-life care for patients with advanced cancer.
View details for DOI 10.1200/JOP.18.00516
View details for PubMedID 30620629
Adaptive radiotherapy for head and neck cancer: Are we ready to put it into routine clinical practice?
2018; 86: 19?24
There is currently great interest in applying neural networks to prediction tasks in medicine. It is important for predictive models to be able to use survival data, where each patient has a known follow-up time and event/censoring indicator. This avoids information loss when training the model and enables generation of predicted survival curves. In this paper, we describe a discrete-time survival model that is designed to be used with neural networks, which we refer to as Nnet-survival. The model is trained with the maximum likelihood method using mini-batch stochastic gradient descent (SGD). The use of SGD enables rapid convergence and application to large datasets that do not fit in memory. The model is flexible, so that the baseline hazard rate and the effect of the input data on hazard probability can vary with follow-up time. It has been implemented in the Keras deep learning framework, and source code for the model and several examples is available online. We demonstrate the performance of the model on both simulated and real data and compare it to existing models Cox-nnet and Deepsurv.
View details for PubMedID 30701130
Automated Survival Prediction in Metastatic Cancer Patients Using High-Dimensional Electronic Medical Record Data.
Journal of the National Cancer Institute
Patients with head and neck cancer who are treated with radiotherapy often have significant weight loss or tumor regression during treatment. Adaptive radiotherapy refers to acquiring new imaging during treatment and changing the parameters of the radiation plan based on the new imaging findings. There is accumulating evidence that adaptive radiotherapy can reduce toxicity and improve tumor control, though it is not yet known which patients benefit most. For patients with profound tumor regression, there is also uncertainty about how much to shrink the region receiving high radiation dose. Another form of adaptive radiotherapy uses advanced imaging such as positron emission tomography to visualize changes in tumor biology during treatment. Tumor regions that are thought to be more radioresistant can then be treated to a higher radiation dose, and vice-versa. Studies employing this strategy to boost radiation dose have shown a high rate of late toxicity, specifically the development of persistent mucosal ulcers. Therefore, this sort of adaptive radiotherapy is currently confined to the research setting.
View details for PubMedID 30409300
Factors Associated With Treatment of Clinical Stage I Non-Small-cell Lung Cancer: A Population-based Analysis.
Clinical lung cancer
2018; 19 (5): e745?e758
Background: Oncologists use patients' life expectancy to guide decisions and may benefit from a tool that accurately predicts prognosis. Existing prognostic models generally use only a few predictor variables. We used an electronic medical record dataset to train a prognostic model for patients with metastatic cancer.Methods: The model was trained and tested using 12588 patients treated for metastatic cancer in the Stanford Health Care system from 2008 to 2017. Data sources included provider note text, labs, vital signs, procedures, medication orders, and diagnosis codes. Patients were divided randomly into a training set used to fit the model coefficients and a test set used to evaluate model performance (80%/20% split). A regularized Cox model with 4126 predictor variables was used. A landmarking approach was used due to the multiple observations per patient, with t0 set to the time of metastatic cancer diagnosis. Performance was also evaluated using 399 palliative radiation courses in test set patients.Results: The C-index for overall survival was 0.786 in the test set (averaged across landmark times). For palliative radiation courses, the C-index was 0.745 (95% confidence interval [CI] = 0.715 to 0.775) compared with 0.635 (95% CI = 0.601 to 0.669) for a published model using performance status, primary tumor site, and treated site (two-sided P<.001). Our model's predictions were well-calibrated.Conclusions: The model showed high predictive performance, which will need to be validated using external data. Because it is fully automated, the model can be used to examine providers' practice patterns and could be deployed in a decision support tool to help improve quality of care.
View details for PubMedID 30346554
Probabilistic Prognostic Estimates of Survival in Metastatic Cancer Patients (PPES-Met) Utilizing Free-Text Clinical Narratives.
2018; 8 (1): 10037
BACKGROUND: The present study examined clinical stage I non-small-cell lung cancer (NSCLC) treatment in the population-based California Cancer Registry.PATIENTS AND METHODS: The characteristics associated with first clinical stage I NSCLC treatment (surgery, radiation, no local therapy) from 2003 to 2014 were identified using logistic regression. Survival was evaluated using Kaplan-Meier and Cox proportional hazard analyses.RESULTS: Surgery was used in most patients who met the inclusion criteria (14,545 of 19,893; 73.1%), although relatively similar numbers had undergone radiation (n= 2848; 14.3%) or not received therapy (n= 2500; 12.6%). Surgery use ranged from 68.5% to 77.2% patients annually. The percentage of patients with no therapy decreased from 18.1% (315 of 1737) in 2003 to 10.3% (176 of 1703) in 2014, and radiation use increased from 10.7% (185 of 1737) in 2003 to 21.2% (361 of 1703) in 2014. Patients who did not receive therapy were more likely to be older, not white, male, and unmarried, to have no insurance or public insurance other than Medicare, to live in a lower socioeconomic status neighborhood, to have been seen at a non-National Cancer Institute cancer center hospital or hospital serving lower socioeconomic status patients, and to have larger tumors. The 5-year all-cause survival after no therapy (12.7%) was significantly worse than that after surgery (64.9%) or radiation (21.5%; P< .0001).CONCLUSION: In the present population-based analysis, surgery was the most common treatment for clinical stage I NSCLC but was not used for almost 27% of patients. Radiation use increased and the proportion of patients who did not receive any therapy decreased over time.
View details for PubMedID 30149883
A Quantitative CT Imaging Signature Predicts Survival and Complements Established Prognosticators in Stage I Non-Small Cell Lung Cancer.
International journal of radiation oncology, biology, physics
We propose a deep learning model - Probabilistic Prognostic Estimates of Survival in Metastatic Cancer Patients (PPES-Met) for estimating short-term life expectancy (>3 months) of the patients by analyzing free-text clinical notes in the electronic medical record, while maintaining the temporal visit sequence. In a single framework, we integrated semantic data mapping and neural embedding technique to produce a text processing method that extracts relevant information from heterogeneous types of clinical notes in an unsupervised manner, and we designed a recurrent neural network to model the temporal dependency of the patient visits. The model was trained on a large dataset (10,293 patients) and validated on a separated dataset (1818 patients). Our method achieved an area under the ROC curve (AUC) of 0.89. To provide explain-ability, we developed an interactive graphical tool that may improve physician understanding of the basis for the model's predictions. The high accuracy and explain-ability of the PPES-Met model may enable our model to be used as a decision support tool to personalize metastatic cancer treatment and provide valuable assistance to the physicians.
View details for PubMedID 29968730
In Regard to Valdes et al.
International journal of radiation oncology, biology, physics
2018; 102 (5): 1593?94
Prognostic Value of Pretreatment FDG-PET Parameters in High-dose Image-guided Radiotherapy for Oligometastatic Non-Small-cell Lung Cancer.
Clinical lung cancer
Prognostic biomarkers are needed to guide the management of early-stage non-small cell lung cancer (NSCLC). This work aims to develop an image-based prognostic signature and assess its complementary value to existing biomarkers.We retrospectively analyzed data of stage I NSCLC in 8 cohorts. On the basis of an analysis of 39 computed tomography (CT) features characterizing tumor and its relation to neighboring pleura, we developed a prognostic signature in an institutional cohort (n = 117) and tested it in an external cohort (n = 88). A third cohort of 89 patients with CT and gene expression data was used to create a surrogate genomic signature of the imaging signature. We conducted further validation using data from 5 gene expression cohorts (n = 639) and built a composite signature by integrating with the cell-cycle progression (CCP) score and clinical variables.An imaging signature consisting of a pleural contact index and normalized inverse difference was significantly associated with overall survival in both imaging cohorts (P = .0005 and P = .0009). Functional enrichment analysis revealed that genes highly correlated with the imaging signature were related to immune response, such as lymphocyte activation and chemotaxis (false discovery rate < 0.05). A genomic surrogate of the imaging signature remained a significant predictor of survival when we adjusted for known prognostic factors (hazard ratio, 1.81; 95% confidence interval, 1.34-2.44; P < .0001) and stratified patients within subgroups as defined by stage, histology, or CCP score. A composite signature outperformed the genomic surrogate, CCP score, and clinical model alone (P < .01) regarding concordance index (0.70 vs 0.62-0.63).The proposed CT imaging signature reflects fundamental biological differences in tumors and predicts overall survival in patients with stage I NSCLC. When combined with established prognosticators, the imaging signature improves survival prediction.
View details for PubMedID 29439884
Mid-radiotherapy PET/CT for prognostication and detection of early progression in patients with stage III non-small cell lung cancer
RADIOTHERAPY AND ONCOLOGY
2017; 125 (2): 338?43
Emerging data support aggressive local treatment of oligometastatic non-small-cell lung cancer (NSCLC) patients. We sought to determine whether the metabolic burden of disease found by fluorodeoxyglucose positron emission tomography at the time of high-dose radiotherapy (RT) for oligometastatic NSCLC can serve as a prognostic biomarker.We conducted a retrospective cohort study of 67 RT treatment courses in 55 patients with oligometastatic NSCLC who had undergone high-dose RT to all sites of active disease at our institution. The metabolic tumor volume, total lesion glycolysis (TLG), and maximum standardized uptake value of all lesions were measured on the pretreatment fluorodeoxyglucose positron emission tomography scans. Cox regression analysis was used to assess the influence of imaging and clinical factors on overall survival (OS).On univariate analysis, a greater metabolic tumor volume and TLG were predictive of shorter OS (hazard ratio of death, 2.42 and 2.14, respectively; P = .009 and P = .004, respectively). The effects remained significant on multivariate analysis. Neither the maximum standardized uptake value nor the number of lesions was significantly associated with OS. Patients within the highest quartile of TLG values (> 86.8 units) had a shorter median OS than those within the lower 3 quartiles (12.4 vs. 30.1 months; log-rank P = .014).The metabolic tumor burden was prognostic of OS and might help to better select oligometastatic NSCLC patients for locally ablative therapy.
View details for PubMedID 29759331
Practical workflow for rapid prototyping of radiation therapy positioning devices
PRACTICAL RADIATION ONCOLOGY
2017; 7 (6): 442?45
Pulmonary function after lung tumor stereotactic ablative radiotherapy depends on regional ventilation within irradiated lung.
Radiotherapy and oncology
2017; 123 (2): 270-275
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.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.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.Several PET metrics were associated with risk of recurrence. Progression on mid-radiotherapy PET/CT was a poor prognostic factor.
View details for PubMedID 28830717
Optimal Radiation Therapy for Small Cell Lung Cancer.
Current treatment options in oncology
2017; 18 (4): 21-?
To determine if regional ventilation within irradiated lung volume predicts change in pulmonary function test (PFT) measurements after stereotactic ablative radiotherapy (SABR) of lung tumors.We retrospectively identified 27 patients treated from 2007 to 2014 at our institution who received: (1) SABR without prior thoracic radiation; (2) pre-treatment 4-dimensional computed tomography (4-D CT) imaging; (3) pre- and post-SABR PFTs <15months from treatment. We defined the ventilation ratio (VR20BED3) as the quotient of mean ventilation (mean Jacobian-based per-voxel volume change on deformably registered inhale/exhale 4-D CT phases) within the 20Gy biologically effective dose (?/?=3Gy) isodose volume and that of the total lung volume (TLV).Most patients had moderate to very severe COPD by GOLD criteria (n=19, 70.1%). Higher VR20BED3 significantly predicted worse change in Forced Expiratory Volume/s normalized by baseline value (?FEV1/FEV1pre, p=0.04); n=7 had VR20BED3>1 (high regional ventilation) and worse ?FEV1/FEV1pre (median=-0.16, range=-0.230 to -0.20). Five had VR20BED3<1 (low regional ventilation) and improved ?FEV1/FEV1pre (median=0.13, range=0.07 to 0.20). In a multivariable linear model, increasing VR20BED3 and time to post-SABR PFT predicted decreasing ?FEV1/FEV1pre (R(2)=0.25, p=0.03).After SABR to high versus low functioning lung regions, we found worsened or improved global pulmonary function, respectively. If pre-SABR VR20BED3 is validated as a predictor of eventual post-SABR PFT in larger studies, it may be used for individualized treatment planning to preserve or even improve pulmonary function after SABR.
View details for DOI 10.1016/j.radonc.2017.03.021
View details for PubMedID 28460826
Prognostic value and molecular correlates of a CT image-based quantitative pleural contact index in early stage NSCLC.
Radiation therapy plays an important role in the management of both limited stage and extensive stage small cell lung cancer. For limited stage disease, there has been a trend toward reduced size of thoracic radiation fields, which has the potential to reduce toxicity. FDG-PET staging helps make this possible by more accurately identifying areas of nodal and metastatic involvement. Trials have demonstrated similar outcomes using a range of radiation fractionation schedules, allowing flexibility in individualizing treatment. Using advanced radiation therapy techniques such as intensity-modulated radiation therapy, it may be possible to deliver fewer, higher dose fractions and achieve similar results to the hyperfractionated regimen. For extensive stage disease, consolidative thoracic radiation therapy after chemotherapy was recently shown to improve overall survival in certain patient subsets. Prophylactic cranial irradiation continues to play an important role in management of all stages of small cell lung cancer. Debate continues about the neurocognitive effects of this treatment, and whether MRI surveillance is an acceptable alternative. Strategies such as hippocampal avoidance may reduce the cognitive effects of prophylactic cranial irradiation in the future. Finally, in the last few years stereotactic ablative radiation therapy followed by chemotherapy has emerged as a promising treatment for stage I small cell lung cancer. This radiation treatment is usually given over 1-5 fractions and appears to provide a good rate of local control with a low rate of serious toxicity.
View details for DOI 10.1007/s11864-017-0467-z
View details for PubMedID 28391424
Chest wall dose reduction using noncoplanar volumetric modulated arc radiation therapy for lung stereotactic ablative radiation therapy.
Practical radiation oncology
To evaluate the prognostic value and molecular basis of a CT-derived pleural contact index (PCI) in early stage non-small cell lung cancer (NSCLC).We 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.At 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.CT-derived pleural contact index is associated with ECM remodelling and may serve as a noninvasive prognostic marker in early stage NSCLC.? 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.
View details for PubMedID 28786009
Sinoatrial node toxicity after stereotactic ablative radiation therapy to lung tumors.
Practical radiation oncology
Stereotactic ablative radiation therapy (SABR) to lung tumors close to the chest wall can cause rib fractures or chest wall pain. We evaluated and propose a clinically practical solution of using noncoplanar volumetric modulated arc radiation therapy (VMAT) to reduce chest wall dose from lung SABR.Twenty lung SABR VMAT plans in which the chest wall volume receiving 30 Gy or higher (V30) exceeded 30 mL were replanned by noncoplanar VMAT with opposite 15° couch kicks. Dosimetric parameters including chest wall V30 and V40; lung V5, V10, V20, and mean dose; Paddick high-dose conformity index; intermediate-dose conformity index; and monitor units (MU) for each plan were used to evaluate the plan quality. The treatment time was also estimated by delivering the entire treatment. Two-sided paired t test was used to evaluate the difference of the dosimetric parameters between coplanar 1 arc (cVMAT1), coplanar 2 arcs (cVMAT2), and noncoplanar two arcs (nVMAT2) plans; differences with P < .05 were considered statistically significant.V30 and V40 for chest wall were reduced on average by 20% ± 9% and 15% ± 11% (mean ± standard deviation) from cVMAT2 plans to nVMAT2 plans (P < .01 for both comparisons) and by 8% ± 7% and 16% ± 13% from cVMAT1 plans to cVMAT2 plans (P < .003 for both comparisons). The differences in lung mean dose were <0.2 Gy among cVMAT1, cVMAT2, and nVMAT2. There were no significant differences in lung V5, V10, and V20. On average, the number of MU increased 14% for nVMAT2 compared with cVMAT2. The Paddick high-dose conformity indexes were 0.88 ± 0.03, 0.89 ± 0.04, and 0.91 ± 0.03, and intermediate-dose conformity indexes were 3.88 ± 0.49, 3.80 ± 0.44 and 3.51 ± 0.38 for cVMAT1, cVMAT2, and nVMAT2, respectively.We found that noncoplanar VMAT plans are feasible, clinically practical to deliver, and significantly reduce V30 and V40 of chest wall without increasing lung dose.
View details for PubMedID 29452868
Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling.
Stereotactic ablative radiation therapy (SABR) is an established treatment for selected lung tumors. Sinoatrial node (SAN) toxicity after thoracic SABR has not been reported in the literature. We sought to understand the risk of SAN toxicity owing to incidental dose to the SAN from SABR.We conducted a retrospective review of patients with early-stage lung cancer or limited pulmonary metastases who underwent thoracic SABR to a right-sided central lung tumor (within 2 cm of the mainstem bronchus or other mediastinal structures) between January 2008 and December 2014, analyzed a subset whose treatment imparted dose to the SAN exceeding 10% of the prescription dose, and examined patient and treatment dosimetric characteristics. Mean follow-up interval was 28 months. Time to toxicity was defined from start of SABR.Of 47 patients with central tumors in the right lung treated with SABR reviewed, 13 met our study criteria. A contouring atlas of regional cardiac anatomy was created. One patient treated with SABR for non-small cell lung cancer at the right hilum developed symptomatic sick sinus syndrome, requiring pacemaker placement 6 months after treatment. Her acute presentation and short interval between SABR and onset of symptoms suggest that SAN toxicity was likely due to radiation-induced injury. Both her age and mean dose to her SAN were the third highest in our cohort. She remained free from cancer progression at 24 months' follow-up. Twelve additional patients who received significant dose to the SAN from SABR did not develop toxicity.While uncommon, SAN toxicity from SABR to right-sided central thoracic tumors should be recognized and followed in future studies.
View details for PubMedID 28669706
Contribution of submandibular gland and swallowing structure sparing to post-radiation therapy PEG dependence in oropharynx cancer patients treated with split-neck IMRT technique
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 post-treatment blood sample, indicating reliable identification of MRD. Post-treatment 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 lung cancer patients can be accurately detected using CAPP-Seq and may allow personalized adjuvant treatment while disease burden is lowest.
View details for PubMedID 28899864
Hypofractionated Intensity-Modulated Radiotherapy for Patients With Non-Small-Cell Lung Cancer.
Clinical lung cancer
2016; 17 (6): 588-594
Radiation therapy-related dysphagia is worsened by xerostomia. The submandibular glands (SMG) produce saliva rich in lubricating mucins, and sparing the SMG has been shown to reduce xerostomia. The goal of this study was to determine whether SMG sparing IMRT is associated with reduced post-treatment PEG dependence in locally advanced oropharynx cancer patients.Patients treated with definitive radiation therapy for oropharynx cancer were included in this retrospective study. Those with disease recurrence were excluded. Salivary glands and swallowing-related organs at risk, including pharyngeal constrictors, were contoured. Primary endpoint was time from end of radiation treatment to freedom from gastrostomy (PEG) tube dependence. Cox proportional hazards regression and logistic regression were used to assess influence of normal tissue doses on swallowing related endpoints.Sixty-nine patients were included. All had stage III/IV disease and 97% received concurrent systemic therapy. Fifty-seven percent had contralateral SMG (cSMG) mean dose <50 Gy, a level shown to predict for xerostomia. Eighty four percent of patients had a PEG tube placed electively. On univariate analysis, the strongest predictor of time to freedom from PEG tube dependence was cSMG dose (HR 0.97 per Gy (95% CI 0.95-0.98), p?0.0001). This relationship persisted on multivariate analysis (p?=?0.052). The dose to superior and middle pharyngeal constrictor muscles, and larynx were also significant on univariate analysis. Patients with cSMG dose less than median (42 Gy, n?=?34) had a significantly shorter time to freedom from PEG dependence: median 1.9 vs. 3.5 months, p?0.0001. At 6 months, 3% of patients with cSMG dose?42 Gy were PEG dependent compared to 31% with cSMG dose?>?42 Gy (p?=?0.002).Patients treated with cSMG sparing radiotherapy had significantly shorter time to PEG tube removal after treatment, suggesting a clinically meaningful reduction in subacute dysphagia compared to non-cSMG sparing treatment.
View details for DOI 10.1186/s13014-016-0726-3
View details for Web of Science ID 000388245500002
View details for PubMedID 27846899
View details for PubMedCentralID PMC5111199
Robust Intratumor Partitioning to Identify High-Risk Subregions in Lung Cancer: A Pilot Study.
International journal of radiation oncology, biology, physics
2016; 95 (5): 1504-1512
Alternative treatment regimens are needed for patients with non-small cell lung cancer (NSCLC) who cannot receive definitive treatment with concurrent chemoradiotherapy, surgery, or stereotactic ablative radiotherapy (SABR).We report survival, patterns of failure and toxicity outcomes for patients with NSCLC who were not eligible for surgical resection, concurrent chemoradiotherapy, or SABR and underwent hypofractionated intensity-modulated radiotherapy (IMRT). Kaplan-Meier survival analysis was used to evaluate the progression-free and overall survival. Competing risk analysis was used to evaluate in-field, locoregional, and distant failure.A total of 42 patients treated to 52.5 to 60 Gy in 15 fractions were included. Most of the patients had metastatic or recurrent disease (64%) and a relatively large, centrally located tumor burden (74%). The median follow-up period was 13 months (interquartile range, 6-18 months). All patients received the total prescribed dose. The median survival was 15.1 months. The overall and progression-free survival rates at 1 year were 63% and 22.5%, respectively. The pattern of failure was predominantly distant, with only 2% of patients experiencing isolated in-field recurrence. The cumulative incidence of in-field failure at 6 and 12 months was 2.5% (95% confidence interval, 0.4%-15.6%) and 16.1% (95% confidence interval, 7.5%-34.7%), respectively. The risk of esophageal toxicity was associated with the esophageal mean dose, maximal point dose, and dose to the 5 cm(3) volume. The risk of pneumonitis was associated with the lung mean dose and volume receiving 18 Gy.Hypofractionated IMRT without concurrent chemotherapy provides favorable rates of local control and survival for well-selected patients with NSCLC who cannot tolerate standard definitive therapy.
View details for DOI 10.1016/j.cllc.2016.05.024
View details for PubMedID 27378172
Pre-treatment non-target lung FDG-PET uptake predicts symptomatic radiation pneumonitis following Stereotactic Ablative Radiotherapy (SABR).
Radiotherapy and oncology
2016; 119 (3): 454-460
To develop an intratumor partitioning framework for identifying high-risk subregions from (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) imaging and to test whether tumor burden associated with the high-risk subregions is prognostic of outcomes in lung cancer.In this institutional review board-approved retrospective study, we analyzed the pretreatment FDG-PET and CT scans of 44 lung cancer patients treated with radiation therapy. A novel, intratumor partitioning method was developed, based on a 2-stage clustering process: first at the patient level, each tumor was over-segmented into many superpixels by k-means clustering of integrated PET and CT images; next, tumor subregions were identified by merging previously defined superpixels via population-level hierarchical clustering. The volume associated with each of the subregions was evaluated using Kaplan-Meier analysis regarding its prognostic capability in predicting overall survival (OS) and out-of-field progression (OFP).Three spatially distinct subregions were identified within each tumor that were highly robust to uncertainty in PET/CT co-registration. Among these, the volume of the most metabolically active and metabolically heterogeneous solid component of the tumor was predictive of OS and OFP on the entire cohort, with a concordance index or CI of 0.66-0.67. When restricting the analysis to patients with stage III disease (n=32), the same subregion achieved an even higher CI of 0.75 (hazard ratio 3.93, log-rank P=.002) for predicting OS, and a CI of 0.76 (hazard ratio 4.84, log-rank P=.002) for predicting OFP. In comparison, conventional imaging markers, including tumor volume, maximum standardized uptake value, and metabolic tumor volume using threshold of 50% standardized uptake value maximum, were not predictive of OS or OFP, with CI mostly below 0.60 (log-rank P>.05).We propose a robust intratumor partitioning method to identify clinically relevant, high-risk subregions in lung cancer. We envision that this approach will be applicable to identifying useful imaging biomarkers in many cancer types.
View details for DOI 10.1016/j.ijrobp.2016.03.018
View details for PubMedID 27212196
SU-D-207B-05: Robust Intra-Tumor Partitioning to Identify High-Risk Subregions for Prognosis in Lung Cancer.
2016; 43 (6): 3349-?
Influence of planning time and treatment complexity on radiation therapy errors.
Practical radiation oncology
2016; 6 (3): 187-193
To determine if pre-treatment non-target lung FDG-PET uptake predicts for symptomatic radiation pneumonitis (RP) following lung stereotactic ablative radiotherapy (SABR).We reviewed a 258 patient database from our institution to identify 28 patients who experienced symptomatic (grade ? 2) RP after SABR, and compared them to 57 controls who did not develop symptomatic RP. We compared clinical, dosimetric and functional imaging characteristics between the 2 cohorts including pre-treatment non-target lung FDG-PET uptake.Median follow-up time was 26.9 months. Patients who experienced symptomatic RP had significantly higher non-target lung FDG-PET uptake as measured by mean SUV (p < 0.0001) than controls. ROC analysis for symptomatic RP revealed area under the curve (AUC) of 0.74, with sensitivity 82.1% and specificity 57.9% with cutoff mean non-target lung SUV > 0.56. Predictive value increased (AUC of 0.82) when mean non-target lung SUV was combined with mean lung dose (MLD). We developed a 0-2 point model using these 2 variables, 1 point each for SUV > 0.56 or MLD > 5.88 Gy equivalent dose in 2 Gy per fraction (EQD2), predictive for symptomatic RP in our cohort with hazard ratio 10.01 for score 2 versus 0 (p < 0.001).Patients with elevated pre-SABR non-target lung FDG-PET uptake are at increased risk of symptomatic RP after lung SABR. Our predictive model suggests patients with mean non-target lung SUV > 0.56 and MLD > 5.88 Gy EQD2 are at highest risk. Our predictive model should be validated in an external cohort before clinical implementation.
View details for DOI 10.1016/j.radonc.2016.05.007
View details for PubMedID 27267049
Mentorship Programs in Radiation Oncology Residency Training Programs: A Critical Unmet Need
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
2016; 94 (1): 27-30
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.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.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.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.
View details for DOI 10.1016/j.prro.2015.10.017
View details for PubMedID 26725961
Simple tool for prediction of parotid gland sparing in intensity-Modulated radiation therapy
2015; 40 (3): 232-234
To conduct a nationwide survey to evaluate the current status of resident mentorship in radiation oncology.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.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.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.
View details for DOI 10.1016/j.ijrobp.2015.09.021
View details for Web of Science ID 000366574700019
View details for PubMedID 26700700
Trimodality Treatment of Malignant Pleural Mesothelioma: An Institutional Review.
American journal of clinical oncology
Sparing one or both parotid glands is a key goal when planning head and neck cancer radiation treatment. If the planning target volume (PTV) overlaps one or both parotid glands substantially, it may not be possible to achieve adequate gland sparing. This finding results in physicians revising their PTV contours after an intensity-modulated radiation therapy (IMRT) plan has been run and reduces workflow efficiency. We devised a simple formula for predicting mean parotid gland dose from the overlap of the parotid gland and isotropically expanded PTV contours. We tested the tool using 44 patients from 2 institutions and found agreement between predicted and actual parotid gland doses (mean absolute error = 5.3Gy). This simple method could increase treatment planning efficiency by improving the chance that the first plan presented to the physician will have optimal parotid gland sparing.
View details for DOI 10.1016/j.meddos.2015.01.002
View details for Web of Science ID 000359449400012
View details for PubMedID 25704638
Assessing the scale of tumor heterogeneity by complete hierarchical segmentation of MRI
PHYSICS IN MEDICINE AND BIOLOGY
2015; 60 (3): 977-993
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.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.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.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.
View details for PubMedID 26353120
The use of stereotactic radiosurgery for brain metastases from breast cancer: Who benefits most?
BREAST CANCER RESEARCH AND TREATMENT
2015; 149 (3): 743-749
In many cancers, intratumoral heterogeneity has been found in histology, genetic variation and vascular structure. We developed an algorithm to interrogate different scales of heterogeneity using clinical imaging. We hypothesize that heterogeneity of perfusion at coarse scale may correlate with treatment resistance and propensity for disease recurrence. The algorithm recursively segments the tumor image into increasingly smaller regions. Each dividing line is chosen so as to maximize signal intensity difference between the two regions. This process continues until the tumor has been divided into single voxels, resulting in segments at multiple scales. For each scale, heterogeneity is measured by comparing each segmented region to the adjacent region and calculating the difference in signal intensity histograms. Using digital phantom images, we showed that the algorithm is robust to image artifacts and various tumor shapes. We then measured the primary tumor scales of contrast enhancement heterogeneity in MRI of 18 rhabdomyosarcoma patients. Using Cox proportional hazards regression, we explored the influence of heterogeneity parameters on relapse-free survival. Coarser scale of maximum signal intensity heterogeneity was prognostic of shorter survival (p = 0.05). By contrast, two fractal parameters and three Haralick texture features were not prognostic. In summary, our algorithm produces a biologically motivated segmentation of tumor regions and reports the amount of heterogeneity at various distance scales. If validated on a larger dataset, this prognostic imaging biomarker could be useful to identify patients at higher risk for recurrence and candidates for alternative treatment.
View details for DOI 10.1088/0031-9155/60/3/977
View details for Web of Science ID 000349438400009
View details for PubMedID 25575341
Submandibular gland-sparing radiation therapy for locally advanced oropharyngeal squamous cell carcinoma: patterns of failure and xerostomia outcomes
Brain metastases (BM) from primary breast cancer can arise despite use of systemic therapies that provide excellent extracranial disease control. Local modalities for treating BM include surgery, whole brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS). We sought to determine the benefits of SRS for management of BM arising from different biologic breast cancer subtypes. We reviewed records of 131 patients who received SRS for breast cancer BM between 2001 and 2013. Survival was estimated by the Kaplan-Meier method. Effects of tumor biology, number and location of lesions, and number of SRS sessions on survival were evaluated by Cox proportional hazards regression. Of the 122 patients with subtypes available, 41 patients (31%) were classified as estrogen receptor positive/HER2 negative (ER(+)HER2(-)); 30 patients (23%), ER(+)HER2(+); 23 patients (18%), ER(-)HER2(+); and 28 patients (21%), ER(-)HER2(-) (or triple negative breast cancer, TNBC). Median age at first SRS was 50 years. Median overall survival for ER(+)HER2(-), ER(+)HER2(+), ER(-)HER2(+), and TNBC was 16, 26, 23, and 7 months, respectively (p < 0.001 for difference between groups). Patients with TNBC had the shortest time to retreatment with WBRT or SRS or death with hazard ratio of 3.12 (p < 0.001) compared to ER(+)HER2(-). In all subtypes other than TNBC, SRS can provide meaningful control of BM even in the setting of multiple lesions and may be worth repeating for new lesions that develop metachronously. For patients with TNBC, prognosis is guarded following SRS, and there is an urgent need to develop more effective treatment strategies.
View details for DOI 10.1007/s10549-014-3242-x
View details for Web of Science ID 000349761200016
View details for PubMedID 25638395
View details for PubMedCentralID PMC4494730
Neutron Radiotherapy for Adenoid Cystic Carcinoma of the Lacrimal Gland
OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY
2013; 29 (4): 256-260
Saliva from submandibular glands (SMG) is necessary to minimize xerostomia. It is unclear whether SMG can be safely spared in patients undergoing bilateral neck radiotherapy for locally advanced oropharyngeal cancer without increasing the risk of marginal recurrence. We evaluated the outcomes of contralateral submandibular gland (cSMG) sparing intensity-modulated radiation therapy (IMRT).All patients with stage III/IV oropharyngeal squamous cell carcinoma treated with bilateral neck IMRT from 2006-2012 at our institution were included. Appropriately selected patients with favorable primary tumor characteristics and no definite contralateral neck disease were treated with cSMG-sparing IMRT. Patterns of failure and xerostomia outcomes were retrospectively analyzed.114 patients were treated. 89% had stage IV disease and 89% received definitive radiation therapy. 76 patients (67%) received cSMG sparing IMRT. With a median follow-up of 30 months, there were 10 local, 9 regional, and 10 distant recurrences. 2-year overall survival was 86% and 2-year loco-regional control was 87%. In cSMG spared patients, the mean cSMG dose was 30.7 Gy. Late grade 2+ xerostomia was significantly reduced in the cSMG spared group compared to those without SMG sparing (6 months: 23% vs. 72%, 12 months: 6% vs. 41%, 24 months: 3% vs. 36%, all p?0.0007). There were no peri-SMG marginal recurrences in the cSMG-spared cohort.cSMG sparing IMRT did not increase marginal failures in this series of locally advanced oropharyngeal SCC patients. Xerostomia was significantly reduced in cSMG spared patients.
View details for DOI 10.1186/s13014-014-0255-x
View details for Web of Science ID 000349258200001
View details for PubMedID 25424729
View details for PubMedCentralID PMC4262974
Challenges and opportunities in patient-specific, motion-managed and PET/CT-guided radiation therapy of lung cancer: review and perspective.
Clinical and translational medicine
2012; 1 (1): 18-?
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.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.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.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.
View details for DOI 10.1097/IOP.0b013e318295f99b
View details for Web of Science ID 000321698400012
View details for PubMedID 23839633
IN VIVO PROTON BEAM RANGE VERIFICATION USING SPINE MRI CHANGES
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
2010; 78 (1): 268-275
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.
View details for DOI 10.1186/2001-1326-1-18
View details for PubMedID 23369522
View details for PubMedCentralID PMC3560984
Administration of oxaliplatin to a pregnant woman with rectal cancer
CANCER CHEMOTHERAPY AND PHARMACOLOGY
2009; 63 (2): 371-373
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.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.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.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.
View details for DOI 10.1016/j.ijrobp.2009.11.060
View details for Web of Science ID 000281304600037
View details for PubMedID 20472369
Chalcone isomerase family and fold: No longer unique to plants
2004; 13 (2): 540-544
The platinum agent oxaliplatin could be useful in treatment of cancer in pregnant women, but it is fetotoxic in rats and its effect on the human fetus is unknown.Oxaliplatin was administered to a 25-year-old pregnant woman with metastatic rectal cancer from 20 to 30 weeks gestational age as part of the mFOLFOX-6 regimen.The patient gave birth to a healthy girl at 33 weeks gestational age. At follow-up, the 3-year-old child had achieved all appropriate growth and developmental milestones.Oxaliplatin is a component of several modern chemotherapy regimens. This report demonstrates the administration of oxaliplatin in the second and third trimesters of pregnancy without apparent fetal harm.
View details for DOI 10.1007/s00280-008-0731-9
View details for Web of Science ID 000261286800020
View details for PubMedID 18357450
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 enzyme's 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.
View details for DOI 10.1110/ps.03395404
View details for Web of Science ID 000188411000024
View details for PubMedID 14718655