Scintigraphy in Renal Diseases: Diagnosis and Treatment - PDF

Nephrology and Urology Prof. Guglielmo – Nuclear Medicine – Radiology – Lesson 03 Role of Scintigraphy in the Diagnosis of Renal Diseases 27/11/2024 – Group 7 (Teitelbaum, Bana) Today we will discuss the role of Scin...

Nephrology and Urology Prof. Guglielmo – Nuclear Medicine – Radiology – Lesson 03 Role of Scintigraphy in the Diagnosis of Renal Diseases 27/11/2024 – Group 7 (Teitelbaum, Bana) Today we will discuss the role of Scintigraphy in the diagnosis of renal diseases. In order to discuss scintigraphy, we must first go back and define Nuclear medicine. It is the field of medicine that uses radiotracers, such as radioactive compounds to diagnose and treat pathologies. The diagnostic aspect currently predominates the majority of nuclear medicine, however the therapeutic aspect is now evolving and increasing. Although diagnostics and therapy exist as separate entities, there is also the so-called ‘theranostics’ combined approach. The American Society of Nuclear Medicine states that we must ‘treat (on a molecular level) what we see’, demonstrating the fact that nuclear medicine is a molecular specialty. We require two things: Scanners, which have specific instrumentations and Radiopharmaceuticals, such as radioactive substances. SCANNERS We use three types of scanners: Gamma-camera, Single-photon Emission Tomography (SPECT), and Positron Emission Tomography (PET).1 The Gamma-camera is quite an old device that is only found in a few departments nowadays, because it only allows for planar acquisition in bone scans (2D). Nowadays we have a more modern type of gamma-camera called SPECT, which rotates around a 360 degrees axis, and is commonly coupled with CT because of anatomical localisation (referred to as SPECT/CT). These scanners work with specific radiopharmaceuticals. Instead, PET scanners can be coupled with CT (PET/CT) or with MRI (PET/MRI), and we have several radiopharmaceuticals that only work with PET scanners. In the Gamma Camera, the radiation is emitted already as a gamma ray, which is detected to form the image. The radioactivity is emitted from within the patient and detected by the system, with the final images being generated on the computer. For PET scanning the methodology is quite similar, however the radiation form is different. PET images are based on annihilation (we will elaborate on what this means later on). RADIOPHARMACEUTICALS The second ‘players’ are radiopharmaceuticals, which are drugs that have (in addition to other compounds) radioisotopes, that give these compounds their characteristic radioactivity and allow them to be detected eg. by a PET/SPECT system. They can be used for both diagnostic and therapeutic purposes: we can observe physiological processes, or treat (mainly oncological) diseases. An ideal radiopharmaceutical must have specific characteristics. The ideal half-life time of the drug is different depending on what it is being used for. If we are using it for diagnostic purposes, a short half-life is needed because the patient is scanned immediately after injection of the radiotracer (as opposed to being scanned ten days later eg.). However, for therapeutic purposes, a longer half-life is preferred, so the drug may act for the longest time possible on the cancer cells. The specific activity of the drug allows us- in the case of high specific activity, to use a small amount of radiotracer. The drug must also localise largely and quickly (for the aforementioned reason about needing to perform the scan quickly). Since drugs can be affected by light, temperature pH etc., it is also important that the drug has good stability. Lastly, the drug must be affordable, available and safe. There are different radioactive 1 The colours are relevant 1 decays coupled with different uses, so Alpha and Beta decay are used in therapy, Gamma decay is used in GC/SPECT imaging and positron emission is used in PET scanning. Discussing the journey of radiopharmaceuticals, we start from the production of a radionuclide. We must use very good radiochemistry to produce the radiotracer. The radiotracers must be tested in vitro and in vivo (often in small animals). Then, we must perform clinical trials in humans, to determine if it is a good/reliable radiotracer to use in clinical practice. Finally, we end up with a real medicinal product that we may use in diagnosis or therapy. Here we have some examples. If we pay particular attention to the indications; bone metabolism, perfusion, renal function, detection of tumours, inflammation etc., these are used in GC/SPECT. Radiotracers used in PET imaging are mainly used for oncological purposes; choline for protein metabolism, fluorodeoxyglucose for glucose metabolism (most commonly used), and fluoride for bone scans. The therapy is composed of different parts: there is a linker that links the radioactive part to the receptor of the cancer cell, so it can destroy the cell. Therefore it has a therapeutic aim. Here we have different types of radiopharmaceuticals used in therapy: beta particles such as Lutathera used in neuroendocrine tumours, and Xofigo for bone metastasis from prostate cancer. Each of them have a unique set of characteristics such as their range, their linear energy transfer (LET) etc. We have radiopharmaceuticals that can be commonly injected, or administered through other routes eg. inhaled radiopharmaceuticals for studying lung ventilation. After an amount of time, usually varying from 3-10 hours, we scan the patient (on a PET or SPECT/CT scan), and then produce the images.2 For the first half of the class we will focus on the Evaluation of kidney dysfunction. Returning to kidney anatomy for a moment, it is important to know the location of the kidneys for the purpose of patient positioning. Transplanted kidneys are most commonly located in the iliac fossa. In this case, we’d have to position the gamma-camera in an anterior view. In all other cases, the acquisition is mostly in the posterior view (since anatomical kidneys are located posteriorly). Returning to physiology, we can remember the presence of the afferent/efferent arterioles, glomeruli, loops of Henle, collecting ducts etc. GFR is about 120 ml/min in a healthy individual, vascularisation is from the renal arteries, and we have the renin-angiotensin system that regulates renal vascular resistance. Here we can see the radiopharmaceuticals commonly used in the assessment of renal function. Each ‘step’ of the glomerular filtration pathway uses a different radiopharmaceutical. For example, the most 2 On around page 16 of her slides are some links through which you can find guidelines/explanations on how nuclear medicine works. 2 used/important radiopharmaceutical for glomerular filtration is DTPA radiolabelled with Technetium-99. For tubular secretion, the most common radiopharmaceutical is MAG3, again labelled with Technetium-99. Tubular fixation is most commonly studied with DSMA. The three most commonly used radiopharmaceuticals are: DTPA for glomerular filtration, DMSA, and MAG3 for active tubular secretion. MAG3 is commonly used in children and in patients with severely impaired renal function, because it has a higher renal extraction (the fraction of radiotracer extracted from the blood is higher). Therefore, in a kidney that is not completely formed/developed (like in children) or is impaired, MAG3 is more useful than DTPA. SCINTIGRAPHY PROTOCOL The only truly necessary preparation for the patient is good hydration. Fasting is not necessary for this study. Then, we inject the radiotracer intravenously. We then acquire the images, usually dynamic (only static in the case of DSMA usage), and usually from a posterior view for anatomical reasons. Then finally, we process the images and report our findings. The acquisition for DTPA and MAG3 is soon after the injection has been administered with the patient lying down, and usually lasts 30 minutes. In some cases, after 15 minutes (halfway through), a direct stimulus is injected eg. furosemide. There is the vascular phase (how the radiotracer arrives in the kidney), followed by the parenchymal phase (how the radiotracer distributes itself in the renal cortex), and finally the excretory phase (how the radiotracer is excreted from the kidney and then by the bladder). Static acquisition instead occurs for DMSA, lasting only 5 minutes each, however with different projections (anteroposterior, lateral and oblique). Here you can see a scan of a patient, with the kidneys and aorta (so called ‘regions of interest’) drawn out. Since there is a lot of artefact on scans like these, we make sure to trace the ROIs slightly outside the anatomical boundaries. After delineation of the ROIs, the software gives back the activity-time curves. We can see how much radioactivity is counted in the kidney over time. At the beginning (0min), the radiotracer is injected. This is followed by a peak as the bolus arrives in the kidneys. Then, the radiotracer leaves the kidneys via the ureter. This graph here shows the vascular, parenchymal (distribution within renal cortex), and excretory phases. There are other parameters we must consider when reporting a renogram; the most important is the relative parenchymal indices. These indicate the split renal function. For example, if the right kidney is at 20% and the left kidney is at 80%, the right kidney is impaired (because normal function should be around 45/47/53% eg.). 3 The clinical indications for scintigraphy are as follows: With Dynamic acquisition: Obstructive uropathy & hydronephrosis Renovascular hypertension Post-renal transplantation Vesico-ureteral reflux With Static acquisition: Pyelonephritis and scarring Renal morphological abnormalities OBSTRUCTIVE UROPATHY & HYDRONEPHROSIS We can have true obstructive uropathy, meaning there is something obstructing/compressing the ureter, so the radiotracer cannot pass into the ureter and instead remains in the kidney/collecting systems. At the same time we can have pseudo-obstructions, which can be related to inadequate urinary flow- if the patient is not properly-hydrated; dilation of the collecting system (enlarged renal pelvis); or the so-called ‘bladder effect’, when the patient voids and generates a high pressure that goes back up the ureter, preventing the kidney from properly excreting urine (with the radiotracer in this case). As mentioned before, we can administer furosemide/lasix halfway through. This acts on the loop of Henle, and allows us to distinguish a simple dilation of the urinary tract from a true obstructive disease. Looking back at the diagram above we can see that A and C are very similar, but in the case of A, there is a true obstruction. If we administer a diuretic treatment, and the collecting system responds to the stimulus, a normal curve will be displayed on the renogram. This differential diagnosis is important to distinguish between hydronephrosis and an obstructive disease. It’s important to detect an obstructive pathology, because if left untreated it can result in severe renal dysfunction. In the case of a true obstruction, the kidney will not respond to furosemide stimulation. Instead, in the case of stasis, the diuretic stimulation will allow the collecting system to excrete the urine. We can observe several renograms here, demonstrating different situations. This first case is the normal situation (Group 1), in which no observable changes occur after administration of furosemide. In the case of an obstruction, there is no response upon furosemide administration causing a plateau (Group 2). In stasis without obstruction, we can observe in the renogram how the kidney accumulates radioactivity, and then drops as soon as furosemide is administered (Group 3a). In the final case (Group 3b), the response is only partial, meaning that the response happens slowly instead of immediately. This graph depicts the same set of possibilities. Green = normal kidney, blue = dilated but not obstructed (in this 4 case it’s even worse because the response is very slow). Yellow = shows radioactivity accumulating over time with no response. The black line indicates the worst possible situation, as it shows that the kidney is ‘non-functional’, or ‘functionally excluded’, as it would be written in the report. This table shows the different conditions, and their corresponding scintigraphy reports. We can observe their clearance phases, since it is important to know the duration in order to assess whether the kidney is impaired or not. We may also observe the common features of the renogram curves. When we process the images on our software, these parameters will be displayed on the images. Here we can observe a colour scan. The lowest values are depicted in black/green. Then, as radioactivity values increase, we can see that the highest values are depicted in orange/white this can be observed on the scale indicated by the red arrow. In this case, a 38 year old woman has bilateral staghorn calculi. In this graph, the green line represents the right kidney and the red line represents the left kidney. Upon administering furosemide after 15 minutes, there is no response. In the colour images, we can see that the concentration of radioactivity is the same in both kidneys- they appear identical, and there is no way to determine which are the before/after images. This same stability is indicated in the graph, with the plateau curve, showing that the concentration of radioactivity is constant over time. The split function of the kidneys is normal even though there is a physical obstruction. Instead, this second case depicts a woman with right calyceal-pyelic dilation. We can observe that the left kidney is normal in the renogram, with the corresponding peak and excretory phase. However, there is a higher concentration of radioactivity in the renal pelvis of the right kidney. Observing the green line of the curve, we can see that radioactivity accumulates and then immediately drops upon administration of furosemide. This drop can be clearly observed between this image and the subsequent image. I’ve drawn a red box with an arrow to indicate the two images. One of the images shows a high concentration of radioactivity in the renal pelvis, which rapidly empties in the next image. We can note that the split function is normal. This next case is of a 33yo man with left ureteropelvic junction stenosis. We can observe how the curve of the right kidney is quite normal, with the expected decrease in 5 radioactivity over time. This can also be seen via the progression of the images indicated by the green arrow. Instead, the curve for the left kidney shows an upward trend, accumulating radioactivity and not responding to diuretics. This can be observed in the images, in which the left kidney looks the same throughout and displays no changes. We can say in this case that there is no response, and the split function is once again within normal limits. RENOVASCULAR HYPERTENSION We can study renovascular hypertension using scintigraphy. We know that it can be due to anatomic stenosis, dysplasia etc. In this case, we use a different diuretic to observe kidney function: Captopril instead of furosemide, because it inhibits ACE. It therefore abolishes the adaptation mechanism (RAAS system), so angiotensin I is not converted to angiotensin II, and GFR is reduced. This can be observed through scintigraphy. Here is a patient with left renal artery stenosis. The first graph indicates the response during basal conditions, and the second graph shows the response post-captopril stimulation. In the first graph, we can observe that both renograms are normal, with radioactivity decreasing over time (observable in the progression of the images). Instead, upon captopril administration we can see that the right kidney responds normally, with radioactivity decreasing from 1min to 20mins. However the curve of the left kidney shows accumulation, indicating damage/stenosis and consequent abnormal renal function. This graph on the left shows more renographic curves. Each curve corresponds to its own treatment for the degree of renal disease. Another indication for Scintigraphy is post-transplantation monitoring, particularly in the event of complications. As previously mentioned, when a kidney is transplanted it is put in the iliac fossa. A possible complication is a Urinoma= an encapsulated extravasation of urine. This can be detected via nuclear medicine. Here is a clinical case of a 53yo woman, post-transplantation. We can observe that the transplanted kidney is normal, as the bladder is filling normally. However, if we acquire an alternative projection eg. lateral/ anterior, we can detect the presence of abnormal radioactivity: there is the collection of radioactive urine in an abnormal structure indicated by yellow circle. Post-transplant monitoring can be used not only to detect complications, but to assess functioning of the transplanted organ. Here is a normal transplanted kidney (we only see one kidney in this case, as the other one may be non-functional/kidney agenesis eg.). We can observe that the renogram curve recorded three years post-transplantation is completely normal. The vascular phase is normal, with the expected peak, followed by the collecting system working to excrete the urine. 6 VESCICO-URETERAL REFLUX This condition is mainly seen in children, with scintigraphy performed to detect the condition. It is defined as a ‘retrograde flow of urine from the bladder into the ureters, or even the kidneys’. It is seen in about 1-2% of the population, and can be primary or secondary. It is important to detect in order to treat it in time, otherwise it can lead to chronic kidney failure. There are several grades of reflux. The left-most image depicts the normal situation, with the urine coloured in grey. Grade 1 reflux is limited to the ureter, whereas in grade 2 the urine reaches the renal pelvis. In grade 3, there is also dilation of the ureter and pelvicalyceal system. Finally in grade 4 and 5, the ureter is tortuous and dilated, also in the papillary/collecting systems. Nuclear medicine can be used for diagnosis, in the form of direct radionuclide cystography. We have the patient lying down on the gamma camera bed, with a bladder catheter inserted. We fill the bladder with saline solution, with the saline bag suspended 70-100cm above the patient so that gravity can assist in the process. It’s important to ensure that bladder filling does not occur too quickly, otherwise the patient will ask to void the urine immediately. During the filling phase, the gamma camera acquires images of the bladder and the reflux (if it’s present). The black spots on this image correspond to the bladder over time. We can observe the filling phase, as the saline travels to the bladder. Here indicated by the black arrows is a reflux of urine (Grade 1 reflux). It is limited to the ureter, and is intermittent (we see it in some images, but not in others as time goes on). Following this, we can observe the emptying phase and whether there is reflux or not upon urinary voiding. These are the scans of DRC performed in two different patients. The radioactive urine in the first patient can be seen highly concentrated in the bladder, with reflux in both the ureter and the renal pelvis indicated in red box. The reflux is intermittent once again, as can be observed by the fluctuations over time3. The second patient has a higher grade of reflux, as we can observe that the renal pelvis is dilated indicated in green box. INDIRECT RADIONUCLIDE CYSTOGRAPHY Indirect radionuclide cystography is performed at the end of a usual renogram. It allows us to explore if the patient has a reflux or not: in this case below, the patient hasn’t got a reflux cause you can’t see any radioactivity in the ureter, so the radionuclide cystography is negative for a reflux. 3 The time sequence corresponds to the small numbers next to each image, going across and then downwards. 7  STATIC ACQUISITIONS Tc-DMSA CLINICAL INDICATIONS The pharmacodynamics of this radiotracer are different from previous ones: in this case, we want the radiotracer to stay entrapped in the kidney and the proximal convoluted tubule cells in particular. The DMSA is linked to the microglobulin green oval and blue dot, entering via endocytosis into the cells of the proximal convoluted tubule and getting trapped there, so that we can image it. Detection of permanent renal parenchymal scarring can be seen at least six months following an acute urinary tract infection, which are quite common in children. Tc-DMSAcan be used for: Detection of acute pyelonephritis Detection of parenchymal damage after trauma (eg: car accident) → use static scintigraphy to see if the kidney is damaged or not Characterisation of structural renal abnormalities (eg: solitary kidney, with agenesis of the other kidney, duplex kidney, small kidney, dysplastic kidney, horseshoe kidney and pseudo-horseshoe kidney) Detection of ectopic renal tissue, including cross-fused renal ectopia We usually ask the parents of the children to help keep their child still under the camera bed for the imaging, since kids/newborns are not used to these types of procedures. From this method, we get the following views: Anterior Posterior Right oblique Left oblique In the image on the right, we can see a 6 month old boy with renal ectopia, because the kidney is below the normal position. CLINICAL INDICATIONS - PYELONEPHRITIS Based on the percentage of impairment of the kidney, we can classify the different degrees of the disease. Severity of critical uptake defect are graded by visual scoring system with DMSA: SCORE 0: Normal cortical function SCORE 1: 25% of impaired cortical function SCORE 2: 25-50% of impaired cortical function SCORE 3: Above 50% of impaired cortical function 8  In this clinical case, we can see the imaging of a 5yo girl with pyelonephritis. The defects are located in the right kidney, seen from the posterior view, even though the uptake indices are quite normal (perhaps due to a compensatory mechanism), so the kidneys work well in any case. Posterior view in both img. CLINICAL INDICATIONS - HORSESHOE KIDNEY There is the presence of a bridge between the 2 portions of the kidney; in the pink case, between the lower poles. In the green case4, instead, we have a different color scale and the bridge is between the upper poles. CHARACTERISATION OF RENAL MASSES This image from the World Health Organisation shows the complexity and evolution of classification of the renal tumors, from 1975 with just 2 histotypes (renal cell adenoma and renal adenocarcinoma), to the most recent classification in 2022 with 21 histotypes. Each of these histotypes has its own molecular characteristics and therapeutic options. HOW CAN NUCLEAR MEDICINE HELP? SPECT/CT [99mTc]Tc-Sestamibi PET/CT or PET/MRI ○ [18F]FDG ○ [68Ga]Ga-DOTATOC/DOTATATE/DOTANOC ○ [68Ga] or [18F] PSMA ○ …and many more currently under investigation Each of them has its own radiotracers, as we can see. 4 Image from a paper on PubMed; she said this to explain why the colors are different 9  1) SPECT/CT [99mTc]Tc-Sestamibi ○ The target of SPECT/CT [99mTc]Tc-Sestamibi is the mitochondria ○ It allows differentiation and distinction between oncocytic tumors, which are less aggressive and benign, and clear cell renal cell carcinoma, which are malignant. ○ The color scale is different in the images below. They go from 0 (in black) to the highest values, in white and orange etc. ○ In the left image: we can see a moderate uptake with renal masses on the CT imaging, ○ In the right image: in clear cell renal cell carcinoma, instead, they don’t have so many mitochondria (low mitochondrial density) and so we can see nearly no uptake. The arrows indicate the lesions. In the image below, you can see a systematic review and meta-analysis of renal masses: Reviews summarize all the evidence in literature about a certain topic, for example in this case the authors collected all the papers about the role of the scintigraphy in the evaluation of renal masses and they compared all the studies to see if there is a true advantage in using this radiotracer/method or not. In distinguishing between oncocytoma and HOCT (hybrid oncocytic chromophobe tumour), the sensitivity5 and specificity6 were 89%, so we can confirm that the test was reliable. In distinguishing between oncocytoma and ccRCC (clear cell renal cell carcinoma), the specificity is even higher (98%) which is satisfactory, since 100% is almost impossible to achieve. If the patient has the disorder. and shows a positive result upon scintigraphy, we can call this a True positive (TP) result (the disease is present and detectable). If we detect a positive result, but the disorder is not present, this is a False positive (FP). On the contrary, if the disease is not present and is not detected, this is a True negative (TN) result. If the disorder is present but not detected, this a False negative (FN) result. Sensitivity is the ratio between all true positive results (TP), divided by all the cases in which the disease was present (TP+FN), regardless of whether or not it was detected. Specificity is the ratio between all true negative results (TN), divided by all cases in which the disease was absent (TN+FP), even if a false positive result was detected. Positive Predictive Value (PPV) = all true positive (TP) results divided by all positive results detected (TP+FP). Negative Predictive Value (NPV) = all true negative (TN) results divided by all negative results detected (FN+TN). 5 Reminder: in medicine, sensitivity may describe how well a test can detect a specific disease or condition in people who actually have the disease or condition. 6 Reminder: when referring to a medical test, specificity refers to the percentage of people who test negative for a specific disease among a group of people who do not have the disease. 10  2) [18F]FDG This is the most commonly used radiopharmaceutical in PET imaging and oncology. The difference is that fluorine-18 atom is in the 2nd position of the glucose molecule → it enters through the cell via the GLUT transporter but it is trapped in the cell so that we can image it, and not transformed into pyruvate. We are able to image it because glucose is not directly converted into pyruvate. In the image on the left, we are able to see the whole GI tract and the skeleton. Unfortunately, we can see the kidneys as well (we will see later why seeing them is bad), pelvis and collecting system. However, the size of the kidneys is still normal (moderate to faint uptake). The bladder is always visible because the imaging component (FDG in this case) is excreted through urine, making it radioactive. Then, there is an inflammation sign in the area of the mouth (visible because it is black) because the patient has a metallic implant in their teeth. Note: with this type of imaging, we see inflammation, not tumors. Question from student about the previous image: has the thyroid got any problems in this case? Answer: the black spot we see in the image is actually not the thyroid (the thyroid is usually lower). FDG is not specific only for tumors, but also for inflammation, so it is used for example in vasculitis, endocarditis, etc. What we see here is actually inflammation. We can see the thyroid in cases of thyroiditis because it is an inflammation. In up to 34% of thyroid tumors, for example, we can see a focal uptake within the thyroid. Several renal pathologies can be seen in the table, described as findings on CT and PET. FDG uptake is variable between these types of tumors and the only avid type of tumor is lymphoma, as previously mentioned. We might see renal lesions on FDG PET, but only in aggressive types of tumors. For example, we can have cases of FDG - renal cell carcinoma avid masses. 11  Here, the AVID TYPE is very noticeable on the left kidney, evidentiated by the green circle. This means it is more aggressive. While here on the right we have an example of a NON-AVID TYPE. Tumor kidneys and masses are normally formed. This changes the therapeutic approach: A. If avid: more aggressive and can metastasize in lymph nodes and lungs. In lymphoma cases, there’s always avidity. B. If non avid: benign or less aggressive, so we can be less aggressive and avoid nephrectomy, being more conservative. The utility of our examination is that with a single scan we can see the whole body before the morphological changes start to occur in lungs, bones etc. With morphological imaging, instead, we can’t see the bones very well; we can see the lesion only if it is already in a very developed stage, making therapy less efficient. PINK Always presence of avidity Clear to see if there is sign of lesion when the avidity is high There is hypodensity in CT imaging and uptake in fused PET-CT imaging BLUE High uptake in the mass High avidity cause it is a lymphoma (as we mentioned before, all lymphomas have high avidity) GREEN We can see how the lymphoma has spread The kidneys are enlarged and not normal at all Cancer can be seen also in humerus and iliac bones (metastasis) 3) [68Ga]Ga-DOTATOC/DOTATATE/DOTANOC This classification of radiotracers is based on somatostatin analogues, so of course they link to somatostatin receptors. The most frequent receptors belong to these 5 types of classes, and have special affinity for receptor 2 and receptor 5. In Italy we mainly use DOTA-TOC but abroad it’s more commonly used 12 DOTA-TATE, but they're quite equivalent as radiotracers in detection rate, as some studies demonstrated. It’s more a question of availability and cost, rather than just deciding which type I prefer using. High physiological uptake in the kidneys → sub-optimal for lesions’ characterization, but several case reports have demonstrated high uptake in metastases (not primary tumor) from renal cell carcinoma, especially the clear cell variant. Example of a PET image left: We can see the kidneys well, which is not a good sign. We published this case report in 2020 right. During the first examination, the clinician thought it was a pancreatic neuroendocrine tumor, because there is a high vascularization at CT san and a metabolism typical of a neuroendocrine tumor. So the patient underwent both PET and DOTATOC-CT. In image E: fainted picture with light grey scale. In image F: light blue uptake with FDG. Blue= lowest vaòue, red= highest value. In image C: uptake in the body of the pancreas is very high, because it is red. Later, we discovered this was actually a clear renal cell carcinoma, and the patient was operated for it. In these images left we can clearly see the localisation of pancreatic metastasis of clear renal cell carcinoma. Kidneys have a similar intensity in all of those images. Metastases are indicated by the black arrows, thanks to the DOTATATE, which allows us to see them properly.. Summing up, compared to FDG, [68Ga]Ga-DOTATOC/DOTATATE/DOTANOC show a high uptake, so it would be interesting to study it in a wider population. 4) [68Ga] or [18F] PSMA PSMA= Prostate Specific Membrane Antigen. Unfortunately, it’s not very specific only for prostate cancer, because the more we use it, the more different types of tumors we see. They can be labeled without fluoride and gadolinium. We see in the image: The kidneys with very high uptake The bladder (cause of radioactive urine) The salivary glands, which can be important when we use a PSMA together with therapy, cause they can get damaged (keep in mind when treating, not during diagnosis). 13 Here we have some recent reviews published from 3 years ago, about all these classes of PSMA in renal cell carcinoma diagnosis. In the table, there is a comparison between them. CC= clear cell CHR= chromophobe P= papillary → papillary variant is more easily seen on FDG rather than on PSMA. CASE A PSMA is not specific for the prostate, as we said, in fact here we can see the analysis of a female patient, not a male patient. Lesions are clearly seen and there is only a faint uptake on the lung nodules. If we combine the 2 radiotracers, instead, we can have a complete view and understanding of the disease and the whole tumor burden. This allows us to choose the proper therapeutic approach. CASE B We can see a very high FDG-avid tumor and the metastasis located in the bones. Instead, we have a very faint uptake on PSM-PET. Each tumor, as we can see, behaves in different ways and doctors can never know in advance what they are going to see in the images. CASE C This is a clear renal cell carcinoma in which the PSMA-PET is used to evaluate the response of the patient to the treatment: bone metastasis responded quite well to this therapy. Nuclear medicine helps in assessing the therapeutic responses, and if it's not enough, the oncologist can shift the therapy. 14 CASE D Recurrence with faint uptake on FDG, while on PSMA it has a strong uptake. Evaluation of radiotherapy response is another aim of these imaging techniques. Reuptake decreases over time, and it’s true also after 12 months (last image on the right). FDG uptake is not specific only for prostate tumors, so that’s why we can see it in the inflammatory processes as well. CASE E High uptake is visible at the baseline and the uptake decreases, which means that the patient is responding well to the radiotherapy. FDG shows a faint uptake, because there is the effect of radioactivity → inflammation around the chemotherapy region leads to increased FDG uptake. 15