Matthew R. McCurdy

Recent advances of laser-spectroscopy-based techniques for applications in breath analysis

Laser absorption spectroscopy (LAS) in the mid-infrared region offers a promising new effective technique for the quantitative analysis of trace gases in human breath. LAS enables sensitive, selective detection, quantification and monitoring in real time, of gases present in breath. This review summarizes some of the recent advances in LAS based on semiconductor lasers and optical detection techniques for clinically relevant exhaled gas analysis in breath, specifically such molecular biomarkers as nitric oxide, ammonia, carbon monoxide, ethane, carbonyl sulfide, formaldehyde and acetone.

Metformin use and improved response to therapy in esophageal adenocarcinoma.

Abstract Background. We investigated the radiographic and pathologic response rate of esophageal adenocarcinoma treated with neoadjuvant chemoradiation in patients taking metformin. Material and methods. Two hundred eighty-five patients with esophageal adenocarcinoma treated with concurrent chemoradiation (CRT) followed by esophagectomy from 1997 to 2012 were included in the study, including 29 diabetics taking metformin, 21 diabetics not taking metformin and 235 non-diabetics. Pre- and post-treatment positron emission tomography (PET) scans were available for 204 patients. Pathologic response was graded at the time of surgery. Response rates were compared using both the χ2 statistic as well as ANOVA with post-hoc LSD analysis. Multivariate logistic regression analysis was performed to control for predictors of pathologic complete response (CR) after CRT. Results. The overall rate of pathologic CR for the study population was 20%. The pathologic CR rate was higher in patients taking metformin (34.5%), compared to diabetic patients not taking metformin (4.8%, p = 0.01) and non-diabetic patients (19.6%, p = 0.05). Pathologic CR was related to metformin dose, with ≥1500 mg/d associated with a higher CR rate. No significant difference seen in pre-CRT maximum tumor SUV (p = 0.93), however post-CRT maximum SUV was significantly decreased in patients taking metformin (p = 0.05). On multivariate logistic regression, metformin use was independently associated with pathologic CR (p = 0.04). Metformin use was also associated with decreased in field loco-regional failure following radiation (p = 0.05). Conclusion. Metformin use is associated with a dose-dependent increased response to CRT in esophageal cancer and may be a sensitizer to this therapy.

Performance of an exhaled nitric oxide and carbon dioxide sensor using quantum cascade laser-based integrated cavity output spectroscopy.

Exhaled nitric oxide (NO) is an important biomarker in asthma and other respiratory disorders. The optical performance of a NOCO(2) sensor employing integrated cavity output spectroscopy (ICOS) with a quantum cascade laser operating at 5.22 microm capable of real-time NO and CO(2) measurements in a single breath cycle is reported. A NO noise-equivalent concentration of 0.4 ppb within a 1-sec integration time is achieved. The off-axis ICOS sensor performance is compared to a chemiluminescent NO analyzer and a nondispersive infrared (NDIR) CO(2) absorption capnograph. Differences between the gas analyzers are assessed by the Bland-Altman method to estimate the expected variability between the gas sensors. The off-axis ICOS sensor measurements are in good agreement with the data acquired with the two commercial gas analyzers. This work demonstrates the performance characteristics and merits of mid-infrared spectroscopy for exhaled breath analysis.

Radiation Pneumonitis: Correlation of Toxicity With Pulmonary Metabolic Radiation Response

PURPOSE To characterize the relationship between radiation pneumonitis (RP) clinical symptoms and pulmonary metabolic activity on post-treatment [(18)F]-fluorodeoxyglucose positron emission tomography (FDG-PET). PATIENTS AND METHODS We retrospectively studied 101 esophageal cancer patients who underwent restaging FDG-PET/computed tomography imaging 3-12 weeks after completing thoracic radiotherapy. The National Institutes of Health Common Toxicity Criteria, version 3, was used to score the RP clinical symptoms. Linear regression was applied to the FDG-PET/computed tomography images to determine the normalized FDG uptake vs. radiation dose. The pulmonary metabolic radiation response (PMRR) was quantified as this slope. Modeling was performed to determine the interaction of PMRR, mean lung dose (MLD), and the percentage of lung receiving >20 Gy with RP outcomes. RESULTS Of the 101 patients, 25 had Grade 0, 10 had Grade 1, 60 had Grade 2, 5 had Grade 3, and 1 had Grade 5 RP symptoms. Logistic regression analysis demonstrated that increased values of both MLD and PMRR were associated with a greater probability of RP clinical symptoms (p = 0.032 and p = 0.033, respectively). Spearmans rank correlation found no association between the PMRR and the dosimetric parameters (planning target volume, MLD, percentage of lung receiving >5-30 Gy). Twofold cross-validation demonstrated that the combination of MLD and PMRR was superior to either alone for assessing the development of clinical RP symptoms. The combined MLD (or percentage of lung receiving >20 Gy) and PMRR had a greater sensitivity and accuracy (53.3% and 62.5%, respectively) than either alone. CONCLUSION The results of this study have demonstrated a significant correlation between RP clinical symptoms and the PMRR measured by FDG-PET/computed tomography after thoracic radiotherapy.

Spatial correspondence of 4D CT ventilation and SPECT pulmonary perfusion defects in patients with malignant airway stenosis

To determine the spatial overlap agreement between four-dimensional computed tomography (4D CT) ventilation and single photon emission computed tomography (SPECT) perfusion hypo-functioning pulmonary defect regions in a patient population with malignant airway stenosis. Treatment planning 4D CT images were obtained retrospectively for ten lung cancer patients with radiographically demonstrated airway obstruction due to gross tumor volume. Each patient also received a SPECT perfusion study within one week of the planning 4D CT, and prior to the initiation of treatment. Deformable image registration was used to map corresponding lung tissue elements between the extreme component phase images, from which quantitative three-dimensional (3D) images representing the local pulmonary specific ventilation were constructed. Semi-automated segmentation of the percentile perfusion distribution was performed to identify regional defects distal to the known obstructing lesion. Semi-automated segmentation was similarly performed by multiple observers to delineate corresponding defect regions depicted on 4D CT ventilation. Normalized Dice similarity coefficient (NDSC) indices were determined for each observer between SPECT perfusion and 4D CT ventilation defect regions to assess spatial overlap agreement. Tidal volumes determined from 4D CT ventilation were evaluated versus measurements obtained from lung parenchyma segmentation. Linear regression resulted in a linear fit with slope = 1.01 (R² = 0.99). Respective values for the average DSC, NDSC(1 mm) and NDSC(2 mm) for all cases and multiple observers were 0.78, 0.88 and 0.99, indicating that, on average, spatial overlap agreement between ventilation and perfusion defect regions was comparable to the threshold for agreement within 1-2 mm uncertainty. Corresponding coefficients of variation for all metrics were similarly in the range: 0.10%-19%. This study is the first to quantitatively assess 3D spatial overlap agreement between clinically acquired SPECT perfusion and specific ventilation from 4D CT. Results suggest high correlation between methods within the sub-population of lung cancer patients with malignant airway stenosis.

INDUCTION AND CONCURRENT TAXANES ENHANCE BOTH THE PULMONARY METABOLIC RADIATION RESPONSE AND THE RADIATION PNEUMONITIS RESPONSE IN PATIENTS WITH ESOPHAGUS CANCER

PURPOSE The primary aim of this study was to assess pulmonary radiation toxicity quantitatively in patients who received thoracic radiotherapy combined with induction and/or concurrent chemotherapy with or without taxanes for esophageal cancer. METHODS AND MATERIALS The study subjects were 139 patients treated at the University of Texas M.D. Anderson Cancer Center for esophageal cancer and who had undergone [(18)F]-fluorodeoxyglucose positron emission tomography/computed tomography between November 1, 2003 and December 15, 2007 for disease restaging after chemoradiotherapy. The patients were grouped into those who had not received taxanes (Group 1), those who had received induction or concurrent taxanes (Group 2), and those who had received both induction and concurrent taxanes (Group 3). Clinical pulmonary toxicity was scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Linear regression was applied to the fluorodeoxyglucose uptake vs. radiation dose to determine the pulmonary metabolic radiation response (PMRR) for each case. The clinical toxicity scores and PMRR among the groups were evaluated for significance differences. RESULTS The crude rate of pneumonitis symptoms was 46%, 62%, and 74% for Group 1, 2, and 3, respectively. The analysis of variance test of log(PMRR) by treatment was significant (p = .0046). Group 3 had a 61% greater PMRR compared with Group 1 (p = .002). Group 2 had a 38% greater PMRR compared with Group 1 (p = .015). Finally, Group 3 had a 17% greater PMRR compared with Group 2 (p = .31). A PMRR enhancement ratio of 1.60 (95% confidence interval, 1.19-2.14) was observed for Group 3 vs. Group 1. CONCLUSION Patients given induction and concurrent taxane chemotherapy had a significantly greater PMRR and clinical pneumonitis symptoms compared with the patients whose chemotherapy regimen did not include taxanes.

Exhaled nitric oxide predicts radiation pneumonitis in esophageal and lung cancer patients receiving thoracic radiation

BACKGROUND AND PURPOSE Radiation pneumonitis is a significant toxicity following thoracic radiotherapy with no method to predict individual risk. MATERIALS AND METHODS Sixty-five patients receiving thoracic radiation for lung or esophageal cancer were enrolled in a phase II study. Each patient received respiratory surveys and exhaled nitric oxide measurements before, on the last day of, and 30-60 days after completing radiotherapy (RT). Pneumonitis toxicity was scored using the common terminology criteria for adverse events, version 4.0. The demographics, dosimetric factors, and nitric oxide ratio (NOR) of end RT/pre-RT were evaluated for correlation with symptomatic patients (Grade ≥ 2). RESULTS Fifty patients completed the trial. The pneumonitis toxicity score was: Grade 3 for 1 patient, Grade 2 for 6 patients, Grade 1 for 18 patients, and Grade 0 for 25 patients. Dosimetric factors were not predictive of symptoms. The NOR was 3.0 ± 1.8 (range 1.47-6.73) for the symptomatic and 0.78 ± 0.29 (range 0.33-1.37) for the asymptomatic patients (p=0.006). A threshold NOR of 1.4 separated symptomatic and asymptomatic patients (p<0.001). The average error was 4%. CONCLUSIONS Elevation in eNO on the last day of radiotherapy predicted subsequent symptomatic radiation pneumonitis weeks to months after treatment.

Proton therapy radiation pneumonitis local dose–response in esophagus cancer patients

PURPOSE This study quantifies pulmonary radiation toxicity in patients who received proton therapy for esophagus cancer. MATERIALS/METHODS We retrospectively studied 100 esophagus cancer patients treated with proton therapy. The linearity of the enhanced FDG uptake vs. proton dose was evaluated using the Akaike Information Criterion (AIC). Pneumonitis symptoms (RP) were assessed using the Common Toxicity Criteria for Adverse Events version 4.0 (CTCAEv4). The interaction of the imaging response with dosimetric parameters and symptoms was evaluated. RESULTS The RP scores were: 0 grade 4/5, 7 grade 3, 20 grade 2, 37 grade 1, and 36 grade 0. Each dosimetric parameter was significantly higher for the symptomatic group. The AIC winning models were 30 linear, 52 linear quadratic, and 18 linear logarithmic. There was no significant difference in the linear coefficient between models. The slope of the FDG vs. proton dose response was 0.022 for the symptomatic and 0.012 for the asymptomatic (p=0.014). Combining dosimetric parameters with the slope did not improve the sensitivity or accuracy in identifying symptomatic cases. CONCLUSIONS The proton radiation dose response on FDG PET/CT imaging exhibited a predominantly linear dose response on modeling. Symptomatic patients had a higher dose response slope.

Elevation in Exhaled Nitric Oxide Predicts for Radiation Pneumonitis

PURPOSE Radiation pneumonitis is a major toxicity after thoracic radiotherapy (RT), with no method available to accurately predict the individual risk. This was a prospective study to evaluate exhaled nitric oxide as a predictive biomarker for radiation pneumonitis in esophageal cancer patients. PATIENTS AND METHODS A total of 34 patients prescribed neoadjuvant chemoradiotherapy for esophageal cancer were enrolled in the present trial. Each patient underwent respiratory surveys and exhaled nitric oxide (NO) measurements before, at the end of, and 1 to 2 months after completing RT. Pneumonitis toxicity was scored using the Common Terminology Criteria for Adverse Events, version 4.0. The demographics, dosimetric factors, and exhaled NO levels were evaluated for correlation with symptomatic patients (scores ≥ 2). RESULTS Of the 34 patients, 28 were evaluable. All had received 50.4 Gy RT with concurrent chemotherapy. The pneumonitis toxicity score was Grade 3 for 1, Grade 2 for 3, Grade 1 for 7, and Grade 0 for 17. The dosimetric factors were not predictive of symptoms. The mean exhaled NO level measured before, at completion, and at restaging was 17.3 ± 8.5 (range, 5.5-36.7), 16.0 ± 14.2 (range, 5.8-67.7), and 14.7 ± 6.2 (range, 5.5-28.0) parts per billion, respectively. The ratio of exhaled NO at the end of RT vs. before treatment was 3.4 (range, 1.7-6.7) for the symptomatic and 0.8 (range, 0.3-1.3) for the asymptomatic (p = .0017) patients. The elevation in exhaled NO preceded the peak symptoms by 33 days (range, 21-50). The interval to peak symptoms was inversely related to the exhaled NO elevation. CONCLUSIONS Elevations in exhaled NO at the end of RT was found to predict for radiation pneumonitis symptoms.

Laser Based Chemical Sensor Technology: Recent Advances and Applications

There is an increasing need in many chemical sensing applications ranging from environmental science to industrial process control as well as medical diagnostics for fast, sensitive, and selective trace gas detection based on laser spectroscopy. The recent availability of continuous wave (cw) near infrared diode lasers-, mid-infrared quantum cascade and interband cascade distributed feedback (QC and IC DFB) lasers as mid-infrared spectroscopic sources addresses this need. A number of spectroscopic techniques have been demonstrated. For example, the authors have employed infrared DFB QC and IC lasers for the detection and quantification of trace gases and isotopic species in ambient air by means of direct absorption, cavity-enhanced, and photoacoustic spectroscopy. These spectroscopic techniques offer an alternative to non-spectroscopic techniques such as mass spectrometry (MS), gas chromatography (GC) and electrochemical sensors. The sensitivity and selectivity that can be achieved by both techniques (excluding electrochemical sensors) are similar, but the sensor response time, instrumentation size and cost of ownership for spectroscopic techniques can be advantageous as compared to MS-GC spectrometry.