**Acknowledgements**

I would first like to thank my supervisor, Assistant Professor Dr. O.P.Verma, whose expertise was invaluable in formulating the research questions and methodology. Your insightful feedback pushed me to sharpen my thinking and brought my work to a higher level. In addition, I would like to thank my parents and my husband for their wise counsel and sympathetic ear. You are always there for me, who provided stimulating discussions as well as happy distractions to rest my mind outside of my research.


We have shown that accelerated treatment planning software for Helical TomoTherapy provides clinically acceptable dosimetry, with conformality and homogeneity that is superior to standard LINAC-based 3D conformal planning and is only slightly inferior to standard Helical TomoTherapy dosimetry (McIntosh et al., 2010). We have also shown that, with planning times of 2-5 minutes, this accelerated treatment planning software provides levels of dosimetric conformality, heterogeneity, and avoidance of organs at risk for simple SBRT treatments that are clinically equivalent to those generated with conventional Helical TomoTherapy treatment planning (Dunlap et al., 2010). This preliminary data supports that treatment planning speed is not likely to be rate limiting in the ultimate clinical

Current standard of care TomoTherapy quality assurance methodology requires that each patient-specific treatment plan be delivered to a cylindrical plastic phantom with ion chamber and film measurement to ensure geometric and planar dose distribution accuracy using gamma criteria of 3%/3mm. However, this method does not measure the dose that the patient is receiving during treatment or provide full 3D dose verification. It causes another delay in delivering the first treatment to the patient as it requires approximately 30 minutes to complete, and is generally done by a medical physicist after daily clinic patient treatment is finished. A methodology to monitor the patient exit dose in real time would increase patient safety through verification of daily treatment accuracy as well as expedite the treatment workflow. Clearly, a real-time quality assurance methodology that does not require moving the patient off the TomoTherapy treatment couch for phantom measurements is essential for the development of a 30-minute Scan-Plan-Verify-Treat workflow. Current dose verification methodologies measuring dose at the time of patient treatment are limited to point measurements on the patient surface (Essers & Mijnheer, 1999), which is rarely in the target volume or a critical OAR, or through expensive implanted dosimeters (Beyer et al., 2007; Scarantino et al., 2004), which are not practical for most palliative patients. Since there is no method to directly measure the three dimensional dose in the patient, alternative approaches are being developed and tested in academic clinical settings. These alternative approaches reconstruct the delivered three dimensional dose distribution based on the measurement of either entrance or exit dose and back-

projecting the measurements onto simulation or image guidance CT image sets.

2008). Investigators are currently working on methods to overcome these challenges.

The opportunity to reconstruct dose from information collected during treatment became available with the incorporation of radiation imaging detectors, such as electronic portal imaging devices (EPID) on linear-accelerators and CT detector arrays on TomoTherapy. Dose reconstruction using in-line EPID was first described by McNutt et al (McNutt, Mackie, & Paliwal 1997; McNutt et al., 1996). The EPID, when deployed during treatment, collects exit fluence from the patient and then back-projects this to X-ray fluence before entering the patient; then, the dose in the patient is re-computed using this entrance fluence and the planning CT images. However, there are many limitations to EPID-based dose verification. For example, the EPID was originally designed for semi-quantitative portal imaging; and for the purpose of dose reconstruction, it suffers from a narrow dynamic range, short life span, non-linearity in the dose response, ghost artifacts from low temporal resolution, and cross-plane scatter photon contribution to the measured fluence (Mijnheer,

implementation of the Scan-Plan-Verify-Treat STAT RAD workflow.

**5.3 Novel CT-detector-based quality assurance methodology**

A kVCT simulation scan has historically been used for simulation in the conventional workflow for both palliative and curative radiation planning. Compared to MVCT scans, it has higher resolution and allows the possibility for administration of iodinated IV and/or GI contrast, which makes it easier to identify soft tissues and bony anatomy for treatment planning. However, contrast agents are not generally given for kVCT simulations of patients for palliative treatment of metastases since the soft tissue and bone windows are adequate. Soft tissue and bone windows of MVCT scans have quite reasonable resolution and can easily be co-registered to higher resolution diagnostic studies for contour transfer. Software has been used clinically since 2004 to automatically co-register kVCT simulation images and daily MVCT scans for image guidance on a daily basis.

Our preliminary unpublished data confirms that the MVCT scan has sufficient resolution, particularly of bone anatomy, for accurate co-registration to contoured diagnostic images and that this one step co-registration process yields comparable agreement to the conventional two step image co-registration workflow with +/- 2-3 mm differences. See Figure 3. This level of agreement is consistent with results reported from image coregistration studies performed on a multi-institutional pediatric clinical trial with coregistration data of 51 patients from 45 institutions using 11 different image software systems. They reported an inherent uncertainty of 2 mm for MRI to CT co-registration (Ulin, Urie, & Cherlow 2010). Thus, preliminary data suggests that the optimization of this one step image co-registration workflow of diagnostic image sets to a MVCT simulation scan will be clinically similar to the conventional two image co-registration workflow. MVCT image guidance scans and kVCT simulation co-registration occurs routinely in the clinic and only takes a few seconds, therefore, we do not believe that this will be a rate-limiting step in the clinical implementation of the Scan-Plan-Verify-Treat STAT RAD workflow. Further optimization of the image co-registration workflow will make the 30-minute Scan-Plan-Verify-Treat STAT RAD workflow feasible.

#### **5.2 Rapid inverse treatment planning on MVCT scans**

CT image sets are used for radiation treatment planning because the electron density of tissues, which is required for calculating dose, is easily determined based on the Hounsfield units. The tissue electron density determination is essentially the same for MVCT and kVCT scans. It has previously been reported that as far as the dose calculations are concerned, treatment planning on either a kVCT simulation image set or a MVCT simulation image set yields treatment plans that are within 1% of each other (Langen et al., 2005).

We have recently published that the TomoTherapy STAT RT treatment planning module can calculate SBRT plans in just a few minutes (Dunlap et al., 2010). The computing speed of radiation treatment planning systems is about to take a quantum leap forward with the incorporation of new algorithms that will take advantage of the processing power of graphics processing units (GPU) whose more rapid and parallel calculating potential can improve treatment planning speed by 10-20 times (Hissoiny, Ozell, & Despres, 2010; Hissoiny, Ozell, and Despres, 2009). Same-day inverse treatment planning of IMRT or 3D TomoTherapy plans has not been a problem for patients treated with STAT RAD to date. We are comparing planning times for current FDA-approved treatment planning systems to those of newer, in-development GPU-based algorithms. In general, highly conformal 3D or IMRT plans can be generated in 2-3 minutes with GPU-based algorithms.

A kVCT simulation scan has historically been used for simulation in the conventional workflow for both palliative and curative radiation planning. Compared to MVCT scans, it has higher resolution and allows the possibility for administration of iodinated IV and/or GI contrast, which makes it easier to identify soft tissues and bony anatomy for treatment planning. However, contrast agents are not generally given for kVCT simulations of patients for palliative treatment of metastases since the soft tissue and bone windows are adequate. Soft tissue and bone windows of MVCT scans have quite reasonable resolution and can easily be co-registered to higher resolution diagnostic studies for contour transfer. Software has been used clinically since 2004 to automatically co-register kVCT simulation images and

Our preliminary unpublished data confirms that the MVCT scan has sufficient resolution, particularly of bone anatomy, for accurate co-registration to contoured diagnostic images and that this one step co-registration process yields comparable agreement to the conventional two step image co-registration workflow with +/- 2-3 mm differences. See Figure 3. This level of agreement is consistent with results reported from image coregistration studies performed on a multi-institutional pediatric clinical trial with coregistration data of 51 patients from 45 institutions using 11 different image software systems. They reported an inherent uncertainty of 2 mm for MRI to CT co-registration (Ulin, Urie, & Cherlow 2010). Thus, preliminary data suggests that the optimization of this one step image co-registration workflow of diagnostic image sets to a MVCT simulation scan will be clinically similar to the conventional two image co-registration workflow. MVCT image guidance scans and kVCT simulation co-registration occurs routinely in the clinic and only takes a few seconds, therefore, we do not believe that this will be a rate-limiting step in the clinical implementation of the Scan-Plan-Verify-Treat STAT RAD workflow. Further optimization of the image co-registration workflow will make the 30-minute Scan-Plan-

CT image sets are used for radiation treatment planning because the electron density of tissues, which is required for calculating dose, is easily determined based on the Hounsfield units. The tissue electron density determination is essentially the same for MVCT and kVCT scans. It has previously been reported that as far as the dose calculations are concerned, treatment planning on either a kVCT simulation image set or a MVCT simulation image set

We have recently published that the TomoTherapy STAT RT treatment planning module can calculate SBRT plans in just a few minutes (Dunlap et al., 2010). The computing speed of radiation treatment planning systems is about to take a quantum leap forward with the incorporation of new algorithms that will take advantage of the processing power of graphics processing units (GPU) whose more rapid and parallel calculating potential can improve treatment planning speed by 10-20 times (Hissoiny, Ozell, & Despres, 2010; Hissoiny, Ozell, and Despres, 2009). Same-day inverse treatment planning of IMRT or 3D TomoTherapy plans has not been a problem for patients treated with STAT RAD to date. We are comparing planning times for current FDA-approved treatment planning systems to those of newer, in-development GPU-based algorithms. In general, highly conformal 3D or

yields treatment plans that are within 1% of each other (Langen et al., 2005).

IMRT plans can be generated in 2-3 minutes with GPU-based algorithms.

daily MVCT scans for image guidance on a daily basis.

Verify-Treat STAT RAD workflow feasible.

**5.2 Rapid inverse treatment planning on MVCT scans**

We have shown that accelerated treatment planning software for Helical TomoTherapy provides clinically acceptable dosimetry, with conformality and homogeneity that is superior to standard LINAC-based 3D conformal planning and is only slightly inferior to standard Helical TomoTherapy dosimetry (McIntosh et al., 2010). We have also shown that, with planning times of 2-5 minutes, this accelerated treatment planning software provides levels of dosimetric conformality, heterogeneity, and avoidance of organs at risk for simple SBRT treatments that are clinically equivalent to those generated with conventional Helical TomoTherapy treatment planning (Dunlap et al., 2010). This preliminary data supports that treatment planning speed is not likely to be rate limiting in the ultimate clinical implementation of the Scan-Plan-Verify-Treat STAT RAD workflow.

#### **5.3 Novel CT-detector-based quality assurance methodology**

Current standard of care TomoTherapy quality assurance methodology requires that each patient-specific treatment plan be delivered to a cylindrical plastic phantom with ion chamber and film measurement to ensure geometric and planar dose distribution accuracy using gamma criteria of 3%/3mm. However, this method does not measure the dose that the patient is receiving during treatment or provide full 3D dose verification. It causes another delay in delivering the first treatment to the patient as it requires approximately 30 minutes to complete, and is generally done by a medical physicist after daily clinic patient treatment is finished. A methodology to monitor the patient exit dose in real time would increase patient safety through verification of daily treatment accuracy as well as expedite the treatment workflow. Clearly, a real-time quality assurance methodology that does not require moving the patient off the TomoTherapy treatment couch for phantom measurements is essential for the development of a 30-minute Scan-Plan-Verify-Treat workflow. Current dose verification methodologies measuring dose at the time of patient treatment are limited to point measurements on the patient surface (Essers & Mijnheer, 1999), which is rarely in the target volume or a critical OAR, or through expensive implanted dosimeters (Beyer et al., 2007; Scarantino et al., 2004), which are not practical for most palliative patients. Since there is no method to directly measure the three dimensional dose in the patient, alternative approaches are being developed and tested in academic clinical settings. These alternative approaches reconstruct the delivered three dimensional dose distribution based on the measurement of either entrance or exit dose and backprojecting the measurements onto simulation or image guidance CT image sets.

The opportunity to reconstruct dose from information collected during treatment became available with the incorporation of radiation imaging detectors, such as electronic portal imaging devices (EPID) on linear-accelerators and CT detector arrays on TomoTherapy. Dose reconstruction using in-line EPID was first described by McNutt et al (McNutt, Mackie, & Paliwal 1997; McNutt et al., 1996). The EPID, when deployed during treatment, collects exit fluence from the patient and then back-projects this to X-ray fluence before entering the patient; then, the dose in the patient is re-computed using this entrance fluence and the planning CT images. However, there are many limitations to EPID-based dose verification. For example, the EPID was originally designed for semi-quantitative portal imaging; and for the purpose of dose reconstruction, it suffers from a narrow dynamic range, short life span, non-linearity in the dose response, ghost artifacts from low temporal resolution, and cross-plane scatter photon contribution to the measured fluence (Mijnheer, 2008). Investigators are currently working on methods to overcome these challenges.

STAT RAD: A Potential Real-Time Radiation Therapy Workflow 35

Several advantages of this streamlined workflow are envisioned that will improve the care of patients with metastatic disease. The most obvious is that patients who live far from treatment centers can be offered palliative radiation therapy as an option. Take for example the case of a patient who lives 50 miles from a radiation oncology center. If they are seen in consultation, undergo a CT simulation on a second visit, and then are treated with 30 Gy in 10 fractions, they will have to drive 1200 miles for this treatment course. Clearly this is not practical for many ill patients in the last few months of life. If they can receive a conformal high dose palliative treatment in one day, it is much more likely that they will receive this treatment. We have been coordinating STAT RAD treatments on days that patients have appointments with other oncologists or specialists. Patients come to the radiation oncology clinic and undergo a consultation and CT simulation and then go to their other appointments while planning and quality assurance measurements are performed, and then they return to the radiation oncology clinic later that same day for treatment. Once the Scan-Plan-Verify-Treat STAT RAD workflow is available, we envision treating patients at the end of the scheduled workday on a same-day physician request basis. This service holds high utilization potential because many times physicians do not know if a patient is in significant need of palliation until they examine the patient at the

Frequently patients are admitted to the hospital for management of cancer-related symptoms such as intractable pain, spinal cord compression, profuse tumor bleeding, or tumor related acute obstruction. These patients are frequently treated with palliative radiation therapy. The STAT RAD workflow enables patients to receive high dose and conformal treatments that start faster than conventional kVCT simulation workflows and

Finally, this workflow makes the treatment of patients with oligometastatic disease more streamlined and practical because it enables SBRT-like dose distributions to be delivered to multiple lesions that currently cannot be treated with SBRT, such as nodal disease or non-

**6.2 Incorporation of translational technology development into routine clinic care for**

Several aspects of the Scan-Plan-Verify-Treat STAT RAD clinical development can be incorporated into the routine care of patients undergoing curative radiation therapy. Specifically, CT detector-based quality assurance of all treatments could be automated and performed daily. Such quality assurance could provide a warning if the delivered dose is greater than a threshold such as +/- 5% for a patient and trigger an investigation into the cause of this deviation. Quality assurance of each fraction of treatment would be a major advancement compared to current quality assurance methods of checking each plan prior to treatment. Using daily quality assurance to monitor changes in patient status such as significant weight loss in a head and neck cancer patient could trigger re-planning that

**6. Clinical benefits and future directions of STAT RAD implementation**

**6.1 Additional benefits to patients with metastatic disease**

can shorten the length of hospitalization to complete treatment.

time of a scheduled appointment.

spinal bone metastases.

could be done on an adaptive basis.

**all patients**

The TomoTherapy unit has an in-line source-patient-detector geometry with CT ion chamber detectors that are used for daily MVCT scan image guidance for accurate patient positioning that remain in place during both imaging and treatment. These CT detectors can also be used to measure the patient exit dose fluence and back-project this onto a planning CT scan for volumetric or 3D dose reconstruction. Dose verification on TomoTherapy was first studied by Kapatoes et al., who calculated the entrance fluence from the exit dose using a transfer matrix, which is calculated based on the radiological path length from the source to the detector (Kapatoes et al., 2001; Kapatoes et al., 2001). The use of a CT ion chamber array has multiple advantages over EPID for exit fluence measurement. It is more durable, and has a much longer life span. It has a wider dynamic range and doesn't limit treatment positions. Finally, it is less sensitive to the noise from cross-plane scatter photons that complicate EPID-based dose reconstruction (Siewerdsen & Jaffray 2001).

Our pre-clinical evaluation of the CT detector-based exit radiation dose verification algorithm has been retrospectively studied by Sheng et al. using in-development software (Sheng et al., 2011). We compared planned and delivered doses with the conventional phantom quality assurance measurements for 24 patients and 347 treatment fractions. The concordance of planned to delivered dose calculated by the in-development software was shown to be +/- 5% (Sheng et al., 2011). This tolerance is within the standard of care of other current clinically available quality assurance methods. Further refinements are expected to improve dose monitoring accuracy for this or other algorithms.

#### **5.4 Optical tracking methods for patient intra-fractional motion monitoring**

Consistent patient positioning during CT image acquisition and treatment is critical to ensure accurate dose delivery. Physical immobilization devices such as external body frames, aquaplast masks and other body molds, and vac-lock vacuum bags are commonly used to ensure patient positioning reproducibility. X-ray or CT image guidance prior to radiation delivery on the treatment unit is routinely employed in the clinic. Methods for optical tracking of markers on the patient surface or tracking of the patient's skin surface itself are available to ensure consistent patient positioning after image guidance and during treatment, known as intra-fractional motion (Wagner et al., 2007; Wiersma et al., 2010). This provides a method without ionizing radiation for confirming patient position that can be used real-time during treatment delivery. With this information, if the patient's position moves outside of acceptable limits in any direction, treatment could be paused. A mechanism to ensure that the patient's position doesn't change between MVCT simulation and treatment delivery would obviate the need for a repeat image guidance MVCT scan just prior to delivery in the Scan-Plan-Verify-Treat workflow.

We have recently developed an in-house optical tracking system using multiple OptiTrack FLEX:V100 cameras (Natural Point, Corvallis, OR). The camera utilizes 26 infrared lightemitting diodes and a charge coupled device to capture the reflective light from markers with special coating. By using multiple cameras, the 3D position of each reflective marker can be determined precisely. Multiple markers can be placed on a patient and monitored simultaneously. In the lab, localization precision of 0.1 mm was achieved (unpublished data). Through strategic positioning of the markers, movements of the head, neck, and extracranial locations can be closely monitored.

The TomoTherapy unit has an in-line source-patient-detector geometry with CT ion chamber detectors that are used for daily MVCT scan image guidance for accurate patient positioning that remain in place during both imaging and treatment. These CT detectors can also be used to measure the patient exit dose fluence and back-project this onto a planning CT scan for volumetric or 3D dose reconstruction. Dose verification on TomoTherapy was first studied by Kapatoes et al., who calculated the entrance fluence from the exit dose using a transfer matrix, which is calculated based on the radiological path length from the source to the detector (Kapatoes et al., 2001; Kapatoes et al., 2001). The use of a CT ion chamber array has multiple advantages over EPID for exit fluence measurement. It is more durable, and has a much longer life span. It has a wider dynamic range and doesn't limit treatment positions. Finally, it is less sensitive to the noise from cross-plane scatter photons that

Our pre-clinical evaluation of the CT detector-based exit radiation dose verification algorithm has been retrospectively studied by Sheng et al. using in-development software (Sheng et al., 2011). We compared planned and delivered doses with the conventional phantom quality assurance measurements for 24 patients and 347 treatment fractions. The concordance of planned to delivered dose calculated by the in-development software was shown to be +/- 5% (Sheng et al., 2011). This tolerance is within the standard of care of other current clinically available quality assurance methods. Further refinements are expected to

Consistent patient positioning during CT image acquisition and treatment is critical to ensure accurate dose delivery. Physical immobilization devices such as external body frames, aquaplast masks and other body molds, and vac-lock vacuum bags are commonly used to ensure patient positioning reproducibility. X-ray or CT image guidance prior to radiation delivery on the treatment unit is routinely employed in the clinic. Methods for optical tracking of markers on the patient surface or tracking of the patient's skin surface itself are available to ensure consistent patient positioning after image guidance and during treatment, known as intra-fractional motion (Wagner et al., 2007; Wiersma et al., 2010). This provides a method without ionizing radiation for confirming patient position that can be used real-time during treatment delivery. With this information, if the patient's position moves outside of acceptable limits in any direction, treatment could be paused. A mechanism to ensure that the patient's position doesn't change between MVCT simulation and treatment delivery would obviate the need for a repeat image guidance MVCT scan just

We have recently developed an in-house optical tracking system using multiple OptiTrack FLEX:V100 cameras (Natural Point, Corvallis, OR). The camera utilizes 26 infrared lightemitting diodes and a charge coupled device to capture the reflective light from markers with special coating. By using multiple cameras, the 3D position of each reflective marker can be determined precisely. Multiple markers can be placed on a patient and monitored simultaneously. In the lab, localization precision of 0.1 mm was achieved (unpublished data). Through strategic positioning of the markers, movements of the head, neck, and

complicate EPID-based dose reconstruction (Siewerdsen & Jaffray 2001).

improve dose monitoring accuracy for this or other algorithms.

prior to delivery in the Scan-Plan-Verify-Treat workflow.

extracranial locations can be closely monitored.

**5.4 Optical tracking methods for patient intra-fractional motion monitoring**

#### **6. Clinical benefits and future directions of STAT RAD implementation**

#### **6.1 Additional benefits to patients with metastatic disease**

Several advantages of this streamlined workflow are envisioned that will improve the care of patients with metastatic disease. The most obvious is that patients who live far from treatment centers can be offered palliative radiation therapy as an option. Take for example the case of a patient who lives 50 miles from a radiation oncology center. If they are seen in consultation, undergo a CT simulation on a second visit, and then are treated with 30 Gy in 10 fractions, they will have to drive 1200 miles for this treatment course. Clearly this is not practical for many ill patients in the last few months of life. If they can receive a conformal high dose palliative treatment in one day, it is much more likely that they will receive this treatment. We have been coordinating STAT RAD treatments on days that patients have appointments with other oncologists or specialists. Patients come to the radiation oncology clinic and undergo a consultation and CT simulation and then go to their other appointments while planning and quality assurance measurements are performed, and then they return to the radiation oncology clinic later that same day for treatment. Once the Scan-Plan-Verify-Treat STAT RAD workflow is available, we envision treating patients at the end of the scheduled workday on a same-day physician request basis. This service holds high utilization potential because many times physicians do not know if a patient is in significant need of palliation until they examine the patient at the time of a scheduled appointment.

Frequently patients are admitted to the hospital for management of cancer-related symptoms such as intractable pain, spinal cord compression, profuse tumor bleeding, or tumor related acute obstruction. These patients are frequently treated with palliative radiation therapy. The STAT RAD workflow enables patients to receive high dose and conformal treatments that start faster than conventional kVCT simulation workflows and can shorten the length of hospitalization to complete treatment.

Finally, this workflow makes the treatment of patients with oligometastatic disease more streamlined and practical because it enables SBRT-like dose distributions to be delivered to multiple lesions that currently cannot be treated with SBRT, such as nodal disease or nonspinal bone metastases.

#### **6.2 Incorporation of translational technology development into routine clinic care for all patients**

Several aspects of the Scan-Plan-Verify-Treat STAT RAD clinical development can be incorporated into the routine care of patients undergoing curative radiation therapy. Specifically, CT detector-based quality assurance of all treatments could be automated and performed daily. Such quality assurance could provide a warning if the delivered dose is greater than a threshold such as +/- 5% for a patient and trigger an investigation into the cause of this deviation. Quality assurance of each fraction of treatment would be a major advancement compared to current quality assurance methods of checking each plan prior to treatment. Using daily quality assurance to monitor changes in patient status such as significant weight loss in a head and neck cancer patient could trigger re-planning that could be done on an adaptive basis.

STAT RAD: A Potential Real-Time Radiation Therapy Workflow 37

Beyer, G. P., C. W. Scarantino, B. R. Prestidge, A. G. Sadeghi, M. S. Anscher, M. Miften, T. B.

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IV - intravenous kVCT – kilovoltage CT LINAC - linear accelerator

**9. References**

MRI – magnetic resonance imaging

SBRT - stereotactic body radiotherapy SRS - stereotactic radiosurgery

PET CT – positron emission tomography CT

pp. 925-35, ISSN 0360-3016

STAT RAD - urgent and rapid radiation treatment

MVCT – megavoltage CT OAR - organ at risk

PTV - planning target volume

0959-8049

No.2, pp. 245-59, ISSN 0360-3016

A simple system to monitor patient motion following image guidance could reduce the risk of geometric misses due to intra-fractional patient motion. If it were determined that a specific patient had more or less intra-fractional motion than accounted for in their PTV expansion, then their treatment plan could be adaptively re-planned to mirror their specific expansion requirements.

#### **6.3 Future directions for spinal SBRT**

The Scan-Plan-Verify-Treat STAT RAD workflow could easily be incorporated into the treatment of spinal SBRT patients. We have previously reported that treatment planning algorithms currently exist that can create highly conformal spinal SBRT plans in just a few minutes (Dunlap et al., 2010) and that the CT detector-based quality assurance algorithms can measure exit dose to within +/- 5% (Sheng et al., 2011). Real-time spinal SBRT simulation, planning, and delivery would eliminate the need for patients to be accurately reset up and positioned between simulation and treatment to within two millimeters of accuracy which is the current accuracy of most co-registration-based image guided systems. In addition, differences in pitch, yaw, or roll of the patient between simulation and treatment delivery setups cannot be routinely corrected by most CT-based image guidance systems, requiring the patient to be re-positioned and re-imaged prior to treatment if they are out of tolerance. With this proposed workflow, the patient could be treated in the planning position, which could potentially eliminate these re-positioning error issues.

#### **7. Conclusion**

As the cancer burden in the population increases and heath care costs continue to rise, a faster, more efficient workflow is needed to treat patients with metastatic disease. Conformal hypofractionated treatment has demonstrated promising results for the palliation of bone metastases, and its incorporation into a workflow such as the STAT RAD workflow also improves patient convenience. In the near future, we believe the optimization of new software and hardware will enable a 30-minute Scan-Plan-Verify-Treat STAT RAD workflow to further maximize patient convenience and efficiency. This more efficient and cost effective workflow may result in more widespread incorporation of palliative radiation for cancer patients failing systemic therapy earlier in their disease process, reducing pain and functional loss and improving quality of life.

#### **8. Abbreviations**

3D - 3-dimensional BED - biologic effective dose CT – computed tomography CTV – clinical target volume EPID - electronic portal imaging device FDA – Food and Drug Administration GI - gastrointestinal GPU - graphics processing unit Gy - gray IMRT- intensity modulated radiation therapy IV - intravenous kVCT – kilovoltage CT LINAC - linear accelerator MRI – magnetic resonance imaging MVCT – megavoltage CT OAR - organ at risk PET CT – positron emission tomography CT PTV - planning target volume SBRT - stereotactic body radiotherapy SRS - stereotactic radiosurgery STAT RAD - urgent and rapid radiation treatment

#### **9. References**

36 Modern Practices in Radiation Therapy

A simple system to monitor patient motion following image guidance could reduce the risk of geometric misses due to intra-fractional patient motion. If it were determined that a specific patient had more or less intra-fractional motion than accounted for in their PTV expansion, then their treatment plan could be adaptively re-planned to mirror their specific

The Scan-Plan-Verify-Treat STAT RAD workflow could easily be incorporated into the treatment of spinal SBRT patients. We have previously reported that treatment planning algorithms currently exist that can create highly conformal spinal SBRT plans in just a few minutes (Dunlap et al., 2010) and that the CT detector-based quality assurance algorithms can measure exit dose to within +/- 5% (Sheng et al., 2011). Real-time spinal SBRT simulation, planning, and delivery would eliminate the need for patients to be accurately reset up and positioned between simulation and treatment to within two millimeters of accuracy which is the current accuracy of most co-registration-based image guided systems. In addition, differences in pitch, yaw, or roll of the patient between simulation and treatment delivery setups cannot be routinely corrected by most CT-based image guidance systems, requiring the patient to be re-positioned and re-imaged prior to treatment if they are out of tolerance. With this proposed workflow, the patient could be treated in the planning position, which could potentially eliminate these re-positioning error issues.

As the cancer burden in the population increases and heath care costs continue to rise, a faster, more efficient workflow is needed to treat patients with metastatic disease. Conformal hypofractionated treatment has demonstrated promising results for the palliation of bone metastases, and its incorporation into a workflow such as the STAT RAD workflow also improves patient convenience. In the near future, we believe the optimization of new software and hardware will enable a 30-minute Scan-Plan-Verify-Treat STAT RAD workflow to further maximize patient convenience and efficiency. This more efficient and cost effective workflow may result in more widespread incorporation of palliative radiation for cancer patients failing systemic therapy earlier in their disease process, reducing pain

expansion requirements.

**7. Conclusion**

**8. Abbreviations**  3D - 3-dimensional

GI - gastrointestinal

Gy - gray

BED - biologic effective dose CT – computed tomography CTV – clinical target volume

GPU - graphics processing unit

EPID - electronic portal imaging device FDA – Food and Drug Administration

IMRT- intensity modulated radiation therapy

**6.3 Future directions for spinal SBRT**

and functional loss and improving quality of life.

STAT RAD: A Potential Real-Time Radiation Therapy Workflow 39

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**3**

S. Zimeras

 *Greece*

*Karlovassi Samos,*

*University of the Aegean,*

**Segmentation Techniques of**

 **Anatomical Structures with Application**

The definition of structures and the extraction of organ's shape are essential parts of medical imaging applications. These might be applications like diagnostic imaging, image guided surgery or radiation therapy. The aim of the volume definition process is to delineate a specific shape of an organ on a digital image as accurate as possible especially for 3D rendering, radiation therapy, and surgery planning. This can be done, either by manual user interaction or applying imaging processing techniques for the automatic detection of specific structures in the image using segmentation techniques. Segmentation is the process that separates an image into its important features (primitives) so that each of them can be addressed separately. This converts the planar pixel of the image into a distinguishable number of individual organs or tumour that can be clearly identified and manipulated. The segmentation process might involve complicate structures and in this case usually only an expert can perform the task of the identification manually on a slice-by-slice base. Humans can perform this task using complex analysis of shape, intensity, position, texture, and proximity to surrounding structures. In this work we present a set of tools that are implemented on several computer based medical application. Central focus of this work, are techniques used to improve time and interaction needed for a user when defining one or more structures based on segmentation techniques. These techniques involve interpolation methods for the manual volume definition and methods for the semi-automatic organ shape

The goal of radiotherapy treatment planning is to justify an effective treatment that will deliver a precise irradiation dose to the target volume without causing damage to the surrounding normal tissues. Therefore patient positioning, target volume definition and irradiation field placement are very critical steps while planning the irradiation process. Clinically a radiotherapy treatment plan is verified by Virtual Simulators (VS). (Sherouse et. al., 1987) first proposed the concept, often defined as CT-Sim to distinguish it from Sim-CT

**1. Introduction**

extraction.

**2. Radiotherapy Treatment Planning (RTP)**

 **in Radiotherapy Treatment Planning**

 *Department of Statistics and Actuarial, Financial Mathematics,*


**7. Conclusions**

This chapter has shown the use of antenna measurement techniques to measure the radiation of devices under tests in EMC. The proposed system has been based on the following technologies: multiprobe measurement systems, software-defined radio receivers, phase recovery, spherical near- to far-field transformation software, post-processing techniques as source reconstructions or calculation of equivalent currents and spherical mode filtering, and combination of measurements and simulations.

This process has been validated with measurements in a Microwave Vision Group StarLab system at 400 MHz and 2 GHz, comparing the results with measurements in a conventional EMC setup. The results have shown good agreement, and this is the first step to advance in the use of new technologies of other disciplines, as antenna measurement, to improve the results obtained with the conventional EMC setups.

This chapter has only introduced a summary of the different works done by the authors during the last few years, but most information can be found in some of the references included at the end of the chapter.

### **Acknowledgements**

This work is included in a collaboration between Microwave Vision Group and Universidad Politécnica de Madrid. The Spanish Government also supports it, Ministry of Economy, National Program of Research, Development, and Innovation through the project FUTURE-RADIO "Radio systems and technologies for high capacity terrestrial and satellite communications in a hyperconnected world" (project number TEC2017-85529-C3-1-R).


*Article* **Spatial–Temporal Variations of Water Ecosystem Services Value and Its Influencing Factors: A Case in Typical Regions of the Central Loess Plateau**

**Yuan Xiu, Ni Wang \*, Fangxu Peng and Quanxi Wang**

State Key Laboratory of Eco-Hydraulics in Northwest Arid Region, Xi'an University of Technology, Xi'an 710048, China<EMAIL_ADDRESS>(Y.X<EMAIL_ADDRESS>(F.P<EMAIL_ADDRESS>(Q.W.) **\*** Correspondence<EMAIL_ADDRESS>
**Abstract:** Water resources provide indispensable ecosystem services, which are related to human wellbeing and sustainable social development. Accurately measuring the water ecosystem services value (WESV), and then grasping its changing characteristics, is particularly important for solving water problems. In this study, the typical area of the central Loess Plateau location is taken as the research area. Based on remote sensing images and statistical data, the direct market method combined with the equivalent factor method was used to calculate the WESV including groundwater and surface water, which is of greatest originality. The temporal and spatial variation characteristics in 2010, 2015 and 2020 were analyzed. Then, four WESV driving factors including per capita GDP, population density, proportion of water areas, and water consumption were selected, and the geographically weighted regression (GWR) model was used to analyze the spatial distribution pattern and temporal variation of WESV's response to the influencing factors. The results showed that WESV experienced a process of first decreasing and then increasing, which was mainly caused by Yulin. For the composition of WESV, the proportion of provisioning services value has increased, which caused the proportion of regulating services value to decrease. The correlations between four factors and WESV were different. The distribution pattern of the influences was spatially heterogeneous, which showed regular variations over time. These results indicate the necessity of WESV's independent research and provide a realistic basis for ecological compensation in the Yellow River Basin.

**Keywords:** water resources; ecological services value; influencing factors; geographically weighted regression (GWR); space–time change; the Loess Plateau


*2.2. Load Profile Smoothing*

Due to the growing share of RESs and their variable generation, the power system operation can be disturbed. It could happen especially for power systems with a significant share of renewables where difficulties in the balancing of demand and supply occur. Therefore, smoothing, which embraces reduction of rapid changes in the load profile, is another example of the AS that can be provided by the DRAs to assist the power system operation [24].

At the PCC, the load profile can be shaped by controlled operation of active resources incorporated into the DRA structure. The load profile smoothing could improve balancing, currently provided by the transmission system connected CDGUs because the smoothed profile is characterized by a smaller variability and milder up and down ramps. A visualization of load profile smoothing is presented in Figure 3.

**Figure 3.** Load profile smoothing.

## *2.3. Balancing and Reserves*

Electrical energy consumption must be equal to its generation at all times. The frequency of the grid is the best indicator of this balance. DERs managed by an aggregator are able to support the maintenance of the frequency within acceptable limits by quickly responding to its deviations. Such services are currently provided mainly by large CDGUs located in transmission networks, but properly aggregated structures may also be present on the balancing markets [25].

The balancing services may be also provided by compensation of balance deviations inside an aggregated structure in order to obtain a determined generation/load profile for the whole cluster. Some resources may be able to respond to other entities' deviations caused, for example, by variable weather conditions or rapidly changing demand.

The reserves are required to maintain the power system's balance in both the short and the long term. In this context, DRAs may additionally share a part of its capacity to cover TSOs' needs and be remunerated for the willingness to provide reserve services and for their activation.

#### **3. Structure of the Distributed Resource Aggregator**

#### *3.1. Roles and Structure of an Aggregator*

The main roles of the DRA coordinator are to select suitable assets located in distribution networks and to group them into a cluster in order to strengthen the significance of resources distributed on a small scale and thereby allow them to participate in wholesale markets, such as the balancing and AS markets. The operation of the aggregated assets is managed by the DRA coordinator in order to optimize the overall profit of the whole cluster. The structure of the DRA comprises assets located in the distribution level: passive loads, ALs, ESs, controllable and noncontrollable power generating resources. Figure 4 presents the proposed structure of the DRA and its cooperation with other entities located in the distribution level.

**Figure 4.** The proposed structure of the distributed resource aggregator (DRA) and its cooperation with other entities.

New technical and legal requirements should be introduced to allow the DRA to operate in the power system. These requirements should consist of basic technical parameters (power, response time, regulatory range, etc.) and legal conditions relating to inter alia, resource ownership, aggregation areas and financial settlements. After defining the aggregated structure, the DRA coordinator submits its technical capabilities to the DSO and makes agreements for the provision of the ASs due to the power system conditions and demands.

The DRA coordinator is responsible for supervision, coordination and control of the operation of resources. The coordinator has the ability to select suitable resources and create an optimal structure oriented towards the desired operation pattern which aims at a maximum profit while assisting the power system's operator.

In order to improve the power system flexibility, the DRA operation may prevent the negative impact of intermittent RES generation (left side of Figure 5) and stabilize operation of base load and combined heat and power (CHP) generation units (right side of Figure 5). The DRA can adjust output power from *PMIN* to *PMAX* to provide ASs and indirectly assist the TSO in the balancing of demand and supply.

**Figure 5.** The proposed position of the DRA operation in the power system.

#### *3.2. Modelling of Distributed Resources*

In the presented concept, four groups of distributed assets were modelled and can be incorporated into the aggregator's structure: intermittent RESs, dispatchable generating units, ESs, ALs. The proposed model is based on mixed integer linear programming (MILP). For further simulation purposes, 15 min intervals of a 24 h time span were assumed.

## 3.2.1. Renewable Energy Resources

RESs represent a group of noncontrollable generating units whose production is dependent only on weather conditions. For the purpose of further simulations, wind and solar generators were implemented in the simulation model. Figure 6 depicts adopted generation profiles for those RESs.

**Figure 6.** Generation profiles for wind and solar sources assumed for the simulation purposes (own development based on [26,27]).

The possibility of RES generation curtailment was also assumed, and is expressed by Equation (1).

$$\forall r \in R, \; \forall t \in T: P\_{\text{min}r} \le P\_{\text{cur }r}^t \le P\_r^t \tag{1}$$

## 3.2.2. Dispatchable Generating Units

The electricity production from units like gas, biogas, biomass, etc., is dependent on the amount of provided fuel; therefore, their output power can be controlled within their operational limits (Equation (2)).

$$\forall \mathcal{g} \in G, \ \forall t \in T: P\_{\text{ring}} \le P\_{\mathcal{g}}^t \le P\_{\text{max}\mathcal{g}} \tag{2}$$


**2.3 FDG-PET**

*Sarcoidosis and Granulomatosis - Diagnosis and Management*

ies are demonstrating some opposite results.

carbon monoxide (DLCO).

(ARDS and infections).

pulmonale.

normal as follows:

• TLC decrease;

• RV decrease;

• FEV1 decrease;

• FVC decrease;

• DLCO decrease; and

• compliance decrease.

• carbon dioxide output (VCO2);

• anaerobic threshold (lactic acid).

angiotensin converting enzyme (ACE) in the blood [1].

• minute ventilation; and

exchange abnormalities.

function tests is found.

• FEV1/VC is equal to or more than 70%;

plethysmography, and a carbon monoxide diffusion capacity test of the lungs for

Restrictive disorders (infiltrative) are characterized by a reduction in lung volume, with difficult in taking air inside the lungs and decreased total lung capacity. Other restrictive disorders are chest wall disorders (neuromuscular, e.g., polio, kyphoscoliosis, pleural disease, and severe obesity); chronic interstitial and infiltrative disease (pulmonary fibrosis, pneumoconioses, granulomatous diseases, pulmonary eosinophilia, and pulmonary alveolar proteinosis); Acute diseases

Typical symptoms are dyspnea, tachypnea, end inspiratory crackles without airway obstruction, honey-comb lung, secondary pulmonary hypertension, and cor

In restrictive pulmonary disease, lung volume is decrease, but flow rate is

Usually, a significant correlation between radiological stage and pulmonary

Cardiopulmonary exercise testing (CPET) is another useful tool to identify and quantify the extent of pulmonary involvement and also may suggest cardiac involvement that otherwise is not evident [2]. It provides an integrative assessment of involving the pulmonary, cardiovascular, muscular, and cellular oxidative

• primarily oxygen uptake (VO2): VO2 at maximal exercise (peak VO2) is considered the best index of aerobic capacity and cardiorespiratory function;

In patients who have normal gas exchange at rest, CPET unmasks the gas

Laboratory tests can identify some serum abnormalities as high blood calcium with a normal parathyroid hormone level and hypercalciuria, or elevated levels of

systems and involves measurements of gas exchange as follows:

Sarcoidosis is commonly considered a restrictive disorder, but more recent stud-

**34**

FDG-PET is a metabolic imaging technique and provides an insight into metabolism of this disease. It relies on the principle of increased accumulation and metabolism of glucose by the malignant or inflammatory areas. FDG is a radioactive analog of glucose that enters cells through the same receptors that are involved in glucose uptake and gets converted into FDG 6 phosphate by the enzyme hexokinase, similar to glucose metabolism by the glycolytic pathway. FDG 6 phosphate is not metabolized further and gets entrapped in the cell. Tissues with high glucose metabolism such as brain tissue gray matter, cancer cells, and inflammatory changes show increased fluorine – 18 fluorodeoxyglucose ((18) F-FDG) accumulation on PET imaging.

As a key component of the inflammatory process, inflammatory cells consume glucose at a much higher level than peripheral noninflammatory cells, leading to higher glucose metabolism and increased uptake of (18) F-FDG within inflammatory foci. Therefore, the level of FDG uptake is proportional to the level of glycolysis in the tissue. This explains the mechanism of increased uptake of FDG in malignancy, inflammatory, and infectious processes [3].

The role of fluoro-deoxy glucose-positron emission tomography (FDG-PET) scanning in assessing the extent of disease spread or metastasis and its utility in assessing response to treatment in the form of chemotherapy or radiotherapy is well defined in many neoplastic conditions, and its utility has also been recognized in certain inflammatory conditions, like sarcoidosis.

During the last years, FDG-PET imaging has been shown to have a central role to detect inflammation activity and has become a novel fundamental tool, playing also an increasingly important role in the management of patients with any inflammatory conditions. FDG-PET can afford precious information in patients with pulmonary and extrapulmonary sarcoidosis and has become a centerpiece for testing the efficacy of different therapies [5]. In difficult clinical cases, it can also be useful to plan the site of biopsy in order to determinate a histopathological diagnosis.

A combined modality using FDG-PET and CT scanning (FDG-PET/CT) has been found to be more sensitive than PET in diagnosing. FDG-PET and a combination of this procedure with computed tomography scanning (FDG-PET/CT) has gained prominent attention in patients with sarcoidosis over the last two decades as a means to assess disease activity and response to therapy. Radionuclide imaging techniques have increasingly been used in the evaluation of organ involvement in sarcoidosis. F-FDG-PET/CT scanning has received increasing attention in last several years [3].

The usefulness of F-FDG-PET/CT is to identify the disease activity and the extent of organ involvement in patients affected by sarcoidosis; F-FDG-PET/CT is still useful to determinate its utility in the evaluation of response to drug treatment, comparing the agreement between clinical, radiological (with chest radiography and/or HRCT of lungs), and metabolic indices (FDG-PET/CT) of disease activity.

*Monitoring disease activity* in sarcoidosis still remains a clinical goal as there is no gold standard. The term "activity" in sarcoidosis means ongoing inflammation that necessitates appropriate drug therapy [3]. PET imaging is a new tool to assess the metabolic activity, but there is still limited data on the role of serial PET scans in monitoring the sarcoidosis activity [6].

*Conventional imaging techniques* used in sarcoidosis are chest radiography and CT. Even though chest radiography and HR-CT are still the fundamental for diagnosing pulmonary involvement, F- FDG PET appears to be superior to both techniques to identify active sites of disease. F- FDG- PET also correlates well with serum biomarkers, such as soluble interleukin-2 receptor in symptomatic patients, and in lung parenchyma correlates with decrease of lung function values over time. Moreover F-FDG-PET even visualizes active lesions (in pulmonary and extrapulmonary sites) in the context of normal serum biomarkers. Also in cardiac involvement in sarcoidosis, FDG-PET is a promising tool associated or complementary to magnetic resonance imaging, especially in planning treatment [7].

*Magnetic resonance imaging* (MRI) is the main imaging method for diagnosis and follow-up of neurosarcoidosis and for evaluation of cardiac involvement. However, these mentioned methods are unable to identify active inflammation; instead, FDG-PET/CT has an important advantage in the detection of reversible, inflammatory, active granulomatous disease in patients with sarcoidosis [8].

*PET* provides high-resolution three-dimensional images of the whole body that facilitates precise localization of abnormalities. Localization is enhanced with PET/ CT. Fluorodeoxyglucose is extremely sensitive with a high negative predictive value; however, the limiting factor of the test is specificity [9, 10]. (18) F-FDG PET/CT allows to obtain a complete morphofunctional cartography of inflammatory active localizations and to follow treatment efficacy in patients with sarcoidosis, particularly in atypical, complex, and multisystemic forms.

Disseminated lesions should alert clinician to consider sarcoidosis-lymphoma syndrome (SLS) or tuberculosis in the differential diagnosis. However, histological confirmation with biopsy will be required in such complex cases.

#### *2.3.1 Pulmonary sarcoidosis*

Pulmonary sarcoidosis is the main localization site in the majority of patients (>90% cases) typically with bilateral mediastinal (hilar) lymphadenopathy diagnosed on chest radiography; and its severity ranges from asymptomatic involvement of mediastinal lymph nodes (mostly hilar) to progressive pulmonary fibrosis and chronic respiratory failure that is unresponsive to therapy. The most common clinical presentations of pulmonary involvement are cough and dyspnea.

The diagnosis of pulmonary sarcoidosis requires a compatible clinical picture supported by radiologic (X-rays chest and/or HRCT of lungs) and pathologic data (pulmonary functional tests and laboratory tests). A recent innovation in diagnosing of pulmonary sarcoidosis is endobronchial ultrasound that increases the yield of transbronchial needle aspiration of hilar and/or mediastinal lymph nodes. F-FDG-PET is highly sensitive in detecting occult sites of disease and is very useful in guiding biopsies of these sites. A combined imaging modality using both FDG-PET and CT scan is more sensitive than PET alone and is now the main proceeding of care in patients needing biopsies of active lesions [11].

For staging of pulmonary disease on chest radiograph, Scadding stages (**Figure 1**) are still widely used depending on the presence of hilar lymph node enlargement and pulmonary opacities on chest radiography as follows:

**37**

*2.3.2 Cardiac sarcoidosis*

*Early Diagnosis of Sarcoidosis*

**Figure 1.**

*DOI: http://dx.doi.org/10.5772/intechopen.90523*

occult sites of disease at the chest CT scan.

*Chest X-rays: reticulonodular pattern with perihilar distribution.*

*HRCT*, however, is still the gold standard imaging modality for primary diagnosis of sarcoidosis and is more accurate than chest X-rays, which is the first imaging level, in identifying the different manifestations of pulmonary sarcoidosis as well its complications. F-FDG-PET, instead, is a new highly sensitive tool in detecting

HRCT most common signs are: micronodules (*miliary sarcoidosis*) and macronodules with perilymphatic distribution, for the most part, symmetrically in the middle zones of the lungs; rarely solitary opacity (*alveolar sarcoidosis*) and with a mass-like presentation (1–4 cm in diameter) may mimic consolidation containing air bronchograms, from confluence of many smaller nodules with irregular margins and presenting as *sarcoid galaxy sign* (mass-like region from confluence of numerous smaller granulomas with a central core and multiple peripheral nodules; central cavitation may occur, and the lesion can be surrounded by ground-glass opacity), more frequent in patients older than 50 years of age of presentation; linear opacities, mostly, in the upper and middle parts of the lungs, most common of stage II or III of disease; and ground glass opacities represent interstitial sarcoid granulomas under resolution rather than alveolitis, above all, located in the lower zones of the lungs [12] (**Figures 2–6**). Functional imaging of sarcoidosis nowadays is performed with (18) F-FDG PET-CT, which improves anatomical localization of sites of abnormality and has a relatively short delay time between radiotracer injection and image acquisition. (18) F-FDG PET-CT can identify disease activity better than conventional makers in a large proportion of patients (very high sensitivity about 80–100%). In patients with positive HRCT but no parenchymal fluorodeoxyglucose F18 uptake, pay attention to

initiation or intensification of immunosuppressive treatment [1, 13].

Cardiac involvement in sarcoidosis is uncommon (5%) and is associated with very poor prognosis [1], because of many complications of cardiac as follows: ventricular tachycardia, conductional abnormalities, congestive heart failure, and sudden cardiac death. Moreover, cardiac sarcoidosis (CS) is an important prognostic factor in patients with this disease. However, early diagnosis of CS in still

*Sarcoidosis and Granulomatosis - Diagnosis and Management*

and in lung parenchyma correlates with decrease of lung function values over time. Moreover F-FDG-PET even visualizes active lesions (in pulmonary and extrapulmonary sites) in the context of normal serum biomarkers. Also in cardiac involvement in sarcoidosis, FDG-PET is a promising tool associated or complementary to

*Magnetic resonance imaging* (MRI) is the main imaging method for diagnosis and follow-up of neurosarcoidosis and for evaluation of cardiac involvement. However, these mentioned methods are unable to identify active inflammation; instead, FDG-PET/CT has an important advantage in the detection of reversible, inflammatory,

*PET* provides high-resolution three-dimensional images of the whole body that facilitates precise localization of abnormalities. Localization is enhanced with PET/ CT. Fluorodeoxyglucose is extremely sensitive with a high negative predictive value; however, the limiting factor of the test is specificity [9, 10]. (18) F-FDG PET/CT allows to obtain a complete morphofunctional cartography of inflammatory active localizations and to follow treatment efficacy in patients with sarcoidosis, particu-

Disseminated lesions should alert clinician to consider sarcoidosis-lymphoma syndrome (SLS) or tuberculosis in the differential diagnosis. However, histological

Pulmonary sarcoidosis is the main localization site in the majority of patients

The diagnosis of pulmonary sarcoidosis requires a compatible clinical picture supported by radiologic (X-rays chest and/or HRCT of lungs) and pathologic data (pulmonary functional tests and laboratory tests). A recent innovation in diagnosing of pulmonary sarcoidosis is endobronchial ultrasound that increases the yield of transbronchial needle aspiration of hilar and/or mediastinal lymph nodes. F-FDG-PET is highly sensitive in detecting occult sites of disease and is very useful in guiding biopsies of these sites. A combined imaging modality using both FDG-PET and CT scan is more sensitive than PET alone and is now the main proceeding of

For staging of pulmonary disease on chest radiograph, Scadding stages (**Figure 1**) are still widely used depending on the presence of hilar lymph node

• Stage I: bilateral mediastinal lymphadenopathy (hilar lymphadenopathy);

• Stage II: bilateral mediastinal lymphadenopathy (hilar lymphadenopathy) and

enlargement and pulmonary opacities on chest radiography as follows:

• Stage III: infiltrates alone, parenchymal disease only; and

(>90% cases) typically with bilateral mediastinal (hilar) lymphadenopathy diagnosed on chest radiography; and its severity ranges from asymptomatic involvement of mediastinal lymph nodes (mostly hilar) to progressive pulmonary fibrosis and chronic respiratory failure that is unresponsive to therapy. The most common clinical presentations of pulmonary involvement are cough and

magnetic resonance imaging, especially in planning treatment [7].

active granulomatous disease in patients with sarcoidosis [8].

confirmation with biopsy will be required in such complex cases.

larly in atypical, complex, and multisystemic forms.

care in patients needing biopsies of active lesions [11].

• Stage 0: normal chest radiographic findings;

infiltrates with parenchymal lesion;

• Stage IV: pulmonary fibrosis.

*2.3.1 Pulmonary sarcoidosis*

dyspnea.

**36**

**Figure 1.** *Chest X-rays: reticulonodular pattern with perihilar distribution.*

*HRCT*, however, is still the gold standard imaging modality for primary diagnosis of sarcoidosis and is more accurate than chest X-rays, which is the first imaging level, in identifying the different manifestations of pulmonary sarcoidosis as well its complications. F-FDG-PET, instead, is a new highly sensitive tool in detecting occult sites of disease at the chest CT scan.

HRCT most common signs are: micronodules (*miliary sarcoidosis*) and macronodules with perilymphatic distribution, for the most part, symmetrically in the middle zones of the lungs; rarely solitary opacity (*alveolar sarcoidosis*) and with a mass-like presentation (1–4 cm in diameter) may mimic consolidation containing air bronchograms, from confluence of many smaller nodules with irregular margins and presenting as *sarcoid galaxy sign* (mass-like region from confluence of numerous smaller granulomas with a central core and multiple peripheral nodules; central cavitation may occur, and the lesion can be surrounded by ground-glass opacity), more frequent in patients older than 50 years of age of presentation; linear opacities, mostly, in the upper and middle parts of the lungs, most common of stage II or III of disease; and ground glass opacities represent interstitial sarcoid granulomas under resolution rather than alveolitis, above all, located in the lower zones of the lungs [12] (**Figures 2–6**).

Functional imaging of sarcoidosis nowadays is performed with (18) F-FDG PET-CT, which improves anatomical localization of sites of abnormality and has a relatively short delay time between radiotracer injection and image acquisition. (18) F-FDG PET-CT can identify disease activity better than conventional makers in a large proportion of patients (very high sensitivity about 80–100%). In patients with positive HRCT but no parenchymal fluorodeoxyglucose F18 uptake, pay attention to initiation or intensification of immunosuppressive treatment [1, 13].


*Proceeding Paper* **Composite Fibers in Concrete: Properties, Challenges, and Future Directions †**

**Samiullah Khan 1, Safeer Khattak 1,\* and Hamza Khan 2**

**Abstract:** Composite fibers are an essential component of modern concrete structures, providing enhanced mechanical properties and durability. There are different types of fibers commonly used in concrete such as steel, glass, carbon, polypropylene fibers, etc. Composite fibers include a combination of two or more of these fibers. Composite fibers are discussed in detail, along with their properties and benefits. This paper also highlights the effects of composite fibers on the various properties of concrete, such as compressive strength, tensile strength, toughness, and durability. Furthermore, this paper discusses some of the challenges and limitations associated with the use of composite fibers in concrete, including issues related to fiber dispersion, fiber–matrix interactions, and costeffectiveness. Finally, this paper concludes with a discussion of the future directions of research on composite fibers in concrete, focusing on potential advancements in fiber technology, improved manufacturing techniques, and the development of new fiber–matrix systems. Overall, this paper provides a comprehensive overview of the current state of the art in composite fibers in concrete and serves as a valuable resource for researchers and practitioners in the field.

**Keywords:** fiber composites; concrete matrix; tensile strength; tensile stress; durability; mechanical properties

#### **1. Introduction**

Due to its adaptability, toughness, and strength, concrete is the most widely used building material worldwide. However, it is prone to cracking and failure under tensile stress, which can result in structural damage and a shorter service life despite its many benefits [1]. Different kinds of fibers are added into concrete to improve its mechanical properties, such as its strength, hardness, and durability, in order to address this problem and increase its tensile strength. Modern concrete constructions require the use of these composite fibers, which are created from materials like steel, glass, carbon, and polypropylene and enable the structures to resist significant stress and strain. The development of fibers dates back to the Neolithic period when people used wheat straw in mud to increase its tensile strength and employed it for various purposes. Over the past few decades, the usage of fibers in concrete has become more widespread. For instance, steel fibers have been utilized to reinforce concrete and lessen cracking since the 1960s [2,3]. Additionally, the use of glass and carbon fibers has become more popular in concrete construction, which offers good corrosion resistance and a high strength-to-weight ratio [4].

This paper provides a thorough analysis of the most recent, cutting-edge research on composite fibers in concrete. The paper begins by outlining the many kinds of fibers that are frequently used in concrete, along with their characteristics and advantages. The impacts of composite fibers on different concrete parameters, including compressive strength, tensile strength, toughness, and durability, are then examined [5]. This research also

**Citation:** Khan, S.; Khattak, S.; Khan, H. Composite Fibers in Concrete: Properties, Challenges, and Future Directions. *Eng. Proc.* **2023**, *44*, 17. https://doi.org/10.3390/ engproc2023044017

Academic Editors: Majid Ali, Muhammad Ashraf Javid, Shaheed Ullah and Iqbal Ahmad

Published: 28 August 2023

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

outlines a number of difficulties and restrictions related to the usage of composite fibers in concrete, including issues related to fiber distribution, fiber–matrix interactions, and cost-effectiveness [6,7]. The use of composite fibers in concrete is then illustrated with examples from both structural and non-structural situations. Finally, the paper concludes with a discussion of future directions in concrete composite fiber research, with a focus on potential advances in fiber technology, improvements in manufacturing techniques, and the development of new fiber matrix systems. Overall, the purpose of this study is to introduce the readers to the field of fibers and their applications while also presenting a thorough grasp of composite fibers in concrete.

#### **2. Types of Composite Fibers in Concrete**

Composite fibers are typically made by combining two or more types of fibers to create a material that exhibits the desired properties. The utilization of fibers to enhance the mechanical properties of concrete is quite common today [8]. By using different types of fibers in concrete, its properties can be altered to the desired strength and durability [9]. Table 1 presents a tabular comparison between different types of composite fibers along with their properties and composition.

**Table 1.** Different types of composite fibers, their properties, and their composition.

#### **3. Mechanical Properties of Concrete**

Concrete's mechanical properties, including compressive strength, tensile strength, toughness, and durability, can be greatly improved by the addition of composite fibers. We present a general overview of how composite fibers affect certain characteristics. The inclusion of fibers in the concrete matrix affects the mechanical characteristics of fiberreinforced concrete (FRC) [10]. Figure 1a,b presents values of compressive strength and tensile strength for different percentages of steel polymer matrix (0–1.25%). The first batch contains no fiber reinforcement and subsequent batches contain fibers in % increments of 0.25%.

#### *3.1. Compressive Strength*

By improving its ability to withstand external loads, the addition of composite fibers can increase the compressive strength of concrete. For instance, it was discovered that steel fibers can boost concrete's compressive strength by up to 15%, depending on the fiber volume fraction and aspect ratio, as illustrated in Figure 1a. The bridging effect of fibers, which slows the spread of cracks and improves material ductility, is thought to be responsible for the increase in compressive strength [7].

**Figure 1.** Mechanical properties of fiber-reinforced concrete. (**a**) Compressive strength. (**b**) Flexural strength of composite fiber concrete.

#### *3.2. Tensile Strength*

One of the issues with concrete is its low tensile strength, and to address this issue, fiber-reinforced concrete, a new type of concrete composite, was designed [8]. Concrete's tensile strength can be considerably increased by the inclusion of composite fibers, making it less likely to crack or break under tensile stress. As seen in Figure 1b, polymer steel composites, for instance, have been proven to increase the tensile strength of concrete by up to 50%.

#### *3.3. Ductility*

The splitting tensile strength of fiber-reinforced concrete (FRC) is a measure of its resistance to tensile forces applied perpendicular to the direction of the applied load. It is a crucial factor in determining how well FRC performs overall in terms of crack resistance across a range of applications.

#### *3.4. Modulus of Elasticity*

The modulus of elasticity, which gauges a material's stiffness or rigidity, can be significantly impacted by the addition of fibers to concrete. The mechanical properties of concrete change as a result of the fibers, which act as a reinforcement within the concrete matrix [3]. When fibers are added to concrete, the material becomes more composite by bridging fissures and has a higher load-bearing capability.

#### *3.5. Toughness*

The ability of a material to withstand energy absorption and prevent fracture or crack propagation is referred to as toughness. By bridging and stopping cracks that may occur while the concrete is under load, composite fibers help to increase the concrete's durability [8]. Composite fibers serve as reinforcement when cracks first appear in the concrete matrix, dispersing stress and stopping the cracks from spreading.

#### *3.6. Durability*

The ability of a substance to resist deterioration and degradation over time, particularly when subjected to extreme environmental conditions, is referred to as durability. Concrete's durability is increased by composite fibers in a number of ways.

#### **4. Challenges and Limitations of Using FRC**

Composite fibers offer many advantages when used as reinforcement in concrete, but there are also some challenges and limitations to consider. Cost is one of the main drawbacks of employing composite fibers in concrete [5]. The compatibility of composite fibers with the concrete matrix is another drawback. To ensure effective fiber adhesion to the matrix, the characteristics of the fibers and the concrete mix must be precisely matched. Composite reinforcements may be less effective and less durable due to incompatibility [5–7]. The use of composite fibers can also provide some difficulties. Composite fibers can present additional difficulties during the mixing procedure.

#### **5. Future Directions in Research on Composite Fibers in Concrete**

Recent years have seen a lot of interest in the use of composite fibers in concrete, and research is still being performed to examine potential new applications and difficulties. The use of short fibers or whiskers is both the simplest and most efficient method. It was discovered that this technique considerably increases concrete's tensile strength and decreases tensile cracking. To create new varieties of composite fibers with enhanced characteristics and performance compared to existing materials, research is currently being conducted. Advanced manufacturing techniques such as 3D printing and automated fiber placement enable composite fibers to be more accurately and efficiently incorporated into concrete [2–4]. These techniques can also be used to tailor the orientation and distribution of fibers within concrete, which can improve the overall performance of composite reinforcements.

#### **6. Conclusions**

Finally, this conference paper on composite fibers will offer insightful information about the wide variety of composite fibers and their uses. This article presents a comparative analysis of the various fiber types, including carbon fiber, glass fiber, steel fiber, natural fiber, basalt fiber, and ceramic fiber. A high strength-to-weight ratio, stiffness, fatigue resistance, impact resistance, heat resistance, affordability, a renewable nature, and biodegradability are just a few of the special advantages that each type of fiber provides. This paper's objective is to present a thorough overview of the various aspects of CFRPs, including their structural and durability properties, ongoing research into their use as reinforcing materials for concrete structures, and the application of FRP sheets in the rehabilitation of deteriorated concrete structures. Though they have not been thoroughly examined, topics pertaining to the production of FRP composites and design processes have been included for informational and comprehensive purposes.

**Author Contributions:** Conceptualization, S.K. (Samiullah Khan) and S.K. (Safeer Khattak); methodology, S.K. (Samiullah Khan); software, S.K. (Samiullah Khan); validation, S.K. (Samiullah Khan), H.K. and S.K. (Safeer Khattak); formal analysis, S.K. (Samiullah Khan); investigation, S.K. (Samiullah Khan); resources, S.K. (Safeer Khattak); data curation, H.K.; writing—original draft preparation, S.K. (Samiullah Khan). All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** All data is obtained from open source articles and journals.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

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*3.4. Antioxidant Activity Measured by the DPPH+*• *Method*

The values of antioxidant activity in the tested herbs against the DPPH•+ radical ranged from 9.5–1061.1 µM Trolox/g DM, which is shown in Table 3. The highest antioxidant activity against the DPPH•+ radical was shown by garlic bulbs (933.050 µM Trolox/g DM), stinging nettle herb (1034.725 µM Trolox/g DM) and cleavers herb (1061.068 µM Trolox/g DM). The lowest antioxidant activity against the DPPH•+ radical was found in the extract from psyllium seed husk, (9.475 µM Trolox/g DM); (Table 3).

#### *3.5. Antioxidant Activity Measured by the FRAP Method*

The three herbs with the highest antioxidant activity determined using the FRAP method were stinging nettle herb (1698.517 µM Trolox/g DM), chamomile flower heads (1699.766 µM Trolox/g DM) and cleavers herb (1769.766 µM Trolox/g DM), as shown in Table 3. The lowest antioxidant activity determined by the FRAP method was found in milk thistle extract (26.252 µM Trolox/g DM), which corresponded to the results obtained earlier in the study among others, total polyphenol content and antioxidant activity against the ABTS•+ radical (Table 3).

#### *3.6. PCA Analysis*

The PCA analysis showed that the first component is essentially related to the antioxidant activity, as the factor describing FRAP, DPPH•+ , ABTS•+ and polyphenols. The second component, with slightly smaller factor loads, describes the variability of the basic composition of the tested raw materials (Figure 1A).

This analysis also confirmed a very high degree of correlation between the antioxidant activity (determined by various methods) and the content of polyphenols, and confirmed the correlation of the dry matter content with the protein content. In turn, the content of DM and CP was negatively correlated with NFE. A thesis can also be formulated about the lack of correlation between antioxidant activity, the content of polyphenols and the proximate composition of the tested raw materials.

The analysis of the factorial coordinates of the cases (Figure 1B) indicates the existence of four clusters of points (surrounded by ellipses). Raw materials in clusters in the second and third quadrants of the coordinate system are characterized by the greatest activity of the antioxidant activity.

Herbs that proved the highest antioxidant activity include: stinging nettle herb, marjoram herb, cleavers herb, common chamomile flower heads and garlic bulbs. Other raw materials are characterized by a smaller antioxidant activity and a significant differentiation of the basic composition. This is evidenced by the indicated extreme groups, i.e., two-element groups in the first and fourth quarters. The first one includes seeds of black cumin and fruits of milk thistle, whose raw materials were characterized by a low content of NFE, in contrast to the husks of psyllium seeds and black chokeberry fruits, of course, with significantly lower antioxidant activity.

*Appl. Sci.* **2023**, *13*, x FOR PEER REVIEW 10 of 15

**Figure 1.** Biplot based on first two principal component axes for nutritional value and antioxidant activity (**A**) and distribution of 27 herbs on the first two components obtained from principal com‐ ponent analysis (**B**). Abbreviation crude protein (CP), crude fibre (CF), ether extract (EE), crude ash (CA), nitrogen free extract (NFE), 2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulfonic acid (ABTS•+ rad‐ ical), 2,2′‐Diphenyl‐1‐picrylhydrazyl (DPPH•+), ferric ion reducing antioxidant parameter (FRAP). **Figure 1.** Biplot based on first two principal component axes for nutritional value and antioxidant activity (**A**) and distribution of 27 herbs on the first two components obtained from principal component analysis (**B**). Abbreviation crude protein (CP), crude fibre (CF), ether extract (EE), crude ash (CA), nitrogen free extract (NFE), 2,20 -azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS•+ radical), 2,20 -Diphenyl-1-picrylhydrazyl (DPPH•+ ), ferric ion reducing antioxidant parameter (FRAP).

#### **4. Discussion**

#### *4.1. Proximate Composition*

The oldest method of herb preservation is drying, which is associated with the loss of water and inactivation of enzymes when begun immediately after harvest. Properly dried herbs do not ferment and do not turn moldy. Moreover, the levels of their active substances do not change over a long time.

The available literature contains little information about the proximate composition of many of the tested plants presented in this study. What is more, there is little information concerning proximate composition of morphological parts of herbs and medical plants.

It should be emphasized that some of the plants we analyzed are a rich source of CP (fenugreek), CF (stinging nettle), EE (black cumin) and NFE (psyllium). However, taking into account their consumption in the average daily diet, which is small and results from the use of these plants as an addition to dishes, their nutritional significance is minimal. Albeit they can be considered for use as raw materials for the production of food for special nutritional purposes.

Concerning protein content, Sadowska et al. [18] reported that whole plant of dried thyme contained 6.48 g of protein per DM; these results are lower than ours.

Some authors reported in their researches that black cumin contains about 32–40% of oil, 16–19.9% of protein, 1.79–3.74% of minerals, 5.5% of fiber [28]. These results are lower than we presented in our study (about 42% of fat, 21% of protein, almost 4% of ash, and 8% of fiber). On the other hand, Boskabady and Shirmohammadi [29] showed that this plant contains 26.7% of protein, 28.5% of fat, 8.4% of crude fiber, and 4.8% of total ash.

Sójka et al. [30] examined basic composition of chokeberry pomace fractions achieved as a result of industrial-scale processing of fruit into juice. They showed that this valuable raw material is rich in fat (13.9%), and proteins (24%). Chokeberry fruit are good sources of dietary fiber, i.e., at the level of 5.6% of fresh mass [31]. The lower content was determined in the present study (6.6%).

Sulieman et al. [32] showed that the contents of fiber, ash, protein, fat in fenugreek seed were 6.50%, 3.20%, 28.55% and 4%, respectively. Other authors analyzed chemical composition of different varieties of fenugreek and the ash content was in the range 3–7%, protein content 23.1–26.8%, fat content 8.8–21.0% and fiber content 5.1–7.1% [33]. These results are similar to our results, except fat content. In our study, the content of fat is much lower (4.5%).

Pi ˛atkowska et al. [34] determined proximate composition of common dandelion. The amount of protein was 15.25%, the crude fiber 13.09%, fat 6.81% and ash 9.11%. These results are similar to ours, except ash content. The content of ash was established as 24.5%.

#### *4.2. Total Polyphenols Content*

The tested herbs were characterized by a varied content of total polyphenols. Antioxidants, especially polyphenolic compounds (secondary metabolites), are produced by the protective systems of various plants in response to the destructive effects of free radicals. Higher plants produce secondary metabolites that protect them against environmental stress, pathogens or herbivores [35]. Depending on the number of aromatic rings and the way they are bound, they are divided into the following classes: flavonoids, phenolic acids, stilbenes and lignans [35–41]. In this study, selected dried herbs and plant materials were compared, from which various morphological parts of the plant were collected. These were plants commonly found in Polish meadows and gardens, easily available and cheap to obtain. The total content of polyphenolic compounds is presented in Table 3. Herbs with the highest content of these components in the conducted research turned out to be marjoram herb, flower heads of chamomile and cleavers herb. It is important to note that in many studies, the total polyphenol content is expressed as gallic acid, and in our research we used chlorogenic acid as the standard. Certainly, this affects the differences in the level of total polyphenols in the discussed material and may affect the interpretation of the results.

Our results are different from data reported by Biezanowska-Kope´c and Pi ˛atkowska [ ˙ 38]. These authors showed lower content of total polyphenols (mg CGA/100 g DM) in leaves of lemon balm, marjoram, and thyme compared to our study. Similarly, the results of Tsivelika et al. [39] in common chamomile are lower than ours, but these results are calculated per mg of gallic acid/g DM). Common cleavers in the study by Mili´c et al. [40] was characterized by a higher content of total polyphenols. This plant is unknown, and any research on the content of polyphenolic compounds may turn out to be important in the context of further study of the common cleavers profile.


**1. Introduction**

Cardio-Oncology is an emerging field that sits at the interface of Cardiology and Oncology and has close relationships with primary care specialties. A variety of oncology drugs can injure the cardiovascular system, causing various forms of cardiovascular toxicities. Further, cardiology drugs are widely used by the general population and by individuals with cancer. Many of these drugs are also frequently used for preventive cardioprotection or for the management of cardiotoxicity that has already occurred. In this review, we highlight several cytochrome P450 (CYP450) enzymes relevant to Cardio-Oncology (Figure 1). We classify drugs as CYP450 substrates, inducers or inhibitors, with an explanation of the three types of drug-enzyme interaction. Drug-drug interactions between Oncology and Cardiology drugs mediated by CYP450 enzymes are also surveyed. In addition, we discuss the fact that differential metabolism of each substrate drug in each specific individual can determine bioavailability. Examples from precision Cardio-Oncology are integrated to illustrate that inter-individual bioavailability can be further enhanced by genomic variation in CYP450 enzymes. Some variants enhance enzyme activity, while others do just the opposite. This helps to determine the level of drug available in the body. Not only genomic variants but also other modifications of the enzyme

gene, RNA or protein, including those due to gene-environment interactions, can alter drug levels and individual response in precision medicine. We hope that this review can assist multidisciplinary teams in Cardio-Oncology with difficult drug-related decisions relevant to metabolism and bioavailability.

**Figure 1.** The pie chart depicts the various P450 isoforms, the percentage of clinically used drugs metabolized by the isoform and factors inducing or inhibiting the respective P450 enzyme, thereby influencing variability. The most important factors influencing variability are in bold, with a vertical arrow indicating increased activity (↑), decreased activity (↓) or both (↑↓). Biologic sex (female (f) or male (m)) and rarely polymorphism (CYP1A2) can be of controversial significance. In total, 248 CYP-related drug metabolism pathways were analyzed (excluding chemicals and endogenous substrates). Used with permission [1].