Numerical integration of bivariate fractal interpolation functions on rectangular domains.

This paper primarily focuses on the derivation of fractal numerical integration for the data sets corresponding to two variable signals defined over a rectangular region. Evaluating numerical integration results through the fractal method helps achieve accurate results with minimum computation effort. The formulation of the fractal numerical integration is achieved by considering the recursive relation satisfied by the bivariate fractal interpolation functions for the given data set. The points in the data set have been used to evaluate the coefficients of the iterated function systems. The derivation of these coefficients considering the index of the subrectangles, and the integration formula has been proposed using these coefficients. The bivariate fractal interpolation functions constructed using these coefficients are then correlated with the bilinear interpolation functions. Also, this paper derives a formula for the freely chosen vertical scaling factor that has been used in reducing the approximation error. The obtained formula of the vertical scaling factor is then used in establishing the convergence of the proposed method of integration to the traditional double integration technique through a collection of lemmas and theorems. Finally, the paper concludes with an illustration of the proposed method of integration and the analysis of the numerical integral results obtained for the data sets corresponding to four benchmark functions.

Effectiveness of triennial screening with clinical breast examination: 14-years follow-up outcomes of randomized clinical trial in Trivandrum, India.

BACKGROUND: This study presents the preliminary results of a randomized controlled trial (RCT) initiated in January 2006 in India to evaluate the effectiveness of clinical breast examination (CBE) in reducing breast cancer mortality as compared to a no-screening control group reported significant downstaging in the intervention group. The present manuscript reports long-term follow-up outcomes. METHODS: Women 30-69 years old from 133 intervention clusters and 141 control clusters were invited to participate. Women in the intervention arm underwent three rounds of CBE every 3 years. CBE-positive women were reexamined by a physician, and triple-assessment was performed on those confirmed to have abnormalities. All participants were followed through home visits and linkage with population-based cancer registry. RESULTS: Of the 55,843 eligible women in the intervention arm, 95.7% had CBE at least once and 11.5% were CBE-positive. Breast cancers were diagnosed in 335 participants in the intervention group and 273 in the control group (N = 59,447). Age-standardized incidence rate of early cancer was 30.4 of 100,000 in the intervention and 21.9 of 100,000 in the control group, with a rate ratio (RR) of 1.4 (95% confidence interval [CI], 1.1-1.8). The age-standardized breast cancer mortality rates were 11.3 and 11.1 per 100,000 in intervention and control arms, respectively (RR, 1.1; 95% CI, 0.8-1.5) after 15 years. Five-year breast cancer survival rates were 77.0% in the intervention and 71.2% in the control groups (overall p value = .043). CONCLUSIONS: Triennial CBE screening failed to demonstrate any mortality benefit despite achieving a shift toward earlier stage at detection and improved survival in the intervention arm. CBE is a valuable tool for diagnosis of breast cancer in symptomatic women especially in areas where mammography and/or breast cancer screening programs are not widely available.

Demographics, Clinicopathological Profile of Oral Lichen Planus of South Kerala Population: A Cross-Sectional Study.

BACKGROUND:  Oral lichen planus (OLP) is a chronic mucocutaneous inflammatory lesion of unknown cause. The buccal mucosa is the most frequently affected anatomic site and the lesion is bilateral. The objective of this retrospective study was to investigate the epidemiological and clinical characteristics of 250 OLP patients in South Kerala. This was done by figuring out these patients' epidemiological and clinical characteristics. Materials and methods: In the present study, patients who reported between September 2018 and December 2021 were selected employing the diagnostic criteria consistent with the WHO classification of OLP. Data of all the patient's characteristic features were collected and evaluated using the Statistical Package for the Social Sciences (SPSS) software for statistical analysis. RESULTS:  Out of 250 patients, 52% were females and 48% were males. Reticular (n = 145, 58%) and erosive forms (n = 105, 42%) were the two clinical presentations of the lesions that were most consistently observed. The age group of 25-34 years reported the highest number of cases (n = 71, 28.4%). According to the chi-square test, there were statistically highly significant differences between the hyperpigmentation, age, and type of OLP. While 43.2% (n = 108) of cases reported a burning sensation, pain, or soreness, 56.8% (n = 142) of cases were asymptomatic. There were statistically significant differences between the type of OLP and the reported symptoms (p = 0.001). Mild to moderate dysplastic changes were documented in 5.6% during the follow-up period. A successful treatment outcome with topical steroid administration was recorded in the study sample. CONCLUSION:  It was apparent that patients typically have bilateral lesions involving the buccal and labial mucosa, manifesting with varying degrees of oral discomfort. Although patients frequently have more than one variant of OLP, the lesions are typically reticular or erosive in nature. A meticulous follow-up is crucial to determine its malignant change.

PCR-based Evaluation of Human Papillomavirus Genotypes in Oral Lichen Planus.

Objective: The objective of the study was to use polymerase chain reaction (PCR) to examine and compare the genotype distribution of human papillomavirus (HPV) in oral lichen planus (OLP). Materials and Methods: Deoxyribonucleic acid (DNA) was extracted from 20 OLP biopsy specimens. Conventional PCR assay employing consensus HPV primers was used to identify HPV DNA. Positive PCR samples were then subjected to PCR assay with HPV type-specific primers. Results: Out of the total 20 OLP specimens evaluated, eight samples (40%) were positive for HPV. Females had a 41.7% higher HPV-positive rate than males. The most common type in the HPV type-specific PCR assay was HPV-18 (75%), which is a high-risk type of HPV linked to malignant diseases. The erosive kind of OLP had the greatest percentage of HPV positives (50%). Conclusion: The present study confirms the detection of HPV in OLP lesions, as determined by PCR-coupled HPV gene sequencing, as well as its likely mechanism of malignant transformation.

Comparison of Diagnostic Ability of Conventional Film and Storage Phosphor Plate in Detecting Proximal Caries with Direct Measurements by Stereomicroscope: A Diagnostic Test Evaluation.

Background: Radiography plays an important role in detection of interproximal caries. The aim of study is to compare diagnostic ability of conventional film and photostimulable phosphor (PSP) with direct measurement using stereomicroscope in detecting proximal caries. Methodology: In this descriptive study - diagnostic test evaluation, 200 proximal surfaces of 100 extracted human posterior teeth were radiographed with dental X-ray unit. Evaluation of conventional and digital radiographs was performed twice by three observers. Carious lesions were classified based on a four-point scale (R0-R3) suggested by Abesi et al. Weighted kappa coefficients were calculated to assess intra- and interobserver agreement for each image set. Indices of diagnostic ability calculation were based on the first readings of the three observers. The scores were compared with the histological gold standard using receiver operating characteristic (ROC) analysis to evaluate diagnostic ability. Results: Intraobserver kappa coefficients calculated for each observer for each method of detecting caries ranged from 0.914 to 0.956. Interobserver kappa coefficients for each image set ranged from 0.8788 to 0.9583. The sensitivity and specificity of film for the first observer were 77.5% and 78.3% and for PSP were 77.5% and 80%, respectively. ROC analysis revealed that there were no statistically significant results (P > 0.05) between Az values for the two detection methods. Conclusion: PSP plate should be preferred over conventional films in detecting cavitated proximal caries. Further studies with more noncavitated proximal surfaces are required to conclusively establish the diagnostic ability of PSP over conventional film.

Duplex real-time PCR methods for molecular detection and characterization of canine tick-borne haemoparasites from Punjab state, India.

BACKGROUND: Microscopy is a routinely used technique for the diagnosis of canine tick-borne haemoparasitic diseases in various clinical laboratories worldwide. In an attempt to provide better diagnostic assay to the clients for effective management of these diseases duplex real-time PCR assays were applied. METHODS AND RESULTS: Blood samples (n = 338) aseptically collected from suspected dogs of Central Plain Zone of Punjab state, India were subjected to SYBR Green based real-time duplex PCR assays for simultaneous detection of B. vogeli & E. canis and B. gibsoni & H. canis. Results revealed an overall prevalence rate of canine tick-borne haemoparasites as 54.1%, amongst which H. canis was the predominant (25.4%), followed by B. gibsoni (16.3%), E. canis (10.7%) and B. vogeli (1.8%). Sensitivity and specificity of the duplex assays ranged from 59.04 to 100.0% and 58.12 to 92.52%, respectively and their strength of agreement was ″fair″ with kappa value statistics. A significant (p < 0.05) association between prevalence of B. gibsoni, H. canis and E. canis infection with risk factors like sex, breed, season and location was recorded. The ancestral background of the field isolates of haemoparasites was also studied by phylogenetic analysis of their nucleotide sequences. CONCLUSIONS: SYBR Green dye based duplex real-time PCR assays proved to be highly sensitive, specific, rapid and affordable diagnostic tests for use by clinicians to save the life of pets.

Clinical Study of BPPV and the Effectiveness of Canalolith Repositioning Manoeuvre in Subjects of BPPV.

Vertigo is an illusion of motion, either of one self or of the environment. Vertigo in BPPV is a very devastating experience for the patient who experiences it. However, it can be reversible with vestibular rehabilitation, with very good results. A study on 72 patients attending Otoneurology clinic in our hospital, diagnosed as BPPV with history and examination were subjected to DHI (Dizziness Handicap Index) questionnaire prior to and after intervention and results were analyzed. BPPV is more commonly seen in elderly individuals above 45 yrs, females and posterior semi circular canal. A significant improvement was noted in all the three components of DHI index in patients treated with CRM (Canalolith Repositioning Manoeuver) when compared to the patients who received only reassurance. CRM is a very safe and effective treatment of BPPV which has the added advantage of being noninvasive procedure, with excellent results.

Role of Human Papilloma Virus in Malignant Transformation of Oral Lichen Planus: A Systematic Review.

Lichen planus (LP) is a chronic inflammatory mucocutaneous disease. The disease has a cell-mediated immune reaction which is precipitated by a specific trigger which turns the self-peptides antigenic. The role of human papillomavirus (HPV) in the malignant transformation of oral LP (OLP) has always been debated. Establishing a definitive part played by HPV in the malignant transformation of OLP, would possibly provide screening for the viruses, HPV vaccination, and antiviral therapy along with conventional treatment in LP which could improve prognosis. This systematic review is to assess the role of HPV in the malignant transformation of OLP. We performed a systematic search of PubMed, MEDLINE, and Google. The information was extracted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. All full-text papers that assessed the association of HPV in malignant transformation of OLP were considered eligible. The outcome parameter included the malignant transformation of OLP. We found a total of 19 studies from which five were found suitable for the review. Results from this systematic review showed HPV is associated with OLP. There is an increased prevalence of HPV in the erosive-atrophic (EA) variant of OLP compared to non-EA variant. There seems to be no strong evidence to prove the association between HPV and malignant transformation of OLP. Taking up the oncogenic potential of high-risk types and OLP as a potentially malignant disorder, more number of studies need to be performed on the dysplastic subtype of OLP and in those OLP lesions that progress to oral squamous cell carcinomas.

Clinico-Histological Evaluation of Dentino-Pulpal Complex of Direct Pulp Capping Agents: A Clinical Study.

INTRODUCTION: Direct pulp capping treatment (DPC) maintains pulp vitality by promoting healing or repair in dentistry, which can be attributed to the advent of bioceramic materials. AIM: This examination looked to evaluate the clinical and histological effectuality of Biodentine with Dycal for DPC. MATERIALS AND METHODOLOGY: In this study, 30 intact human orthodontic teeth undergoing therapeutic extraction were chosen to perform DPC. They were arbitrarily divided into two groups (n = 15) and DPC with Biodentine and Dycal was performed. Composite resin was used as permanent restoration. After a period of 1 and 6 weeks, clinical as well as electric pulp tests were carried out. Asymptomatic patients were re-called after 6 weeks; follow-up radiograph was taken. Electric pulp testing and thermal testing was done to check the pulpal status of the teeth. This was followed by atraumatic extraction, and the teeth were sent for histological examination. SPSS Version 21.0. Armonk, NY: IBM Corp.was used for data analysis. RESULTS: There was no pain and sensitivity in using Biodentine. Whereas, sensitivity and pain was noted when Dycal was used. The dentinal bridge was better with Biodentine when compared with Dycal. CONCLUSION: In accordance with the obtained results, it was concluded that on clinical and histological evaluation, Biodentine performed better as DPC agent. Subsequently, Biodentine is more dependable for the long-haul protection of dental pulp than Dycal.

Comparative Evaluation of Salivary Visfatin Levels in Healthy and Periodontally Diseased Patients before and after Scaling and Root Planing.

AIM: The aim of this study was to compare the levels of salivary visfatin in healthy controls, patients with gingivitis and patients with chronic periodontitis and also to assess the outcome of scaling and root planing (SRP) on the levels of salivary visfatin in patients with gingivitis and chronic periodontitis. MATERIALS AND METHODS: A total of 48 patients, both males and females, in the age group of 25-50 years were enrolled into three groups, based on their clinical parameters: Group I (Healthy controls - 16), Group II (Patients with gingivitis - 16), and Group III (Patients with chronic periodontitis - 16). Groups II and III were examined 2 months after SRP. The clinical parameters that were recorded include plaque index, modified gingival index, gingival bleeding index, pocket depth, and clinical attachment level. The samples of saliva were collected from each patient and the levels of visfatin were evaluated using enzyme-linked immunosorbent assay kit. RESULTS: The mean concentration of salivary visfatin at baseline was found to be highest in Group III and lowest in Group I. A statistically significant reduction (P < 0.01) in the mean concentration of salivary visfatin and the clinical parameters were observed after 2 months of SRP. CONCLUSION: The levels of salivary visfatin can thus be considered as an inflammatory biomarker for periodontal diseases. However, future longitudinal prospective studies are needed to support these findings.

BRCA-2 (+) high-grade serous fallopian tube cancer diagnosed as an isolated breast mass by mammography.

Ovarian cancer typically presents at advanced stage with intra-abdominal metastases. Rarely, ovarian cancer presents with distant metastases with little to no intra-abdominal disease burden. The patient was a BRCA-2 germline mutation carrier diagnosed with a Stage IVB high-grade carcinoma of the fallopian tube following discovery of a right axillary breast mass on screening mammography. Pre-operative imaging was without evidence of metastatic disease in the abdomen or pelvis. She underwent surgical staging followed by adjuvant chemotherapy and maintenance poly-ADP ribose polymerase (PARP) inhibition. She is without evidence of disease 24 months following her surgical staging procedure. An isolated oligo metastasis in the axilla is a rare presentation of ovarian carcinoma. Extra-abdominal metastases can present a diagnostic challenge in ovarian cancer necessitating thorough pathologic and radiologic work-up, particularly in the absence of intra-abdominal disease.

Longitudinal Molecular Imaging of Progesterone Receptor Reveals Early Differential Response to Endocrine Therapy in Breast Cancer with an Activating ESR1 Mutation.

Activating mutations in the estrogen receptor (ER) α-gene (ESR1) result in constitutive transcriptional activity in the absence of estrogen and are associated with endocrine resistance in metastatic ER-positive (+) breast cancer. It is not known how activating ESR1 mutations may alter the predictive values of molecular imaging agents for endocrine therapy response. This study investigated the effect of an activating ESR1 mutation on pretreatment 18F-fluoroestradiol (18F-FES) uptake and early assessment of endocrine therapy response using 18F-FDG and 18F-fluorofuranylnorprogesterone (18F-FFNP) PET/CT imaging of tumor glucose metabolism and progesterone receptor (PR) expression, respectively. Methods: ER+, PR+ T47D breast cancer cells expressing wild-type (WT) ER or an activating ESR1 mutation, Y537S-ER, were used to generate tumor xenografts in ovariectomized female immunodeficient mice supplemented with 17ß-estradiol. Tumor growth curves were determined in the presence or absence of estrogen and for ethanol vehicle control or fulvestrant treatment, a selective ER degrader. Pretreatment 18F-FES uptake was compared between Y537S-ER and WT-ER tumors. Longitudinal PET/CT imaging with 18F-FFNP and 18F-FDG was performed before and 7-9 d after the start of endocrine therapy with fulvestrant. Radiopharmaceutical uptake in Y537S-ER and WT-ER tumors was compared between baseline and follow-up scans. Statistical significance was determined using paired t testing for longitudinal imaging and 2-way ANOVA for the 18F-FFNP tissue biodistribution assay. Results: Y537S-ER xenografts showed estrogen-independent growth, whereas WT-ER tumors grew only with estrogen. Fulvestrant treatment for 28 d significantly reduced tumor volumes for WT-ER but only stabilized volumes for Y537S-ER. Baseline 18F-FES uptake did not significantly differ between WT-ER and Y537S-ER tumors. Fulvestrant treatment induced a similar early metabolic response for both WT-ER and Y537S-ER tumors. 18F-FFNP uptake in WT-ER tumors was significantly reduced after 7 d of fulvestrant treatment; however, this reduction did not occur in Y537S-ER tumors, which showed no significant change between baseline and follow-up PET/CT. Conclusion: Molecular imaging of PR expression dynamics could be a noninvasive approach for early identification of reduced effectiveness of endocrine therapy resulting from activating ESR1 mutations.

Novel coronavirus- A comprehensive review.

Recently coronavirus outbreak which started in Wuhan, China, has caused international concern that has affected more than 29 lakh people worldwide and with no vaccine or specific antiviral drugs present as well as oblivious testing of carriers who are generally asymptomatic, the use of general health intervention techniques are failing to comply. As compared to other epidemics like severe acute respiratory syndrome-coronavirus (SARS-CoV) and the Middle-East respiratory syndrome (MERS-CoV), coronavirus (also named as COVID-19) exhibit mild symptoms in the majority of cases. But in the case of a vulnerable population, it can prove to be life-threatening. Relying on proper barrier technique, use of chest computed tomography scans, managing co-morbid conditions of susceptible patients, identifying the pattern of disease spread as well as the use of polymerase chain reaction to assess the specificity of cases will eventually prove to be efficacious since most of the positive cases are asymptomatic at the beginning which poses a challenge to the primary health care physicians. The development of vaccines will also take some time so it is better to know about COVID-19 better and also follow quarantine restrictions properly till then. In this review, we try to put forward all the relevant studies which have been published by the end of March 2020 so as to summarize the natural history, diagnosis as well as treatment strategies for eradicating COVID-19, which will help in managing this pandemic.

Progesterone Receptor Gene Variants in Metastatic Estrogen Receptor Positive Breast Cancer.

Tumor mutations in the gene encoding estrogen receptor alpha (ESR1) have been identified in metastatic breast cancer patients with endocrine therapy resistance. However, relatively little is known about the occurrence of mutations in the progesterone receptor (PGR) gene in this population. The study objective was to determine the frequency and prognostic significance of tumor PGR mutations for patients with estrogen receptor (ER)-positive metastatic breast cancer. Thirty-five women with metastatic or locally recurrent ER+ breast cancer were included in this IRB-approved, retrospective study. Targeted next-generation sequencing of the PGR gene was performed on isolated tumor DNA. Associations between mutation status and clinicopathologic factors were analyzed as well as overall survival (OS) from time of metastatic diagnosis. The effect of the PGR variant Y890C (c.2669A>G) identified in this cohort on PR transactivation function was tested using ER-PR- (MDA-MB-231), ER+PR+ (T47D), and ER+PR- (T47D PR KO) breast cancer cell lines. There were 71 occurrences of protein-coding PGR variants in 67% (24/36; 95% CI 49-81%) of lesions. Of the 49 unique variants, 14 are single nucleotide polymorphisms (SNPs). Excluding SNPs, the median OS of patients with PGR variants was 32 months compared to 79 months with wild-type PGR (p = 0.42). The most frequently occurring (4/36 lesions) non-SNP variant was Y890C. Cells expressing Y890C had reduced progestin-stimulated PR transactivation compared to cells expressing wild-type PR. PGR variants occur frequently in ER+ metastatic breast cancer. Although some variants are SNPs, others are predicted to be functionally deleterious as demonstrated with Y890C PR.

Comparison of chemical extraction methods for determination of 146S content in foot-and-mouth disease oil-adjuvanted vaccine.

AIMS: To compare antigen extraction efficiency of chemical methods such as benzyl alcohol, chloroform, sodium citrate, extraction buffer with Tween-20 (EBT) and isopropyl myristate for determination of 146S content in the fresh and stored FMD oil-adjuvanted vaccines. METHODS AND RESULTS: Standard vaccine with antigen payload of 10, 5 and 5 µg per cattle dose (2 ml) for serotypes O, A and Asia1, respectively, was used to compare the antigen extraction efficiency of five chemical methods: benzyl alcohol, chloroform, sodium citrate, EBT buffer and isopropyl myristate. The purity of the extracted 146S antigen was quantified by caesium chloride (CsCl) ultracentrifugation. Serotype-specific sandwich ELISA (sELISA) was developed to identify the serotype and to compare the 146S in aqueous phase and ultrafractions. The antigen recovery was also tested in stored trivalent vaccine. Coefficient of regression was calculated to assess the predictive power of the benzyl alcohol extraction method. Of the five methods, benzyl alcohol showed consistent antigen recovery of >90% in monovalent as well as trivalent vaccines. Ultrafraction showed a 1·4 ratio at A259/239 nm in UV spectrophotometry indicating the presence of 146S. sELISA revealed that the antigen recovery was significantly less in ultrafractions than that of aqueous phase. Further, there was no significant difference in antigen recovery from stored trivalent vaccine for 12 months, indicating the usefulness of the benzyl alcohol method. Linear regression model revealed R2  = 0·99 with a narrow band of predictive interval. CONCLUSIONS: The benzyl alcohol method was efficient in extracting 146S from the monovalent and trivalent fresh and stored FMD vaccines. CsCl density gradient precisely quantified the 146S, while sELISA identified the serotype of the vaccine. SIGNIFICANCE AND IMPACT OF THE STUDY: When the benzyl alcohol method is coupled with CsCl density gradient and sELISA, it has the potential to determine the 146S content of FMD vaccine.

Sensitivity and Isoform Specificity of 18F-Fluorofuranylnorprogesterone for Measuring Progesterone Receptor Protein Response to Estradiol Challenge in Breast Cancer.

The purpose of this study was to evaluate the ability of 21-18F-fluoro-16α,17α-[(R)-(1'-α-furylmethylidene)dioxy]-19-norpregn-4-ene-3,20-dione (18F-FFNP) to measure alterations in progesterone receptor (PR) protein level and isoform expression in response to estradiol challenge. Methods: T47D human breast cancer cells and female mice-bearing T47D tumor xenografts were treated with 17ß-estradiol (E2) to increase PR expression. 18F-FFNP uptake was measured using cell uptake and tissue biodistribution assays. MDA-MB-231 breast cancer clonal cell lines were generated that express the A or B isoforms of human PR. PR protein levels, transcriptional function, and subcellular localization were determined. In vitro 18F-FFNP binding was measured via saturation and competitive binding curves. In vivo 18F-FFNP uptake was measured using tumor xenografts and positron emission tomography. Statistical significance was determined using analysis of variance and t-tests. Results: After 48 and 72 h of E2, 18F-FFNP uptake in T47D cells was maximally increased compared to both vehicle and 24 h E2 treatment (p<0.0001 vs ethanol; P = 0.02 and P = 0.0002 vs 24 h for 48 and 72 h, respectively). T47D tumor xenografts in mice treated with 72 h E2 had maximal 18F-FFNP uptake compared to ethanol-treated mice (11.3±1.4 vs 5.2±0.81 %ID/g; P = 0.002). Corresponding tumor-to-muscle uptake ratios were 4.1±0.6, 3.9±0.5, and 2.3±0.4 for 48 h E2, 72 h E2, and ethanol-treated mice, respectively. There was no significant preferential 18F-FFNP binding or uptake by PR-A versus PR-B in the PR isoform-specific cell lines and tumor xenografts. Conclusion:18F-FFNP is capable of measuring estrogen-induced shifts in total PR expression in human breast cancer cells and tumor xenografts with equivalent isoform binding.

Cancer overturned: Endometrioma mimicking granulosa cell tumor and the importance of FOXL2 analysis.

BACKGROUND: Various ovarian neoplasms may show histological findings that are morphologically indistinguishable from adult granulosa cell tumor (AGCT). CASE PRESENTATION: A 36 year-old women presented with left lower extremity pain and numbness. Ultrasound revealed a 10 cm left adnexal mass treated with ovarian cystectomy. Histopathology revealed endometriotic cyst with intramural granulosa cell tumor. She underwent a laparoscopic left salpingo-oophorectomy and omental biopsy by Gynecologic Oncology. Pathologic review of residual ovarian abnormality prompted a molecular analysis. FOXL2 gene mutation was absent supporting the diagnosis of benign endometrioma. CONCLUSIONS: A somatic missense mutation in the FOXL2 gene is a sensitive molecular marker for AGCT. Mutation analysis can help distinguish malignant from benign pathology to provide appropriate treatment and disease surveillance.

18F-16α-17ß-Fluoroestradiol Binding Specificity in Estrogen Receptor-Positive Breast Cancer.

Purpose To determine the binding specificity of 18F-16α-17ß-fluoroestradiol (FES) in estrogen receptor (ER) α-positive breast cancer cells and tumor xenografts. Materials and Methods Protocols were approved by the office of biologic safety and institutional animal care and use committee. By using ER-negative MDA-MB-231 breast cancer cells, clonal lines were created that expressed either wild-type (WT; 231 WT ER) or G521R mutant ERα (231 G521R ER), which is defective in estradiol binding. ERα protein levels, subcellular localization, and transcriptional function were confirmed. FES binding was measured by using an in vitro cell uptake assay. In vivo FES uptake was measured in tumor xenografts by using small-animal positron emission tomographic/computed tomographic imaging of 24 mice (17 WT ER tumors, nine mutant G521R ER tumors, eight MDA-MB-231 tumors, and four MCF-7 ER-positive tumors). Statistical significance was determined by using Mann-Whitney (Wilcoxon rank sum) test. Results ERα transcriptional function was abolished in the mutated 231 G521R ER cells despite appropriate receptor protein expression and nuclear localization. In vitro FES binding in the 231 G521R ER cells was reduced to that observed in the parental cells. Similarly, there was no significant FES uptake in the 231 G521R ER xenografts (percent injected dose [ID] per gram, 0.49 ± 0.042), which was similar to the negative control MDA-MB-231 xenografts (percent ID per gram, 0.42 ± 0.051; P = .20) and nonspecific muscle uptake (percent ID per gram, 0.41 ± 0.0095; P = .06). Conclusion This study showed that FES retention in ER-positive breast cancer is strictly dependent on an intact receptor ligand-binding pocket and that FES binds to ERα with high specificity. These results support the utility of FES imaging for assessing tumor heterogeneity by localizing immunohistochemically ER-positive metastases that lack receptor-binding functionality. © RSNA, 2017 Online supplemental material is available for this article.