Raman spectroscopy and diffuse reflectance spectroscopy for diagnosis of human cancer and acanthosis nigricans

Cancer and diabetes are common chronic diseases in today\u27s world causing numerous deaths in adults as well as children. Most common types of cancers in adults include prostate, lung, breast, colorectal and head and neck squamous cell carcinoma, while among children; leukemia, and brain and central nervous system cancers are quite common. In each of these cases, early detection of the cancer or disease dramatically increases the chances of successful treatment. In recent years, there has been much interest in using Raman spectroscopy and diffuse reflectance spectroscopy as analytical optical spectroscopic methods for early diagnosis of diseases. Raman spectroscopy can be used to measure changes in the bio-molecular composition of a tissue specimen, and diffuse reflectance spectroscopy can measure chromophores of the skin. In this research, archived (formalin-fixed paraffin processed) tissues of head and neck squamous cell carcinoma, prostate, and pediatric tumors have been investigated using Raman spectroscopy. We have utilized statistical methods such as principal component analysis (PCA) and discriminant function analysis (DFA) to analyze the spectral output and distinguish between normal and cancerous tissues. The results show cancerous tissues can be successfully distinguished from normal tissues in three cancer types in ex vivo. However, due to loss of biochemical in the tissue processing (paraffinizing and deparaffinizing procedure), the prediction ability of the archived tissues are less compared to frozen tissues as observed in the pediatric tumor investigation. We also investigated the diagnostic capability of diffuse reflectance spectroscopy and colorimetry on a skin disease, acanthosis nigricans in vivo. The aim is to quantify and characterize the skin color change associated with acanthosis nigricans skin disease in insulin-resistant obese individuals. We observe both the instruments can be utilized to detect acanthosis nigricans with more than 87% sensitivity and 94% specificity when combined with advanced chemometric methods

The Influence of Dosimetric Parameters on Quality of Life for Early Stage Non-small Cell Lung Cancer Patients Treated with Stereotactic Body Radiation Therapy

Background: Lung stereotactic body radiotherapy (SBRT) has become a standard treatment option for early stage non-small cell lung cancer (NSCLC) patients who are medically inoperable. The influence of radiation dose/volume parameters on quality of life is not known. Our hypothesis is that clinically meaningful declines in quality of life over time will be associated with increased radiation lung dose/volume parameters. Objectives: To investigate clinical toxicity and quality of life (QOL) outcomes of stage I NSCLC patients after SBRT as a function of radiation dose/volume parameters. Methods: In this IRB-approved study, 55 stage I NSCLC patients who received SBRT (12 Gy x 4) and completed QOL forms were analyzed. Clinical symptoms and QOL were measured at baseline and at 3, 6, 12, 18, 24, and 36 months post-SBRT. Clinical toxicity was graded using the common terminology criteria for adverse effects (CTCAE v4.0). Quality of life was followed using the validated Functional Assessment of Cancer Therapy-Trial Outcome Index (FACT-TOI) instrument. Dosimetric parameters, including the mean lung radiation dose (MLD), and the volume of normal lung receiving \u3e 5, 10, 13 or 20 Gy (V5, V10, V13, and V20) were measured from the radiation treatment plan. Student\u27s t-test and Pearson correlation analyses were used to examine the relationships between radiation lung metrics and clinically meaningful changes in QOL and/or clinical toxicities. Kaplan-Meier method was used to estimate rates of local control (LC), disease free survival (DFS), and overall survival (OS). Results: With a median follow-up of 24 months, the 3 year LC, DFS, and OS were 93%, 65% and 84%, respectively, with 5.5% grade 3 toxicity and no grade 4 or 5 toxicities. Clinically meaningful declines in patient reported QOL (FACT-TOI, lung cancer subscale, physical well-being, and/or functional well-being) post-treatment significantly correlated with increased dosimetric parameters, such as V10, V13, and V20. Conclusions: While lung SBRT is associated with excellent LC and minimal clinical toxicity for early stage NSCLC, clinically meaningful declines in QOL significantly correlated with increasing lung dose/volume parameters. This suggests that further improvements in the techniques of lung SBRT have the potential to further enhance patients\u27 QOL following this treatment

The Influence of Dosimetric Parameters on Quality of Life for Early Stage Non-small Cell Lung Cancer Patients Treated with Stereotactic Body Radiation Therapy

Background: Lung stereotactic body radiotherapy (SBRT) has become a standard treatment option for early stage non-small cell lung cancer (NSCLC) patients who are medically inoperable. The influence of radiation dose/volume parameters on quality of life is not known. Our hypothesis is that clinically meaningful declines in quality of life over time will be associated with increased radiation lung dose/volume parameters. Objectives: To investigate clinical toxicity and quality of life (QOL) outcomes of stage I NSCLC patients after SBRT as a function of radiation dose/volume parameters. Methods: In this IRB-approved study, 55 stage I NSCLC patients who received SBRT (12 Gy x 4) and completed QOL forms were analyzed. Clinical symptoms and QOL were measured at baseline and at 3, 6, 12, 18, 24, and 36 months post-SBRT. Clinical toxicity was graded using the common terminology criteria for adverse effects (CTCAE v4.0). Quality of life was followed using the validated Functional Assessment of Cancer Therapy-Trial Outcome Index (FACT-TOI) instrument. Dosimetric parameters, including the mean lung radiation dose (MLD), and the volume of normal lung receiving \u3e 5, 10, 13 or 20 Gy (V5, V10, V13, and V20) were measured from the radiation treatment plan. Student\u27s t-test and Pearson correlation analyses were used to examine the relationships between radiation lung metrics and clinically meaningful changes in QOL and/or clinical toxicities. Kaplan-Meier method was used to estimate rates of local control (LC), disease free survival (DFS), and overall survival (OS). Results: With a median follow-up of 24 months, the 3 year LC, DFS, and OS were 93%, 65% and 84%, respectively, with 5.5% grade 3 toxicity and no grade 4 or 5 toxicities. Clinically meaningful declines in patient reported QOL (FACT-TOI, lung cancer subscale, physical well-being, and/or functional well-being) post-treatment significantly correlated with increased dosimetric parameters, such as V10, V13, and V20. Conclusions: While lung SBRT is associated with excellent LC and minimal clinical toxicity for early stage NSCLC, clinically meaningful declines in QOL significantly correlated with increasing lung dose/volume parameters. This suggests that further improvements in the techniques of lung SBRT have the potential to further enhance patients\u27 QOL following this treatment

Characteristics of a novel treatment system for linear accelerator–based stereotactic radiosurgery

The purpose of this study is to characterize the dosimetric properties and accuracy of a novel treatment platform (Edge radiosurgery system) for localizing and treating patients with frameless, image-guided stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT). Initial measurements of various components of the system, such as a comprehensive assessment of the dosimetric properties of the flattening filter-free (FFF) beams for both high definition (HD120) MLC and conical cone-based treatment, positioning accuracy and beam attenuation of a six degree of freedom (6DoF) couch, treatment head leakage test, and integrated end-to-end accuracy tests, have been performed. The end-to-end test of the system was performed by CT imaging a phantom and registering hidden targets on the treatment couch to determine the localization accuracy of the optical surface monitoring system (OSMS), cone-beam CT (CBCT), and MV imaging systems, as well as the radiation isocenter targeting accuracy. The deviations between the percent depth-dose curves acquired on the new linac-based system (Edge), and the previously published machine with FFF beams (TrueBeam) beyond Dmax were within 1.0% for both energies. The maximum deviation of output factors between the Edge and TrueBeam was 1.6%. The optimized dosimetric leaf gap values, which were fitted using Eclipse dose calculations and measurements based on representative spine radiosurgery plans, were 0.700 mm and 1.000 mm, respectively. For the conical cones, 6X FFF has sharper penumbra ranging from 1.2–1.8 mm (80%-20%) and 1.9–3.8 mm (90%-10%) relative to 10X FFF, which has 1.2–2.2mm and 2.3–5.1mm, respectively. The relative attenuation measurements of the couch for PA, PA (rails-in), oblique, oblique (rails-out), oblique (rails-in) were: -2.0%, -2.5%, -15.6%, -2.5%, -5.0% for 6X FFF and -1.4%, -1.5%, -12.2%, -2.5%, -5.0% for 10X FFF, respectively, with a slight decrease in attenuation versus field size. The systematic deviation between the OSMS and CBCT was -0.4 ± 0.2 mm, 0.1± 0.3mm, and 0.0 ± 0.1 mm in the vertical, longitudinal, and lateral directions. The mean values and standard deviations of the average deviation and maximum deviation of the daily Winston-Lutz tests over three months are 0.20 ± 0.03 mm and 0.66 ± 0.18 mm, respectively. Initial testing of this novel system demonstrates the technology to be highly accurate and suitable for frameless, linac-based SRS and SBRT treatment

Kinetic modeling of tumor regression incorporating the concept of cancer stem-like cells for patients with locally advanced lung cancer

Abstract Background Personalized medicine for patients receiving radiation therapy remains an elusive goal due, in part, to the limits in our understanding of the underlying mechanisms governing tumor response to radiation. The purpose of this study was to develop a kinetic model, in the context of locally advanced lung cancer, connecting cancer cell subpopulations with tumor volumes measured during the course of radiation treatment for understanding treatment outcome for individual patients. Methods The kinetic model consists of three cell compartments: cancer stem-like cells (CSCs), non-stem tumor cells (TCs) and dead cells (DCs). A set of ordinary differential equations were developed to describe the time evolution of each compartment, and the analytic solution of these equations was iterated to be aligned with the day-to-day tumor volume changes during the course of radiation treatment. A least squares fitting method was used to estimate the parameters of the model that include the proportion of CSCs and their radio-sensitivities. This model was applied to five patients with stage III lung cancer, and tumor volumes were measured from 33 cone-beam computed tomography (CBCT) images for each of these patients. The analytical solution of these differential equations was compared with numerically simulated results. Results For the five patients with late stage lung cancer, the derived proportions of CSCs are 0.3 on average, the average probability of the symmetry division is 0.057 and the average surviving fractions of CSCs is 0.967, respectively. The derived parameters are comparable to the results from literature and our experiments. The preliminary results suggest that the CSC self-renewal rate is relatively small, compared to the proportion of CSCs for locally advanced lung cancers. Conclusions A novel mathematical model has been developed to connect the population of cancer stem-like cells with tumor volumes measured from a sequence of CBCT images. This model may help improve our understanding of tumor response to radiation therapy, and is valuable for development of new treatment regimens for patients with locally advanced lung cancer

Raman Spectroscopy for Assessing Radiation-Induced Pulmonary Fibrosis

Purpose: Raman spectroscopy measures the change in the energy of scattered light compared to the excitation photons to quantify molecular changes. In this study, Raman spectroscopy was used to investigate molecular changes in mice following radiation-induced pulmonary fibrosis. Methods: Fourteen C57BL/6J male mice were investigated. The whole lungs of seven mice were irradiated with 15 Gy in a single fraction using 6 MV photons. Seven additional mice were used as controls. At specified times after irradiation, 48 hr (3 irradiated and 3 control mice) and 6 months (4 irradiated and 4 control mice), lungs were excised, flash frozen, and sectioned. Alternating sections were either stained with hematoxylin and eosin and evaluated by a pathologist or unstained for Raman measurements. Raman data were acquired from areas of alveolar wall thickening or areas near hyaline membranes (48 hr) and severe distortion of structure (due, for example, to fibrosis at 6 months), and compared with that from normal lung parenchyma. A total of 244 Raman spectra were acquired and analyzed using principal component analysis (PCA), discriminant function analysis (DFA) and Raman intensity ratio metric method. Results: PCA captured 95% of the variance in the Raman spectral features. PCA/DFA analysis showed severe distortion (fibrosis) was identifiable 92% of the time. Acute injury (48 hr) compared to normal lung parenchyma was identified with 100% sensitivity and specificity. A minor alveolar septal thickening in normal controls was noted between spectra collected at 48 hr and 6 month time points. Consistent with fibrosis, multiple Raman bands (850, 1002, 1309, 1448, 1656 cm-1) assignable to proteins and lipids increased whereas others (1223 and 1578 cm-1) assignable to nucleic acids decreased. Consistent with acute damage, increased Raman intensity ratio of 1448/1002 and 1658/1002 (protein) was observed. Conclusion: Preliminary findings support the use of Raman spectroscopy to characterize radiation-induced fibrosis

Kinetic modeling of tumor regression incorporating the concept of cancer stem-like cells for patients with locally advanced lung cancer

BACKGROUND: Personalized medicine for patients receiving radiation therapy remains an elusive goal due, in part, to the limits in our understanding of the underlying mechanisms governing tumor response to radiation. The purpose of this study was to develop a kinetic model, in the context of locally advanced lung cancer, connecting cancer cell subpopulations with tumor volumes measured during the course of radiation treatment for understanding treatment outcome for individual patients. METHODS: The kinetic model consists of three cell compartments: cancer stem-like cells (CSCs), non-stem tumor cells (TCs) and dead cells (DCs). A set of ordinary differential equations were developed to describe the time evolution of each compartment, and the analytic solution of these equations was iterated to be aligned with the day-to-day tumor volume changes during the course of radiation treatment. A least squares fitting method was used to estimate the parameters of the model that include the proportion of CSCs and their radio-sensitivities. This model was applied to five patients with stage III lung cancer, and tumor volumes were measured from 33 cone-beam computed tomography (CBCT) images for each of these patients. The analytical solution of these differential equations was compared with numerically simulated results. RESULTS: For the five patients with late stage lung cancer, the derived proportions of CSCs are 0.3 on average, the average probability of the symmetry division is 0.057 and the average surviving fractions of CSCs is 0.967, respectively. The derived parameters are comparable to the results from literature and our experiments. The preliminary results suggest that the CSC self-renewal rate is relatively small, compared to the proportion of CSCs for locally advanced lung cancers. CONCLUSIONS: A novel mathematical model has been developed to connect the population of cancer stem-like cells with tumor volumes measured from a sequence of CBCT images. This model may help improve our understanding of tumor response to radiation therapy, and is valuable for development of new treatment regimens for patients with locally advanced lung cancer

Accumulated Dose Estimation in Lung Stereotactic Body Radiation Therapy using Deformable Image Registration Algorithm

Purpose: To estimate accumulated dose to targets and OARs for lung cancer patients treated with SBRT. Methods: CBCT and planning CT (pCT) image datasets for lung cancer patients treated with SBRT (12Gyx4), were deformably registered. ITV-PTV margin was uniformly 5 mm. The pCT was deformed and resampled based on the displacement vector field (DVF) from the pCT/CBCT registration, so as to minimize HU issues associated with CBCT. Deformable image registration (DIR) was based on a multi-resolution b-spline algorithm with mutual-information as the similarity metric. Dose-ofthe- day was calculated on the deformed pCT datasets, for each of the four fractions, and dose was accumulated using an energy-mass-mapping algorithm. Results: Mean (standard deviation) of cumulative mean dose minus plan mean dose was -0.6% (1.2%) for the GTV, -0.9% (1.3%) for the PTV, -1.8% (1.2%) for the spinal cord, and -1.6% (4.1%) for total lung-PTV. Mean (standard deviation) of cumulative D95 minus plan D95 was -0.5% (1.3%) for the GTV and -2.9% (2.6%) for the PTV. Mean (standard deviation) of cumulative max. dose minus plan max. dose was -1.1% (1.0%) for the GTV, -1.1% (0.9%) for the PTV, 3.4% (11.7%) for the spinal cord, and 1.1% (2.0%) for total lung-PTV. Mean (standard deviation) of cumulative min. dose minus plan min. dose was 2.1% (3.5%) for the GTV and -14.2% (5.9%) for the PTV. Conclusion: Cumulative doses using deformable dose accumulation were found to be less than planned doses. The planned dose degradation is noted in the DVH shoulders, where min. differences \u3e10% are observed for the PTV, albeit with the GTV min. dose maintained within (2- 4%). OAR max. doses for critical structures such as the spinal cord are shown to increase \u3e10%, which is an important consideration for this serial organ, in the context of SBRT lung treatment

Retrospective correlation of radiation pneumonitis with dose distributions computed with different algorithms for locally advanced lung cancer patients.

Purpose: To correlate radiation pneumonitis (RP) with dose distributions, computed with different algorithms for 51 patients with locally advanced lung cancer. Methods: We retrospectively investigated dose distributions for 51 lung cancer patients treated with 60-66 Gy in 2 Gy fractions. The majority of tumors were centrally located. A radiation oncologist graded the RP based on the CTCAE scheme, defining clinical symptoms according to severity, grades 1-4. Nineteen patients experienced RP. Treatment plans were computed using AAA in Eclipse with IMRT or 3D conformal techniques. These plans were recomputed using the AcurosXB and pencil beam (PB) algorithms with identical plan parameters. Dosimetric parameters for normal lung (total lung-CTV) such as mean lung dose (MLD), V5, and V20 were correlated with RP. Results: Overall RP grade increases with MLD, V20, and V5. MLD showed the strongest association with RP grade (R2 = 0.74). As a function of RP grade, AAA, AcurosXB, and PB algorithms showed similar curves and trends, though the curves for AAA and AcurosXB were in better agreement relative to PB. V5 was found to be noticeably lower for PB algorithm relative to AAA and AcurosXB. Percent difference of mean V5 for RP grade 1, 2, and 4 are -5.2±0%, -3.4±0.9%, and -2.1±1.9%, respectively, relative to AAA. This is due to lack of inability to account for the lateral electron spreading using the PB algorithm. Conclusion: For the purposes of outcome modeling, AAA, AcurosXB and PB algorithms showed similar correlations with radiation-induced pneumonitis, however, AAA and AcurosXB curve shapes were in better agreement. These findings need to be validated with a large dataset