**3. Scintimetric classification of skeletal hot spot in bone scan**

X-ray is not sufficient to diagnose bone metastases. Nuclear scintigraphy imaging has always been helpful for early diagnosis of bone disease. The diphosphonates

**Figure 2.** *Dr. V. Siva's retention ratio.*

labeled as "99mTechnetium" in Bone scan detects the osteoblastic response that takes place in malignant cells. This method is best suited for the entire body scan at affordable cost and with high sensitivity and availability. But there is a problem with specificity [11]. The crystal immature bone surfaces absorb the "99mTcpolyphosphate" along with its variants through ionic deposition.

The rise in bone vascularity raises this process along with matrix localization. Hence, the focal hotspots or abrupt scintiscan area is the region of elevated osteoblastic activity. The Scintiscan bone has been shown to be more sensitive than x-rays to detect bone's focal illness. The major flaw in this process is the non-specificity of the study [12].

There are reasons Prostatic Carcinoma metastasis, which is usually found in bone, has gained a lot of attention for investigation. The anatomical aspects of the prostate gland are the first reason. Baston's plexus is the venous drainage of the prostate gland with a unique range of venous plexus. The Lumbosacral plexus of veins is directly connected with it. In the advanced stage of prostate cancer, this metastatic lesion occurs especially in the axial skeleton [13].

It is not possible to cover the metastatic association in ribs, skull and the bones with this anatomical elaboration. According to Paget, there have been mutations in carcinoma prostate cells in osteotropic cells either with activation of particular proteases and cytokine or with genetic form. They can be latent till an expected change takes place around them like a seed. Hence, there is some clue in the 'seed and soil' theory from the next standpoint [14]. The elevated levels of TGF-β and "bone morphogenetic proteins (BMPs)" had been established in metastasis of bones in prostate cancer cells [15–18]. These cells of "osteotropic metastatic seeds" are combined to the endothelium of bones better than other tissues' endothelium [19].

The skeletal tissue contains Tc-99 mm MDP as the ionic radiopharmaceutical radius is much like the same of "Calcium Hydroxy-appetite crystal". Hence, it is added to the skeletal tissue. Hence, even Osteomyelitis, Paget's disease and Post Traumatic skeletal disorders occur with focal skeletal hotspots. For skeletal hotspots, the major cause must be determined with invasive procedure and further scanning as well. Several quantitative measures are there to improve the specificity of bone scan. Along with fusion imaging procedures like PET-CT and SPECT–CT, BONE SPECT and other cross-sectional techniques have been introduced. We have proposed a novel Scintimetric technique in this work for bone scanning to verify and rule out metastatic or malignant nature of skeletal areas in the non-invasive bone imaging.

The bone scans have focal hotspot margins of 4 and 24 h followed by injecting radiopharmaceutical drawings with a tool and experts tabulate the maximum perpixel counts in such scans. The ratio of two values is taken to determine the focal hotspot changes in the scan with time interval. It is defined as Scintimetry of one region regarding time and is termed "Time Bound Scintimetry". In addition, it is possible to infer the metabolic turnover in hotspots.

### **4. Temporal scintimetry method and Dr. Siva's retention ratio**

A method named "Temporal Scintimetry" has been proposed by Israel et al. [9]. The Non lesion (NL) and Lesion (L) count ratio has been measured over the bone at 4 h in bone imaging. It is also performed again in bone scan at 24 h as well.

$$\text{"Israel"s ratio} = \text{L} / \text{N} \, 24 \, \text{h} / \text{L} / \text{N} \, 4 \, \text{h}"\tag{1}$$

*Focal Increased Radiopharmaceutical Uptake Differentiation Using Quantitative Indices DOI: http://dx.doi.org/10.5772/intechopen.99065*

There has been too negligible variation in measurements among patients who have been treated with metastasis and with degenerative disease and it was steep in metastatic lesions. The decimal values came up in the result only as the indicator is high according to the "Radioactive decay law". We also presented Dr. V. Siva's 4/24 h retention ratio in this work to classify the 'focal hot spots' and to find the difference between benign lesions and metastatic lesions with this procedure [10]:


### **5. Dr. V. Siva's retention ratio = 4/24 h focal hot spot count**

#### **5.1 Clinical applications of scintimetric characterization of the skeletal hotspots in the differentiation of benign and metastatic lesion**

The bone scan was performed 4 h following the 15–25 mCi of IV injection containing "Tc-99 m Methylene Di-Phosphonate "with proper hydration with the entire body acquisition of dual head gamma camcorder of Siemen's eCAM. Next day, the full-body bone imaging is done again with the same protocol and injection. The General Display protocol is used to select both images of 4 h and 24 h. The 4 h anterior and 24 h posterior scans are selected with Region Ratio protocol and the experts tabulate the maximum counts at a focal area. The region ratio protocol is used to calculate Dr. V. Siva 4/24 h retention ratios and it is also tabulated.

In a study, a group of 32 patients with proven and known Paget's disease, Avascular Necrosis, Osteomyelitis, and degenerative problems and 75 patients with proven Carcino Prostate biopsy reports were included. There was metastatic involvement in 53 people in a Carcinoma Prostate group, out of which 22 were reported negative for metastases. The "11.5 ± 2.8" is the mean value of the 4/24 retention ratio of Dr. V. Siva in malignant bone lesions and "0.08 ± 0.02" is the mean value of Israel's 24/4 ratio in the group with Carcinoma Prostate. The mean value of "4.8 ± 2.5" was found in benign bone lesions in Dr. V Siva's 4/24 retention ratio and "-0.06 ± 0.02" was the mean value of Israel's 24/4 ratio. The statistical values are estimated using the online "Social Sciences Statistics" calculator. The T value comes out to be 17.1 from the two independent values of the student T test. There was a significant result at p <0.05 value and <0.00001 is the p value. There was a significant outcome at p <0.05 value. **Figure 3** illustrates the graphical calculation of dispersion and major difference between metastatic and benign lesions:

**Figure 3.** *The graphical representation of difference between A – Benign and B – Malignant lesions.*

The Quantitative and non-invasive classification of "Skeletal Metastasis" with Tc99m MDP scans in Carcinoma prostate was presenting good values with Retention Ratio of Dr. V. Siva as per Serum PSA levels [20].

### **6. Evaluating pathological/non-healing fractures using scintimetry**

The authors in [21] have documented the "Scintimetric" assessment of "delayed union of skeletal fractures". The retention values of 4/24 for all cases were characterized into benign fracture and metastatic fracture as per the scientometric classification of skeletal hot spots. Around 37% (11) were pathological fractures and 63% (19) were benign ones due to benign bone tumors and stress fracture out of 30 non-union/delayed skeletal fractures reported. Dr. V. Siva's 4/24 h retention ratio had 12.5 ± 3.1 of mean value for pathological group with typical estimation of ± 0.61 for errors and the error estimation (±0.38) was measured with mean value "6.68 ± 2.8" of benign group. The statistical calculation found a major difference between two values with <0.0001 of p value.

The authors in [22] also reported the comparative study of Scintimetric classification by the "Triple Phase Bone Scan" and Retention Ratio by Dr. V Siva in skeletal fracture as compared to the entire body counts. The authors in [23] also described the use cases of "scientometric classification of skeletal hotspots" also in a diagnostic facility.

## **7. Scintimetry in rheumatoid arthritis**

The bone imaging of two-sided hands is helpful to determine the severity of afflictions in interphalangeal joints. The accumulation of delayed 24 h imaging of hands and quantitative retention ratio measurements was helpful. The authors in [24] also published a groundwork report on Scintimetric assessment of the involvement of rheumatoid arthritis by retention ratio of Dr. V Siva. The mean of "5.91 ± 0.35" was found in the maximum counts of skeletal zones of patients in 3 h and 24 h scans as well as the 4/24 h ratio with means of 0.3496 in standard error. The 8.8408 was the estimated variance and 2.9734 was the standard and estimated deviation. The 6.6306 was the estimated variance for the sample size and 2.575 was the standard estimated deviation by modification from HOJO. The sample population was very small and it was totally unavoidable. It opens further research paths on a global scale.

#### **8. Diastolic dysfunction assessment, characterization and identification**

The left ventricle has the diastolic function that plays an important role in efficacy and preservation of left systolic ventricular function. Hence, there have been a lot of concerns on determining the "Left Ventricular Diastolic function" as well as the management and detection of left heart failure. The "M-mode echocardiography" is usually taken to evaluate the same at the mitral valve orifice with "E/A ratio" tracing. The "Left Ventricular Diastolic function" Stage I is represented by <0.8 of E/A ratio, Stage II by >1.4, and Stage III by >1.8 [25, 26]. The tissue characterization and "Color Doppler echocardiography" are the methods to refine these parameters [27].

The advancement of studies related to "ECG-Gated SPECT" has given great insights for its evaluation. The visual insights to "Regional Wall Motion Abnormalities" and "Ejection Fraction" with "Gated SPECT Myocardial Perfusion Studies" are widely used and popular. However, it is still important to explore

#### *Focal Increased Radiopharmaceutical Uptake Differentiation Using Quantitative Indices DOI: http://dx.doi.org/10.5772/intechopen.99065*

the portal to extract and analyze vital info from the analysis of "Phase image" of systolic and diastolic phases in cardiac cycle. After the use of "Gated SPECT Myocardial Perfusion Imaging" described by Morgan and Mannting [28] in the year 1993, Raymond Taillefer et al. [29] explained the "Diastolic image analysis" and its utility in early diagnosis of C.A.D. among women over "Summed Image Analysis" in the year 1999.

A "Gated SPECT Perfusion Processing" protocol has been developed by Siemens on the basis of Depuey et al. [30] who have covered individual image analysis in "Ejection fraction calculation", "Diastole and Systole", and "Regional Wall Thickness". With "phase image analysis" in processing of "Gated SPECT Perfusion", the "Irregular, In-homogenous, and Insufficient Tracer distribution" incidence is inferred having regular, homogenous and even tracer distribution in summed scans to show diastolic dysfunction. The "SNMICON" presentation [31] also highlights the association with the markers of "echocardiographic diastolic dysfunction", especially "Diabetes Mellitus and Hypertension" and E/A ratio.

The ideal correlation between S/D ratio and rate of Peak flow is estimated by considering the "Time Volume" curves that are obtained from E/A ratio and ECG-gated SPECT [32]. The "Time To Peak Flow" and "Peak Flow Rate" are the parameters of diastolic dysfunction. Their normal values have been documented to determine diastolic function with total agreement between "Echocardiographic assessment and QGSPECT" using 16-frame "99mTc-Sestamibi Gated Myocardial Perfusion SPECT" [33]. According to RD Lele et al., diastolic dysfunction was 92/121 (76) and "echocardiographic E/A ratio" detected only 53/121 (43%) [29]. The common individual risk factor was "Left Ventricular Hypertrophy (LVH)" with heavy risk related to unfavorable results [34, 35]. Some of the major causes are hypertension and hypertrophic cardiomyopathy (HCM) [36] and aortic stenosis, obesity, and chronic kidney problems are responsible for the thickness of the left LV wall [37–40].

There were 75 males aged 31 to 67 years participated in a study to evaluate the left "ventricular diastolic dysfunction" with average age of 51.9 ± 7.4 years and there were 25 females from 31 to 55 years with mean 45.9 ± 6.6 years of mean age. The patients using "Thallum-201 Bruce protocol 2-mCi" on a treadmill were injected after exercise with "Gated SPECT MPI" through IV. They were equipped with E-Cam Dual Head Gamma cam by Siemens. The "Gated SPECT PERFUSION ANALYSIS" protocol was used by the ICON software to analyze the images. The irregular, in-homogenous and insufficient tracer distribution was found in diastolic phase scans instead of usual Systolic phase scans. These images show changes in diastolic dysfunction in "left ventricular muscle tissue" (**Figure 4**).

The images on the upper row show diastolic phase in various angles. These scans show in-homogenous, constantly decreased, irregular, and insufficient distribution of tracer, which indicate perfusion absence. The images on the lower row of the systolic phase illustrate stable and normal tracer distribution. In this study, the discordance between systolic and diastolic phases has been displayed and it is related to straight changes because of diastolic dysfunction in the "left ventricular muscle mass". These images display Bull's eye map assessment and 'left ventricular ejection fraction' of the end systolic perfusion, end diastolic perfusion, and wall thickening. The systolic and diastolic phases are described in the images on the lower and upper row, respectively. The bull's eye map of "diastolic phase ED perfusion" describes affliction from moderate to severe levels as per the ES perfusion on systolic phase and color scale that displays color and normal scale. The left ventricular ejection which is calculated from the "end systolic ES volumes" and derived end diastolic ED" is normal.

The research findings have been noted as below. The researchers have tabulated the echocardiographic grading of "left ventricular diastolic dysfunction" apart from the findings given above. They saved the scan data of systolic and diastolic pictures in H.L.A., S.A., and V.L.A. views. The inner and outer margins are drawn by the "ventricular wall outline" in the systolic and diastolic phase and counts were calculated in the area of interest with the ICON software's region ratio count protocol (**Figure 5**).

The S/D ratio was used to tabulate the diastolic and systolic counts in female and male patients in this study. We also analyzed the S/D ratios of diastolic dysfunction stage II and Stage III individually. We found the discordance between systolic and diastolic pictures in 98/100 (98%). The Grade II and Grade III classify the echocardiographic images of this disorder with E/A ratio in 87/100 (87%). Similarly, hypertension was reported in 63% and diabetes in only 16%. There was no major statistical change in S/D ratio between both groups (**Figure 6**).

The Grade II LVDD has 1.47 ± 0.32 of S/D ratio and Grade III LVDD has 1.81 ± 0.03 of S/D ratio. With "Paired Student t-test", the statistical data found a major difference between Stage II and Stage III in S/D ratio (**Figure 7**).

The visual analysis of the images of systolic and diastolic phases led to interpretation and identification of heart's "Left ventricular diastolic dysfunction". This method identified 98% (98/100) people with this condition. On the other hand, the E/A echocardiographic test detected only 87% of patients. The direct changes


#### **Figure 5.**

*Scintimetric method of calculating Distolic and systolic for deriving S/D ratio.*

*Focal Increased Radiopharmaceutical Uptake Differentiation Using Quantitative Indices DOI: http://dx.doi.org/10.5772/intechopen.99065*

**Figure 6.** *No difference between A-male and B-female scintimetric S/D values.*

**Figure 7.** *Significant difference between A-stage II and B-stage III scintimetric S/D values.*

in "Left ventricular cardiac myocytes" base the visual analysis to diagnose diastolic dysfunction. Hence, they could detect 98% of cases with diastolic dysfunction. RD Lele et al. [34] detected only 76% (92/121) cases with diastolic heart function by using "16-Gated Myocardial Perfusion SPECT" and "time volume curve" analysis.

On the other side, diastolic dysfunction is detected in 98% patients with "direct visual image interpretative assessment" of systolic and diastolic phases. However, there is a need to extend this study further to all the rest of "Gated SPECT" research for a large number of patients. It is also important to contemplate the separated comparison of ES and ED perfusions in both rest and stress gated myocardial imaging results. Along with it, the normal population should also be included as this study group covered only patients.
