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Immunodiagnosis of human malignancy.

Definition of normal cell membrane antigens using immunologic techniques has permitted investigators to distinguish normal cells from malignant cells. Malignant cells express fetal antigens in concentrations different from normal mature cells. Mutant cells express differentiation as well as those antigens reflecting the altered cell genome. Normal cells can be transformed into malignant cells using either chemical agents or viruses. As these agents are incorporated into the genome, surface antigens are expressed that differ from normal cell isoantigens. These antigenic determinants can serve as tumor-associated or perhaps tumor-specific markers. Immunochemical methods now exist that permit isolation and purification of these antigens. Monoclonal antibodies have been generated that react with single epitopes associated with these antigens. Very sensitive and highly specific radioimmunoassays and enzyme immunosorbent assays can detect microgram quantities of these antigens in body fluids and as such permit serodiagnostic evaluation. Monoclonal antibodies can also be used for radioautography, immunofluorescent, and immunoperoxidase staining for diagnostic purposes of both cytologic and fixed tissue sections. The binding affinity and specificity of these monoclonal antibody reagents has successfully been used for in vivo tumor localization. Isotopically labeled monoclonal antibodies bind preferentially to tumor cells in the host and are useful for specific radionuclide scintigraphy. These recently developed immunodiagnostic techniques not only add specificity in terms of diagnostic accuracy but are useful for early detection of recurrent disease and in vivo localization of tumor deposits. Therapeutic implications are discussed.

Antibodies, Monoclonal↗

Radiation safety of the sentinel lymph node technique in breast cancer.

Many publications attest to the potential of the sentinel lymph node technique in advancing the clinical management of melanoma and, more recently, breast cancer. Whilst not yet universally regarded as the standard of care, the technique is gaining wide acceptance. Use of a radiolabelled colloidal tracer is central to optimising sensitivity, and this brings with it the need to address radiation safety issues relating to the use of radioactive materials in the operating theatre and pathology laboratory, and the generation of radioactive waste. The radiation dose to the patient should also be determined if the professional is to reassure the patient by placing this in its proper context. For the purpose of this investigation, biodistribution data were obtained from patient studies to quantify the migration of tracer beyond the injection site, thereby permitting a detailed assessment of the internal dosimetry of the tracer and the resulting radiation dose to the patient. Uptake of tracer in the sentinel nodes, reticulo-endothelial system and circulating blood was investigated. The radiation dose to surgical staff was recorded using whole-body monitors and extremity dosimeters worn at the fingers. Clinical waste in the operating theatre was monitored and the radioactive content of significantly contaminated items determined. The radiation dose to pathology staff was estimated from knowledge of the radioactive content of the specimens obtained and a study of work practices. Migration of tracer was found to be minimal, with greater than 95% retention at the injection site. The effective dose resulting to the patient was 2.1x10(-2) mSv/MBq, with a mean breast dose of 7.2x10(-1) mGy/MBq. A mean whole-body dose of 0.34 microSv was received by surgical staff per procedure, with a mean finger dose of 0.09 mSv (90 microSv). Radiation doses received by pathology staff will be predominantly below measurable levels and are likely to be negligible unless primary specimens from a large number of studies are analysed promptly upon their excision. At operation, surgical swabs can become significantly contaminated and have been found to contain up to 22% of the administered activity, dependent upon the surgical procedure performed. It is concluded that moderate activities of technetium-99m labelled tracer are administered to the patient, and the radiation risk to the patient is consequently low relative to that from many other medical exposures. The radiation doses to staff groups involved in all aspects of the technique are low, and under normal circumstances and levels of workload, routine radiation monitoring will not be required. Standard biohazard precautions prevent direct intake of radioactive contamination. Radioactive waste is created in the operating theatre, and may be generated in the pathology laboratory if specimens are not routinely stored until fully decayed. This will require special handling if the disposal of radioactive material is not permitted.

Breast Neoplasms↗

Simple proton spectroscopic imaging.

Simple modification of a spin echo imaging pulse sequence generates useful spectroscopic information at 0.35 T. New images are produced that show water only, fat only, and the difference between water and fat intensity. Imaging speed, spatial resolution, and signal-to-noise ratio are comparable with ordinary imaging. The method provides new parameters for tissue characterization and improved contrast between some organs.

Adipose Tissue↗

A nonimaging scintillation probe to measure penile hemodynamics.

UNLABELLED: We have developed a penile nonimaging scintillation (PNIS) probe consisting of a plastic well-type scintillation crystal interfaced to a portable computer and acquisition board. This report describes the design of the PNIS probe, performance characteristics, mode of usage and illustrative results which demonstrate its capabilities. METHODS: With the PNIS probe, penile blood-pool studies were performed in nine patients utilizing 3.7 MBq (100 microCi) autologous 99mTc-labeled red blood cells (RBCs). Venous blood standards were assayed to enable conversion of the count rate to volummetric measurements. Washin of peripherally administered 99mTc-RBCs was mathematically analyzed to estimate penile blood volume and cavernosal flow rate in the flaccid state. The rate of change of penile blood volume after intracavernosal vasodilators was used to generate measures of stimulated flow. RESULTS: A major advantage of this device over the gamma-camera is a 3300-fold increase in count rate sensitivity, which allows for markedly improved temporal resolution while significantly reducing the radiopharmaceutical dosage. Additionally, the PNIS probe is portable, economical and is not dependent on operator-defined regions of interest. Count rate sensitivity is relatively constant within the bore, with the exception of the proximal region adjacent to the opening, where geometric efficiency is reduced. CONCLUSION: The PNIS probe is an effective device for measuring penile activity in radionuclide studies, allowing for acquisition of time-activity curves of the penis during flaccid washin of peripherally labeled red blood cells and after pharmacologic stimulation to induce erection.

Adult↗

Synthesis of aminobenzyltriethylenetetraaminohexaacetic acid: conjugation of the chelator to protein by an alkylamine linkage.

The conjugation of a chelating agent to an antibody as an anchoring site for a radionuclide is the first step in the successful preparation of a radiolabeled antibody for a diagnostic and therapeutic application. The high affinity of the protein bound chelator towards radionuclide ensures a higher selectivity in the delivery of the radionuclide to the targeted tissue. 4-Aminobenzylderivativetriethlenetetraaminohexaacetic acid (TTHA), a hexadentate chelating agent has been now prepared for conjugation with proteins in view of the higher affinity of TTHA metal ions as compared to DTPA. The latent crosslinking potential of alpha-hydroxy aldehydes has been used to conjugate the new chelating agent to proteins through an alkylamine linkage. On incubation of amino benzyl TTHA with glycoladehyde at neutral pH and room temperature, the reagent is converted to oxo ethyl amino benzyl TTHA. On addition of albumin to this reaction mixture, the oxo ethylamino benzyl TTHA generates reversible schiff base adducts with the amino groups of albumin. The reduction of the Schiff base adducts of the chelator with the protein by sodium cyanoborohydride stabilizes the schiff base adducts as stable alkylamine linkages. 4-Thiocyanatobenzyl TTHA has also been prepared and conjugated to albumin through a thiocarbamoyl linkage. Both preparations of TTHA conjugated albumin complexed with 99mTc and 111In, with high affinity and no decomposition of the complex was noticed for at least up to 6 hrs after the preparation. The radiolabels complexed with these TTHA -albumin conjugates could not be 'chased' out by free DTPA. A comparison of the biodistribution of 111In, bound to the TTHA conjugated through an alkylamine and a thiocarbamoyl linkage showed that 111In complexed with alkylamine linked TTHA was retained in blood to a level nearly 17% higher compared to that seen with thicarbamoyl linked TTHA, one hr after the injection into mice. Thus, the alkylamine linkage appears to be more stable under the in vivo conditions. The glycolaldehyde mediated alkylation procedure offers a mild, simple and rapid method for preparation of drug-protein (antibody) conjugates.

Acetates↗

Radionuclide therapy with bone-seeking compounds: Monte Carlo calculations of dose-volume histograms for bone marrow in trabecular bone.

The purpose of the present work was to investigate how haematopoietic stem cell survival is affected by the differences in the dose distribution that arise from different radionuclides contained in bone-seeking radiopharmaceuticals. This was carried out in three steps: (a) calculations of representative dose distributions in individual bone marrow cavities that are irradiated by sources of 89Sr, 186Re, 117mSn or 153Sm, uniformly distributed on the bone surfaces; (b) assessment of the corresponding haematopoietic stem cell survival and (c) a comparison of these results with results obtained using the assumption of a uniform dose distribution. Two different idealized models of the geometry of trabecular bone were formulated, each consisting of an infinite array of identical elements. Monte Carlo simulations were used to generate dose-volume histograms that were used to assess haematopoietic stem cell survival with two different assumptions about spatial cell distributions. Compared with a homogeneous dose distribution, the estimated cell survival was markedly higher for 117mSn and 153Sm, and only slightly different for 89Sr and 186Re. The quantitative results differed between the two geometric models and the assumptions about spatial cell distribution, but the trends were the same. The results imply that it is necessary to include dose distributions for individual bone marrow cavities in considerations concerning bone marrow toxicity.

Age Factors↗

Fluorescent thyroid imaging: clinical evaluation of an alternative instrument.

Fluorescent imaging of the thyroid was performed successfully in 43 patients with incident low-energy photons generated by an x-ray tube. The images were comparable in quality and information content to those obtained with 123l or 99mTc pertechnetate. The estimated absorbed radiation dose to the gland is approximately 40 mrads. Fluorescent imaging is a clinically useful means of evaluating the thyroid.

Evaluation Studies as Topic↗

Metabolic cardiac imaging in severe coronary disease: assessment of viability with iodine-123-iodophenylpentadecanoic acid and multicrystal gamma camera, and correlation with biopsy.

Fifteen patients with coronary disease and resting left ventricular ejection fractions of less than or equal to 0.35 underwent resting metabolic cardiac imaging utilizing 1 mCi [123I]iodophenylpentadecanoic acid (IPPA) intravenously and a multicrystal gamma camera. Parametric images of regional rates of IPPA clearance and accumulation were generated. Forty-two vascular territories (22 infarcted) were evaluated by metabolic imaging as well as transmural myocardial biopsy. Despite resting akinesis or dyskinesis in 20/22 (91%) infarcted territories, 16/22 (73%) of these territories were metabolically viable. Transmural myocardial biopsies in all patients (43 sites, 42 vascular territories) during coronary bypass surgery confirmed IPPA results in 39/43 patients (91%). When compared to biopsy, scan sensitivity for viability was 33/36 (92%) with a specificity of 6/7 (86%). Eighty percent of bypassed, infarcted but IPPA viable segments demonstrated improved regional systolic wall motion postoperatively as assessed by exercise radionuclide angiography. We conclude resting IPPA imaging identifies viable myocardium, thereby providing a safe, cost-effective technique for myocardial viability assessment.

Biopsy↗

Myocardial perfusion with rubidium-82. II. Effects of metabolic and pharmacologic interventions.

In order to validate a new method for quantifying coronary blood flow, we injected intravenously a bolus of rubidium-82 (Rb-82) into 28 open-chested dogs under a wide range of flow and physiologic conditions, using beta probes to monitor myocardial radioactivity. Extraction fraction and perfusion were measured using a functional model that separates the data into the free and trapped myocardial rubidium. Extraction and uptake of rubidium were lower during acidosis than during alkalosis and were unchanged by glucose-insulin, digoxin, or propranolol. Myocardial flow, as indicated by rubidium, correlated linearly with simultaneous measurements of flow by microspheres in the same sample volume over a wide range of flow (r = 0.97, n = 106, range 0.02-7.76 ml/min/g). Regional myocardial blood flow can be accurately determined using generator-produced Rb-82. Studies using current state-of-the-art, fast positron-emission tomographic cameras are required to determine the utility of this approach in man.

Animals↗

Evaluating the Swirler nebulizer: a user's perspective.

The change from multi-use to single-use nebulizer systems could potentially result in greatly increased expense for aerosol ventilation imaging and a larger waste disposal problem. We have therefore investigated a new compact single-use nebulizer system, the Swirler (Amici), for ventilation lung imaging using 99Tcm-DTPA aerosol. Seventy-five patients requiring lung ventilation/perfusion imaging were studied. The ventilation imaging was assessed using three different fills: Group 1, 1000 MBq in 2 ml; Group 2, 1000 MBq in 4 ml; and Group 3, 2000 MBq in 4 ml. The nebulization times to give 1200 counts s-1 on the posterior ventilation image were similar for Groups 1 and 3 (mean 4 min) but slower for Group 2 (mean 6 min). Room contamination was very low when performed in a room with an extractor device. The mean room air contamination was 117.0 Bq l-1 min-1 for Group 1 amd 27.6 Bq l-1 min-1 for Group 2, comparable to previous nebulizers we have used. Dose rates measured at the surface of the lead shielded nebulizer were 6.8 microSv h-1 for 1000 MBq in 2 ml and 10.9 microSv h-1 for 2000 MBq in 4 ml. The mass median diameter (span) without the extension tubing was 1.39 microns (1.85) and with a small extension tube reduced to 1.11 microns (1.70). Qualitative and quantitative assessment of image quality showed good peripheral airways penetration of particles with no uninterpretable scans, comparable with other systems we have used. In practical terms, the device is much more compact than other systems and therefore generates a much smaller volume of waste. It is an easy device to use. However, when ventilating patients supine or erect, we found that it was necessary to use the small extension tube.

Aerosols↗

Effect of variable left ventricular vertical orientation on planar myocardial perfusion images.

Differences in vertical orientation of the left ventricle within the chest cavity cannot be corrected by gamma camera positioning. The effect of variations in vertical angulation on the appearance of the diagnostically important left anterior oblique (LAO) view has not been previously evaluated. In the current study, a computer simulation of a normal left ventricle was created and "imaged," varying only the degree of vertical rotation. The effect of six vertical positions on the LAO image was assessed visually and with horizontal and circumferential profile analysis. Results indicate a homogenous distribution of counts in the horizontal views. With increasing verticality, there are fewer counts in the valve plane, while the inferoapex initially increases in count density, and then progressively decreases. Quantification revealed count variations of up to 37% in the valve plane and 45% in the inferoapex due entirely to differences in vertical orientation of the left ventricular simulation. A survey of 167 patients who underwent routine stress thallium imaging showed a vertical angulation that varied from 7 degrees to 64 degrees (mean = 37 degrees) as determined from the anterior view. Clinical images were similar in appearance to computer generated images after correction for anterior view foreshortening. The present study suggests that the accuracy of current quantitative thallium methods to detect coronary artery disease might be enhanced by the use of a revised set of normal standards corrected for vertical orientation of the left ventricle.

Computers↗

Therapy of neuroendocrine tumors with radiolabeled MIBG and somatostatin analogues.

The increased understanding of the neuroendocrine tumors at a cellular and molecular level has led to the development of new radiopharmaceuticals for imaging. Two of the imaging agents include 131I metaiodobenzylguanidine (131I-MIBG) and 111In-DTPA-D-Phe1-octreotide (111In-pentetreotide) each having specific localization in certain neuroendocrine tumors. The selective uptake of these radiopharmaceuticals by the tumor cells has generated interest in potential use for targeted radiotherapy for neuroendocrine tumors. 131I-MIBG has been used to treat patients with pheochromocytoma, neuroblastoma, carcinoid tumors, medullary thyroid carcinoma, and paragangliomas. The tumor responses have been variable with the most encouraging results being in patients with pheochromocytoma. The dose-limiting toxicity has been thrombocytopenia or granulocytopenia. 111In-pentetreotide has been used as therapy in only a few patients and has resulted in objective evidence of tumor responses. A therapeutic agent using a somatostatin analogue will most likely require radiolabeling with a beta- or possibly an alpha-emitting radionuclide to achieve significant and durable tumor responses.

3-Iodobenzylguanidine↗

Skeletal complications of Gaucher disease.

Gaucher disease is a collection of related disorders of sphingolipid catabolism caused by the deficiency of a specific beta-glucosidase. The inefficiency of this enzyme, glucocerebrosidase, to degrade its natural substrate leads to the accumulation of the complex lipid glucocerebroside in tissue macrophages. The pathogenesis of the disease is, as yet, poorly understood. The manifestations of the disease are protean with hepatosplenomegaly and bone deterioration frequently the predominating signs. The disease most frequently causes disability because of its effects on the skeleton. This review seeks to summarize the current clinical understanding of these complications. Experience with 327 patients reveals that the bone disease in this disorder is extremely variable. The severity of the problems range from asymptomatic persons with neither radiographic, scintigraphic, nor histologic evidence of bone involvement to those whose skeleton is completely devastated by a process of osteopenia, osteonecrosis, and osteosclerosis. These severely affected individuals show the most bizarre deformities in their bones and are subject to pathologic fracture. Most patients fortunately, are less profoundly affected, but many are plagued by bone pain of an arthritic nature or by an acute prostrating bone crisis probably best described as a bone infarction. The accepted etiology that these crises are a result of vascular compromise produced by occlusion of vessels by Gaucher cells is not supported by scintigraphic or histologic studies. Moreover, the vascular hypothesis does not explain the variety of lesions of the skeleton seen in this multifocal bone disease. Preliminary metabolic and endocrinologic studies suggest that this is not a systemic disorder of metabolism which affects bone uniformly. On the contrary, the lesions are multiple and localized, and sometimes much of the skeleton is preserved. These observations suggest that bone is affected because of collections of Gaucher cells scattered throughout its substance and may be the result of a toxic process around these foci. Alternatively, the storage of glucocerebroside in tissue macrophages may disturb the generation of competent osteoclasts and thus result in a failure to maintain a healthy skeleton. Further research is needed to delineate the pathogenesis of this disorder before any effective therapy can be developed.

Adolescent↗

Iodide organification defect in a cold thyroid nodule: absence of iodide effect on cyclic AMP accumulation.

A follicular adenoma of the thyroid was 'hot' one hour after 99mTc pertechnetate administration, but 'cold' 24 h after 131I iodide administration. Incubation of the tissue in vitro demonstrated a defect in iodide binding to proteins that was abolished by addition of an H2O2 generating system. In this tissue iodide failed to inhibit TSH-induced cyclic AMP accumulation. The results show that iodide oxidation is required for its inhibitory action on cyclic AMP accumulation in human thyroid.

Adenoma↗

Equilibrium radionuclide gated angiography in patients with tricuspid regurgitation.

Equilibrium gated radionuclide angiography was performed in 2 control groups (15 patients with no organic heart disease and 24 patients with organic heart disease but without right- or left-sided valvular regurgitation) and in 9 patients with clinical tricuspid regurgitation. The regurgitant index, or ratio of left to right ventricular stroke counts, was significantly lower in patients with tricuspid regurgitation than in either control group (range and mean +/- standard error of the mean 0.4 to 1.0, 0.7 +/- 0.1 versus 1.0 to 1.5, 1.3 +/- 0.1 and 1.0 to 2.9, 1.5 +/- 0.1, respectively, p less than 0.001). Time-activity variation over the liver was used to compute a hepatic expansion fraction which was significantly higher in patients with tricuspid regurgitation than in either control group (1.4 to 11.4, 5.8 +/- 1.0% versus 0.6 to 3.4, 1.9 +/- 0.3% and 1.0 to 5.1, 2.3 +/- 0.2%, respectively, p less than 0.001). Fourier analysis of time-activity variation in each pixel was used to generate amplitude and phase images. Only pixels with values for amplitude at least 7% of the maximum in the image were retained in the final display. All patients with tricuspid regurgitation had greater than 100 pixels over the liver automatically retained by the computer. These pixels were of phase comparable to that of the right atrium and approximately 180 degrees out of phase with the right ventricle. In contrast, no patient with no organic heart disease and only 1 of 24 patients with organic heart disease had any pixels retained by the computer. In conclusion, patients with tricuspid regurgitation were characterized on equilibrium gated angiography by an abnormally low regurgitant index (7 of 9 patients) reflecting increased right ventricular stroke volume, increased hepatic expansion fraction (7 of 9 patients), and increased amplitude of count variation over the liver in phase with the right atrium (9 of 9 patients).

Adolescent↗

New hybrid count- and geometry-based method for quantification of left ventricular volumes and ejection fraction from ECG-gated SPECT: methodology and validation.

BACKGROUND: We have previously developed a new method for quantitative assessment of left ventricular (LV) volumes and ejection fraction (EF) from electrocardiography-gated single photon emission computed tomography (SPECT). The aims of this study were to present the methodology, to validate the gated SPECT cardiac quantification (GSCQ) method in phantoms and patients, and to determine normal values of LVEF. METHODS AND RESULTS: A simple thresholding technique was used to generate binary images from nongated SPECT images. The K-means cluster classification algorithm was used to separate the LV region from non-LV regions on the binary images. A count- and geometry-based algorithm was applied to define endocardial and epicardial boundaries for calculation of LV volumes and LVEF. Overall correlation between GSCQ-quantified volumes and actual phantom volumes was good ( r = 0.97 and standard error of estimation (SEE) = 9.99 mL for normal phantoms, r = 0.99 and SEE = 6.97 mL for phantoms with defects). In patient studies, LVEF derived by GSCQ from SPECT and from equilibrium radionuclide angiography also showed good correlation ( r = 0.90 and SEE = 6.2%). The lower limit of normal LVEF from 8-frame gated SPECT by use of GSCQ was 45%. Quantification of LVEF by the GSCQ method was highly producible and was not significantly affected by the presence of myocardial perfusion defects or intense gastrointestinal activity. CONCLUSIONS: The GSCQ method provides reliable and consistent assessments of LV volumes and EF. This methodology is less affected by intense gastrointestinal activity than other methods.

Adult↗

The humoral immune response to macrocyclic chelating agent DOTA depends on the carrier molecule.

UNLABELLED: The chelating agent 1,4,7,10-tetraazacyclododecane-N,N', N",N"'-tetraacetic acid (DOTA) is used to label monoclonal antibodies (mAbs) and peptides with (90)Y. DOTA allows the generation of clinically useful stable metallic radioconjugates for the treatment of a variety of tumors, but its immunogenicity has remained controversial. In this study, we evaluated the immune response to DOTA in a preclinical mouse model and in patients entered in a clinical trial. METHODS: Sera were obtained from BALB/c mice injected intraperitoneally or subcutaneously with different doses and formulations of syngeneic and xenogeneic mAbs or peptide (murine mAb Mov19 [mM19]; its chimeric version; murine V/human C ChiMov19 [cM19]; or Tyr(3)-octreotide)-DOTA conjugates. Sera from patients with neuroendocrine tumors, enrolled in a protocol for somatostatin receptor-mediated radionuclide therapy with (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide (DOTATOC), were also collected before and after each treatment. Levels and specificity of antibody response to relevant (Mov19, ChiMov19, or Tyr(3)-octreotide) and nonrelevant (human serum albumin) DOTA targets were tested by enzyme-linked immunosorbent assay and competition assays. An anti-DOTA mAb (IgG1) derived from a ChiMov19-DOTA immunized mouse was used, in a competitive radioimmunoassay, to determine the efficiency of DOTA presentation on the different carriers. RESULTS: Depending on the immunogenicity and dosage of the mAb, a specific anti-DOTA response was revealed in the preclinical system. However, DOTA-peptide conjugate induced no immune-detectable response against either chelator or carrier. DOTA was poorly presented on small peptides, as determined using the anti-DOTA mAb. CONCLUSION: A humoral response against DOTA is possible, but only as a consequence of the response elicited against the carrier. Octreotide was not immunogenic. Thus, (90)Y-DOTATOC can be considered a safe and useful tool for receptor-mediated radionuclide therapy of somatostatin receptor-overexpressing tumors.

Animals↗

Reverse of the differential uptake intensity of Tc-99m MIBI and Tc-99m V-DMSA by multiple myeloma lesions in response to therapy.

PURPOSE: The objective of this study was to compare the uptake changes of Tc-99m 2-methoxy isobutyl isonitrile (MIBI) and Tc-99m pentavalent dimercaptosuccinic acid (V-DMSA) in multiple myeloma (MM) lesions in response to high-dose chemotherapy (HDC). MATERIALS AND METHODS: The authors compared Tc-99m MIBI and Tc-99m V-DMSA scans before and after HDC in a patient with focal MM lesions without amyloidosis who had received previous standard chemotherapy as well. RESULTS: HDC had the effect of eliminating all Tc-99m MIBI uptake in the lesions. Tc-99m V-DMSA uptake was increased in lesions presenting significant initial Tc-99m MIBI uptake. In 1 particular lesion that demonstrated this phenomenon, magnetic resonance showed necrosis of the area of MM. CONCLUSION: The authors consider that the effect of increasing Tc-99m V-DMSA uptake in the absence of an increase in viable plasma cells possibly reflects the treatment-generated inflammatory and fibrotic changes and not necessarily viable tumor tissue. Exclusive focal Tc-99m V-DMSA uptake in this clinical setting could be considered as a sign of effectively treated lesions and not a sign of deterioration.

Adult↗