Quantitative Brain Amyloid PET.

Since the development of amyloid tracers for PET imaging, there has been interest in quantifying amyloid burden in the brains of patients with Alzheimer disease. Quantitative amyloid PET imaging is poised to become a valuable approach in disease staging, theranostics, monitoring, and as an outcome measure for interventional studies. Yet, there are significant challenges and hurdles to overcome before it can be implemented into widespread clinical practice. On November 17, 2022, the U.S. Food and Drug Administration, Society of Nuclear Medicine and Molecular Imaging, and Medical Imaging and Technology Alliance cosponsored a public workshop comprising experts from academia, industry, and government agencies to discuss the role of quantitative brain amyloid PET imaging in staging, prognosis, and longitudinal assessment of Alzheimer disease. The workshop discussed a range of topics, including available radiopharmaceuticals for amyloid imaging; the methodology, metrics, and analytic validity of quantitative amyloid PET imaging; its use in disease staging, prognosis, and monitoring of progression; and challenges facing the field. This report provides a high-level summary of the presentations and the discussion.

Remote Contrast Sensitivity Testing Seems to Correlate With the Degree of Glaucomatous Macular Damage.

PRCIS: Remote contrast sensitivity (CS) testing through a free downloadable home test correlates with glaucomatous macular damage measured by 10-2 visual field (VF) testing. PURPOSE: To assess the feasibility and validity of home CS monitoring as a measure of glaucomatous damage using a free downloadable smartphone application. METHODS: Twenty-six participants were asked to remotely use the Berkeley Contrast Squares (BCS) application, a free downloadable tool that records the user's CS for varying degrees of visual acuity. An instructional video detailing how to download and use the application was sent to the participants. Subjects were asked to send logarithmic CS results with a minimum 8-week test-retest window, and test-retest reliability was measured. Results were validated against office-based CS testing that was collected within the previous 6 months. Validity analysis was also carried out to determine whether CS as measured by BCS is a good predictor of 10-2 and 24-2 VF mean deviation (MD). RESULTS: There was a high BCS test-retest reliability with an intraclass correlation coefficient score of 0.91 and a significant correlation between repeat test results and baseline test scores (Pearson, 0.86, P < 0.0001). There was significant agreement between unilateral CS scores as measured by BCS and office-based CS testing ( b = 0.94, P < 0.0001, 95% CI: 0.61 to 1.27). Unilateral CS as measured by BCS was significantly associated with 10-2 VF MD ( r2 = 0.27, P = 0.006, 95% CI: 3.7 to 20.6), but not with 24-2 VF MD ( P = 0.151). CONCLUSION: This study suggests that a free, rapid home CS test correlates with glaucomatous macular damage as measured by 10-2 VF.

SARS-CoV-2 vaccine safety and immunogenicity in patients with hematologic malignancies, transplantation, and cellular therapies.

Individuals with hematological malignancies and hematopoietic stem cell transplant (HCT) recipients are immunologically heterogenous groups with varying degrees of immunosuppression at increased risk of severe disease and mortality from SARS-CoV-2 infection. SARS-CoV-2 vaccines are key interventions to preventing severe COVID-19 and its complications. While these individuals were excluded from initial vaccine trials, there is now a growing body of acceptable safety and immunogenicity data among these individuals. A consistent signal for new or worsening graft versus host disease in allogeneic HCT recipients has not been demonstrated post-vaccination. Immunogenicity in these populations is variable depending on disease and treatment factors. However, serological responses may not accurately reflect vaccine protection as correlates of protection within these populations are not yet established. Large-scale studies powered to identify rare serious events, resolve differences in vaccine responses between different vaccination strategies, and identify immune correlates of protection within these populations are needed.

Neoadjuvant chemotherapy with or without radiotherapy versus upfront surgery for resectable pancreatic adenocarcinoma: a meta-analysis of randomized clinical trials.

BACKGROUND: The role of neoadjuvant chemotherapy (NC) in resectable pancreatic cancer (RPC) has yet to be defined. This review aims to analyze the benefit of NC in RPC compared with upfront surgery (US) in terms of overall survival (OS) and disease-free survival (DFS). PATIENTS AND METHODS: PubMed, CENTRAL (The Cochrane Library), and Embase were systematically reviewed until 3 November 2021. Abstract proceedings and virtual meeting presentations from the American Society of Clinical Oncology and the European Society of Medical Oncology conferences, reference articles of published clinical trials, and review articles were considered. Only randomized clinical trials (RCTs) comparing NC administration with or without radiotherapy previous with surgery (experimental arm) versus US followed by adjuvant chemotherapy with or without radiotherapy (control arm) for RPC were included. RESULTS: A total of 1135 studies were screened. Of these, 1117 studies were primarily excluded. Of the remaining 18 studies, 5 were excluded because of no adequate trial design for this work and 7 others had no available results. Finally, 6 trials with 469 patients with pancreatic cancer randomized to NC (n = 212) or US (n = 257) were selected. Compared with US, NC significantly improved OS [hazard ratio (HR) 0.75; 95% confidence interval (CI) 0.58-0.98; P = 0.033] and DFS (HR 0.73; 95% CI 0.59-0.89; P = 0.002). While the NC approach was not significantly associated with lower resection rate [relative risk (RR) 0.92; 95% CI 0.84-1.01; P = 0.069], the R0 resection rate was significantly higher for NC than for US (RR 1.31; 95% CI 1.13-1.52; P = 0.0004). CONCLUSION: This is the first meta-analysis of RCTs showing that NC improves OS for RPC compared with US followed by adjuvant therapy. Ongoing RCTs should confirm these findings with FOLFIRINOX to generalize the indication of NC.

Ozono y COVID-19: bases fisiológicas y sus posibilidades terapéuticas según el estadio evolutivo de la infección por SARS-CoV-2 / Ozone and COVID-19: physiological bases and their therapeutic possibilities according to the evolutionary stage in SARS-CoV-2 infection

No existe a la fecha un tratamiento definitivo para la nueva pandemia SARS-CoV-2. Están reconocidos tres estadios evolutivos en la infección por SARS-CoV-2 (infección temprana, fase pulmonar e hiperinflamación sistémica), con signos y síntomas clínicos característicos. Hay en marcha 80 ensayos experimentales internacionales que buscan un tratamiento efectivo para la pandemia COVID-19. De ellos, solo hay tres que consideran como alternativa de tratamiento la ozonoterapia (autohemoterapia mayor). No existe ningún estudio que evalúe la insuflación rectal de ozono, a pesar de ser una técnica segura, barata, sin riesgos y que es una vía de administración sistémica (oxígeno-ozono 95 %-5 %) y que justifica la realización de ensayos clínicos para validar las propiedades teóricas del ozono en el manejo del SARS-CoV-2, dados los excelentes resultados observados en el manejo del ébola. El ozono tiene demostradas cuatro propiedades biológicas que podrían ser de potencial utilidad teórica como terapia complementaria en las diferentes fases de la infección por SARS-CoV-2. El ozono podría inactivar el virus por oxidación indirecta (ROS y LOP) y podría estimular el sistema inmune celular y humoral, siendo útil en la fase de infección temprana (estadios 1 y 2a). El ozono puede mejorar el intercambio gaseoso, reducir la inflamación y modular el sistema antioxidante, por lo que sería útil en la fase de hiperinflamación o "tormenta de citocinas", y en la fase de hipoxemia y/o fallo multiorgánico (estadios 2b y estadio 3). Dada la actual pandemia, urge llevar a cabo un estudio experimental que confirme o descarte las propiedades biológicas del ozono y le permita así ser una terapia complementaria o compasiva para el manejo efectivo de la infección por SARS-CoV-2.(AU)

To date, there is no definitive treatment for the new SARS-CoV-2 pandemic. Three evolutionary stages are recognized in SARS-CoV-2 infection (early infection, pulmonary phase and systemic hyperinflammation), with characteristic clinical signs and symptoms. There are 80 international experimental trials underway seeking an effective treatment for the COVID-19 pandemic. Of them, there are only 3 that consider to Ozone Therapy as an alternative (major auto hemotherapy). There is no study that evaluates Rectal Ozone Insufflation, despite being a safe, cheap, risk-free technique and that it is a systemic administration route (Oxygen-Ozone 95 %-5 %) and that justifies conducting clinical trials to validate the theoretical properties of Ozone in the management of SARS-CoV-2, given the excellent results observed in the management of ebola. Ozone has 4 proven biological properties that could be of potential theoretical utility as a complementary therapy in the different phases of SARS-CoV-2 infection. Ozone could inactivate the virus by indirect oxidation (ROS and LOP) and could stimulate the cellular and humoral immune system, being useful in the early infection phase (stages 1 and 2a). Ozone can improve gas exchange, reduce inflammation, and modulate the antioxidant system, so it would be useful in the hyperinflammation or cytokine storm phase, and in the hypoxemia and / or multi-organ failure phase (stages 2b and stage 3). Given the current pandemic, it is urgent to carry out an experimental study to confirm or rule out the biological properties of Ozone and thus allow it to be a complementary or compassionate therapy for the effective management of SARS-CoV-2 infection.(AU)

Alternative strategies of posttransplant influenza vaccination in adult solid organ transplant recipients.

Solid organ transplant (SOT) recipients are at increased risk of influenza disease and associated complications. The mainstay of prevention is the annual standard-dose influenza vaccine, as studies showed decreased influenza-related morbidity and mortality in vaccinated SOT recipients compared to those unvaccinated. Nonetheless, the immune response in this high-risk population is suboptimal compared to healthy individuals. Over the past two decades, several vaccination strategies have been investigated to overcome this inadequate immune response in SOT recipients. Howbeit, the best vaccination strategy and optimal timing of influenza vaccination remain unclear. This review will provide a detailed summary of studies of various influenza vaccination strategies in adult SOT recipients, discussing immunogenicity results, and addressing their limitations and knowledge gaps.

Effect of feedback regulation on stem cell fractions in tissues and tumors: Understanding chemoresistance in cancer.

While resistance mutations are often implicated in the failure of cancer therapy, lack of response also occurs without such mutants. In bladder cancer mouse xenografts, repeated chemotherapy cycles have resulted in cancer stem cell (CSC) enrichment, and consequent loss of therapy response due to the reduced susceptibility of CSCs to drugs. A particular feedback loop present in the xenografts has been shown to promote CSC enrichment in this system. Yet, many other regulatory loops might also be operational and might promote CSC enrichment. Their identification is central to improving therapy response. Here, we perform a comprehensive mathematical analysis to define what types of regulatory feedback loops can and cannot contribute to CSC enrichment, providing guidance to the experimental identification of feedback molecules. We derive a formula that reveals whether or not the cell population experiences CSC enrichment over time, based on the properties of the feedback. We find that negative feedback on the CSC division rate or positive feedback on differentiated cell death rate can lead to CSC enrichment. Further, the feedback mediators that achieve CSC enrichment can be secreted by either CSCs or by more differentiated cells. The extent of enrichment is determined by the CSC death rate, the CSC self-renewal probability, and by feedback strength. Defining these general characteristics of feedback loops can guide the experimental screening for and identification of feedback mediators that can promote CSC enrichment in bladder cancer and potentially other tumors. This can help understand and overcome the phenomenon of CSC-based therapy resistance.

False-Negative Rates of Breast Cancer Screening with and without Digital Breast Tomosynthesis.

Background Screening with digital breast tomosynthesis (DBT) improves breast cancer detection and recall rates compared with those obtained with digital mammography (DM); however, the impact of DBT on patient survival has not been established. False-negative (FN) screening examinations can be a surrogate for long-term outcomes, such as breast cancer morbidity and mortality. Purpose To determine if screening with DBT is associated with lower FN rates, detection of cancers with more favorable prognoses, and improved performance outcomes versus DM. Materials and Methods This retrospective study involved 10 academic and community practices. DM screening examinations 1 year prior to DBT implementation and DBT screening examinations from the start date until June 30, 2013, were linked to cancers through June 30, 2014, with data collection in 2016 and analysis in 2018-2019. Cancers after FN examinations were characterized by presentation, either symptomatic or asymptomatic. FN rates, sensitivity, specificity, cancer detection and recall rates, positive predictive values, tumor size, histologic features, and receptor profile were compared. Results A total of 380 641 screening examinations were included. There were 183 989 DBT and 196 652 DM examinations. With DBT, rates trended lower for overall FN examinations (DBT, 0.6 per 1000 screens; DM, 0.7 per 1000 screens; P = .20) and symptomatic FN examinations (DBT, 0.4 per 1000 screens; DM, 0.5 per 1000 screens; P = .21). Asymptomatic FN rates trended higher in women with dense breasts (DBT, 0.14 per 1000 screens; DM: 0.07 per 1000 screens; P = .07). With DBT, improved sensitivity (DBT, 89.8% [966 of 1076 cancers]; DM, 85.6% [789 of 922 cancers]; P = .004) and specificity (DBT, 90.7% [165 830 of 182 913 examinations]; DM, 89.1% [174 480 of 195 730 examinations]; P < .001) were observed. Overall, cancers identified with DBT were more frequently invasive (P < .001), had fewer positive lymph nodes (P = .04) and distant metastases (P = .01), and had lower odds of an FN finding of advanced cancer (odds ratio, 0.9 [95% CI: 0.5, 1.5]). Conclusion Screening with digital breast tomosynthesis improves sensitivity and specificity and reveals more invasive cancers with fewer nodal or distant metastases. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Schattner in this issue.

PET Imaging of Phosphodiesterase-4 Identifies Affected Dysplastic Bone in McCune-Albright Syndrome, a Genetic Mosaic Disorder.

McCune-Albright syndrome (MAS) is a mosaic disorder arising from gain-of-function mutations in the GNAS gene, which encodes the 3',5'-cyclic adenosine monophosphate (cAMP) pathway-associated G-protein, Gsα. Clinical manifestations of MAS in a given individual, including fibrous dysplasia, are determined by the timing and location of the GNAS mutation during embryogenesis, the tissues involved, and the role of Gsα in the affected tissues. The Gsα mutation results in dysregulation of the cAMP signaling cascade, leading to upregulation of phosphodiesterase type 4 (PDE4), which catalyzes the hydrolysis of cAMP. Increased cAMP levels have been found in vitro in both animal models of fibrous dysplasia and in cultured cells from individuals with MAS but not in humans with fibrous dysplasia. PET imaging of PDE4 with 11C-(R)-rolipram has been used successfully to study the in vivo activity of the cAMP cascade. To date, it remains unknown whether fibrous dysplasia and other symptoms of MAS, including neuropsychiatric impairments, are associated with increased PDE4 activity in humans. Methods:11C-(R)-rolipram whole-body and brain PET scans were performed on 6 individuals with MAS (3 for brain scans and 6 for whole-body scans) and 9 healthy controls (7 for brain scans and 6 for whole-body scans). Results:11C-(R)-rolipram binding correlated with known locations of fibrous dysplasia in the periphery of individuals with MAS; no uptake was observed in the bones of healthy controls. In peripheral organs and the brain, no difference in 11C-(R)-rolipram uptake was noted between participants with MAS and healthy controls. Conclusion: This study is the first to find evidence for increased cAMP activity in areas of fibrous dysplasia in vivo. No differences in brain uptake between MAS participants and controls were detected-a finding that could be due to several reasons, including the limited anatomic resolution of PET. Nevertheless, the results confirm the usefulness of PET scans with 11C-(R)-rolipram to indirectly measure increased cAMP pathway activation in human disease.

Combination of statin/vitamin D and metastatic castration-resistant prostate cancer (CRPC): a post hoc analysis of two randomized clinical trials.

In castration-resistant prostate cancer (CRPC) patients, observational studies have reported that statins may boost the antitumor activity of abiraterone (AA) and data suggest an improvement in efficacy; conclusions with vitamin D are less clear but an eventual benefit has been pointed. We conducted a post hoc analysis of individual patient data of CRPC patients treated with prednisone and/or AA with or without statins/vitamin D on randomized clinical trials. In the COU-AA-301 trial, use of AA with statin and vitamin D reduced the risk of death by 38% (p = 0.0007) while AA alone was associated with a decrease of 10% (p = 0.025), compared to prednisone alone. Meanwhile, in the COU-AA-302 trial, use of AA plus statin plus vitamin D was associated with a reduced risk of death of 26% (p = 0.0054). In this data analysis from two prospective randomized clinical trials, statin and vitamin D use was associated with superior overall survival in metastatic CRPC patients treated with AA and prednisone. To our knowledge, this is the first report suggesting the impact of statin plus vitamin D in this population. New strategies using big data may help to clarify these questions easily and in a most cost-effective approach.

Differential regulation of claudin-2 and claudin-15 expression in children and adults with malabsorptive disease.

Intestinal Na+-nutrient cotransport depends on claudin-2 and claudin-15 mediated Na+ recycling. Expression of these proteins is coordinately regulated during postnatal development. While expression of claudin-2 and claudin-15 has been studied in inflammatory bowel disease (IBD) and celiac disease (CD), it has not been assessed in other malabsorptive diseases, and no reports have compared expression in children and adults. We used quantitative immunofluorescence microscopy to assess claudin-2 and claudin-15 expression in duodenal biopsies from children and adults with malabsorptive disease and healthy controls. Consistent with previous work in rodents, claudin-2 expression in healthy children was markedly greater, and claudin-15 expression was less, than that in adults. Claudin-2 expression was increased in adults with CD and downregulated in children with graft-versus-host disease (GVHD). In contrast, claudin-15 expression was reduced in adults with GVHD and common variable immunodeficiency (CVID). These data show that one of the two Na+/water pore-forming claudins is upregulated in CD and downregulated in GVHD and CVID. The specific claudin whose expression changes, however, reflects the age of the patient (child or adult). We conclude that contributions of claudin-2 and claudin-15 to pathophysiology of and responses to diarrhea in children and adults with GVHD and CVID differ from those in CD and IBD.

18F-FDG PET/TC para la estadificación y la delineación del volumen de radioterapia en el cáncer de cabeza y cuello / 18F-FDG PET/CT in staging and delineation of radiotherapy volume for head and neck cancer

OBJETIVOS: Investigar el uso de la 18F-FDG(flúor-18 fluorodesoxiglucosa) PET/TC en la estadificación del cáncer de cabeza y cuello (CCC) y su repercusión en la decisión terapéutica y planificación de tratamiento radioterápico. MATERIAL Y MÉTODOS: Se incluyen 100 pacientes con CCC y la siguiente localización tumoral: 18% cavidad oral, 20% orofaringe, 12% hipofaringe, 11% nasofaringe, 37% laringe, 2% senos paranasales. La estadificación tumoral según la AJCC (American Joint Committee of Cancer, 7th) es: 5%-I, 7%-II, 14%-III, 61%-IVA, 7%-IVB, 6%-IVC. Se les realiza una TC y una 18F-FDG PET/TC en condiciones de simulación para comparar la reclasificación del estadiaje. Además, se analizan los cambios de actitud terapéutica. RESULTADOS: La 18F-FDG PET/CT detecta 6 pacientes metastásicos que requieren tratamiento paliativo y 8 tumores sincrónicos, siendo uno paliativo. Se produce una reclasificación del estadiaje en 27 pacientes. La extensión tumoral varía en 28 (14% sobre-estadificación, 14% infra-estadificación), implicando una variación en el contorneo del GTV (Gross Tumor Volume). La estadificación ganglionar cambia en 47: 8 pacientes son infra-estadificados (N2C cambia a N2A/N2B/N1) y 2 son falsos positivos. Diecinueve pacientes son falsos negativos y 5 con afectación ganglionar unilateral (N1/N2A/N2B) muestran actividad metabólica bilateral. Estos cambios de estadificación implican una adaptación del volumen ganglionar a irradiar. CONCLUSIONES: La 18F-FDG PET/TC produce una reclasificación superior al 10% en casi todas las categorías estudiadas (cTNM, extensión tumoral, enfermedad ganglionar) y detecta más estadíos metastásicos y tumores sincrónicos que los estudios convencionales, lo que genera un impacto en el manejo del paciente y contorneo de los volúmenes de radioterapia

PURPUSE: The aim is to investigate the use of 18F-FDG (fluorine-18 fluorodeoxyglucose) PET/CT in head and neck cancer (HNC) staging and its effect on the therapeutic strategy and radiotherapy (RT) planning. METHODS AND MATERIALS: One hundred patients with HNC were included. Primary tumor sites: 18% oral cavity, 20% oropharynx, 12% hypopharynx, 11% nasopharynx, 37% larynx, 2% paranasal sinuses. Patients were staged according to the American Joint Committee of Cancer 7th edition. Stage: 5% stage I, 7% stage II, 14% stage III, 61% stage IVA, 7% stage IVB and 6% stage IVC. A contrast-enhanced CT and a 18F-FDG PET/CT acquired under RT position were performed. Both exams were compared to analyze patients' staging reclassification. Changes in therapeutic strategy were analyzed. RESULTS: 18F-FDG PET/CT detected 6 distant metastases and treatment intention changed to palliative. Eight synchronous tumors were detected; one received palliative treatment.18F-FDG PET/CT reclassified cTNM staging in 27patients. Tumor extension changed in 28 (14% up-staged; 14% down-staged), implying a change in GTV (Gross Tumor Volume) delineation. Nodal detection was reclassified in 47 PATIENTS: 8 patients down-staged (N2C to N2A/N2B/N1) and 2 were false positive. Nineteen patients were false negatives and 5 staged as N+(N1/N2A/N2B) turned out into N2C. These staging modifications imply adapting the nodal volume to be irradiated. CONCLUSIONS: 18F-FDG PET/CT reclassification was higher than 10% in almost all categories studied (cTNM, tumor extension and nodal disease) and detects more metastases and synchronous tumors than conventional studies, which has an impact on the therapeutic patient management and RT planning

18F-FDG PET/CT in staging and delineation of radiotherapy volume for head and neck cancer. / 18F-FDG PET/TC para la estadificación y la delineación del volumen de radioterapia en el cáncer de cabeza y cuello.

PURPOSE: The aim is to investigate the use of 18F-FDG (fluorine-18 fluorodeoxyglucose) PET/CT in head and neck cancer (HNC) staging and its effect on the therapeutic strategy and radiotherapy (RT) planning. METHODS AND MATERIALS: One hundred patients with HNC were included. Primary tumor sites: 18% oral cavity, 20% oropharynx, 12% hypopharynx, 11% nasopharynx, 37% larynx, 2% paranasal sinuses. Patients were staged according to the American Joint Committee of Cancer 7th edition. Stage: 5% stage I, 7% stage II, 14% stage III, 61% stage IVA, 7% stage IVB and 6% stage IVC. A contrast-enhanced CT and a 18F-FDG PET/CT acquired under RT position were performed. Both exams were compared to analyze patients' staging reclassification. Changes in therapeutic strategy were analyzed. RESULTS: 18F-FDG PET/CT detected 6 distant metastases and treatment intention changed to palliative. Eight synchronous tumors were detected; one received palliative treatment. 18F-FDG PET/CT reclassified cTNM staging in 27patients. Tumor extension changed in 28 (14% up-staged; 14% down-staged), implying a change in GTV (Gross Tumor Volume) delineation. Nodal detection was reclassified in 47 patients: 8 patients down-staged (N2C to N2A/N2B/N1) and 2 were false positive. Nineteen patients were false negatives and 5 staged as N+(N1/N2A/N2B) turned out into N2C. These staging modifications imply adapting the nodal volume to be irradiated. CONCLUSIONS: 18F-FDG PET/CT reclassification was higher than 10% in almost all categories studied (cTNM, tumor extension and nodal disease) and detects more metastases and synchronous tumors than conventional studies, which has an impact on the therapeutic patient management and RT planning.

Optoacoustic Breast Imaging: Imaging-Pathology Correlation of Optoacoustic Features in Benign and Malignant Breast Masses.

OBJECTIVE: Optoacoustic ultrasound breast imaging is a fused anatomic and functional modality that shows morphologic features, as well as hemoglobin amount and relative oxygenation within and around breast masses. The purpose of this study is to investigate the positive predictive value (PPV) of optoacoustic ultrasound features in benign and malignant masses. SUBJECTS AND METHODS: In this study, 92 masses assessed as BI-RADS category 3, 4, or 5 in 94 subjects were imaged with optoacoustic ultrasound. Each mass was scored by seven blinded independent readers according to three internal features in the tumor interior and two external features in its boundary zone and periphery. Mean and median optoacoustic ultrasound scores were compared with histologic findings for biopsied masses and nonbiopsied BI-RADS category 3 masses, which were considered benign if they were stable at 12-month follow-up. Statistical significance was analyzed using a two-sided Wilcoxon rank sum test with a 0.05 significance level. RESULTS: Mean and median optoacoustic ultrasound scores for all individual internal and external features, as well as summed scores, were higher for malignant masses than for benign masses (p < 0.0001). High external scores, indicating increased hemoglobin and deoxygenation and abnormal vessel morphologic features in the tumor boundary zone and periphery, better distinguished benign from malignant masses than did high internal scores reflecting increased hemoglobin and deoxygenation within the tumor interior. CONCLUSION: High optoacoustic ultrasound scores, particularly those based on external features in the boundary zone and periphery of breast masses, have high PPVs for malignancy and, conversely, low optoacoustic ultrasound scores have low PPV for malignancy. The functional component of optoacoustic ultrasound may help to overcome some of the limitations of morphologic overlap in the distinction of benign and malignant masses.

Downgrading and Upgrading Gray-Scale Ultrasound BI-RADS Categories of Benign and Malignant Masses With Optoacoustics: A Pilot Study.

OBJECTIVE: False-positive findings remain challenging in breast imaging. This study investigates the incremental value of optoacoustic imaging in improving BI-RADS categorization of breast masses at ultrasound. SUBJECTS AND METHODS: The study device is an optoacoustic breast imaging device with a handheld duplex laser and internal gray-scale ultrasound probe, fusing functional and morphologic information (optoacoustic ultrasound). In this prospective multisite study, breast masses assessed as BI-RADS category 3, 4A, 4B, 4C, or 5 by site radiologists underwent both gray-scale ultrasound and optoacoustic imaging with the study device. Independent reader radiologists assessed internal gray-scale ultrasound and optoacoustic ultrasound features for each mass and assigned a BI-RADS category. The percentage of mass reads for which optoacoustic ultrasound resulted in a downgrade or upgrade of BI-RADS category relative to internal gray-scale ultrasound was determined. RESULTS: Of 94 total masses, 39 were biopsy-proven malignant, 44 were biopsy-proven benign, and 11 BI-RADS category 3 masses were stable at 12-month follow-up. The sensitivity of both optoacoustic ultrasound and internal gray-scale ultrasound was 97.1%. The specificity was 44.3% for optoacoustic ultrasound and 36.4% for internal gray-scale ultrasound. Using optoacoustic ultrasound, 41.7% of benign masses or BI-RADS category 3 masses that were stable at 12-month follow-up were downgraded to BI-RADS category 2 by independent readers; 36.6% of masses assigned BI-RADS category 4A were downgraded to BI-RADS category 3 or 2, and 10.1% assigned BI-RADS category 4B were downgraded to BI-RADS category 3 or 2. Using optoacoustic ultrasound, independent readers upgraded 75.0% of the malignant masses classified as category 4A, 4B, 4C, or 5, and 49.4% of the malignant masses were classified as category 4B, 4C, or 5. CONCLUSION: Optoacoustic ultrasound resulted in BI-RADS category downgrading of benign masses and upgrading of malignant masses compared with gray-scale ultrasound.

The expression of inflammatory markers and their potential influence on efflux transporters in drug-resistant mesial temporal lobe epilepsy tissue.

OBJECTIVE: The role of neuroinflammation in mesial temporal lobe epilepsy (MTLE), and how it relates to drug resistance, remains unclear. Expression levels of the inflammatory enzymes cyclooxygenase (COX)-1 and COX-2 have been found to be increased in animal models of epilepsy. Knowing the cellular expression of COX-1 and COX-2 is the key to understanding their functional role; however, only 3 studies have investigated COX-2 expression in epilepsy in humans, and there are no reports on COX-1. In addition, previous studies have shown that certain inflammatory proteins up-regulate ATP binding cassette (ABC) transporter expression (thought to be responsible for drug resistance), but this relationship remains unclear in human tissue. This study sought to measure the expression of COX-1, COX-2, and translocator protein 18 kDa (TSPO, an inflammation biomarker acting as a positive control), as well as ABC transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), in brain tissue samples from people with drug-resistant MTLE. METHODS: Formalin-fixed paraffin-embedded surgical brain tissue was obtained from 33 patients with drug-resistant MTLE. Multiplex immunofluorescence was used to quantify the expression and distribution of COX-1, COX-2, TSPO, P-gp, and BCRP. RESULTS: COX-1 was expressed in microglia, and COX-2 and TSPO were expressed in microglia and neurons. BCRP density correlated significantly with TSPO density, suggesting a potential relationship between inflammatory markers and efflux transporters. SIGNIFICANCE: To the best of our knowledge, this study is the first to measure the cellular expression of COX-1, COX-2, and TSPO in microglia, astrocytes, and neurons in surgical brain tissue samples from patients with drug-resistant MTLE. Further research is needed to determine the effects of the COX inflammatory pathway in epilepsy, and how it relates to the expression of the ABC transporters P-gp and BCRP.

Informing Women and Their Physicians about Recommendations for Adjunct Breast MRI Screening: A Cohort Study.

It is unclear how best to communicate recommendations for breast cancer screening with MRI as an adjunct to mammography for women at high risk. This study compares the rates of breast MRI screening for two different methods of communication. The retrospective IRB-approved cohort study was conducted at Invision Sally Jobe Breast Centers (ISJBC). ISJBC provided Gail model risk assessment to all women presenting for screening mammography. Women with scores ≥ 19.6% were considered to be high risk. Over 2 years, ISJBC used two different methods to inform women at elevated lifetime risk and their physicians about recommendations for adjunct MRI screening (N = 561, mean age = 52 years, s.d. = 8.7). During Window A, information was sent to referring physicians as a part of the dictated imaging report, while later, in Window B, the information was sent to referring physicians as well as to the women themselves in a letter. Analyses were stratified by mammography screening frequency. One-time screeners presented in only Window A or Window B. Repeat screeners came both in Window A and in Window B. Breast MRI screening rates were significantly higher in Window B than in Window A (one-time screeners, N = 459, 9.8% vs. 14.4%, p = 0.047; repeat screeners, N = 102, 0% vs. 6.9%, p = 0.016). Although an observational study cannot assess causality, direct communication of risk-based recommendations for adjunct breast MRI screening to women and to their referring physicians was associated with an increased rate of screening breast MRI completion at the same clinic at which the women underwent mammography.

A Pivotal Study of Optoacoustic Imaging to Diagnose Benign and Malignant Breast Masses: A New Evaluation Tool for Radiologists.

Purpose To compare the diagnostic utility of an investigational optoacoustic imaging device that fuses laser optical imaging (OA) with grayscale ultrasonography (US) to grayscale US alone in differentiating benign and malignant breast masses. Materials and Methods This prospective, 16-site study of 2105 women (study period: 12/21/2012 to 9/9/2015) compared Breast Imaging Reporting and Data System (BI-RADS) categories assigned by seven blinded independent readers to benign and malignant breast masses using OA/US versus US alone. BI-RADS 3, 4, or 5 masses assessed at diagnostic US with biopsy-proven histologic findings and BI-RADS 3 masses stable at 12 months were eligible. Independent readers reviewed US images obtained with the OA/US device, assigned a probability of malignancy (POM) and BI-RADS category, and locked results. The same independent readers then reviewed OA/US images, scored OA features, and assigned OA/US POM and a BI-RADS category. Specificity and sensitivity were calculated for US and OA/US. Benign and malignant mass upgrade and downgrade rates, positive and negative predictive values, and positive and negative likelihood ratios were compared. Results Of 2105 consented subjects with 2191 masses, 100 subjects (103 masses) were analyzed separately as a training population and excluded. An additional 202 subjects (210 masses) were excluded due to technical failures or incomplete imaging, 72 subjects (78 masses) due to protocol deviations, and 41 subjects (43 masses) due to high-risk histologic results. Of 1690 subjects with 1757 masses (1079 [61.4%] benign and 678 [38.6%] malignant masses), OA/US downgraded 40.8% (3078/7535) of benign mass reads, with a specificity of 43.0% (3242/7538, 99% confidence interval [CI]: 40.4%, 45.7%) for OA/US versus 28.1% (2120/7543, 99% CI: 25.8%, 30.5%) for the internal US of the OA/US device. OA/US exceeded US in specificity by 14.9% (P < .0001; 99% CI: 12.9, 16.9%). Sensitivity for biopsied malignant masses was 96.0% (4553/4745, 99% CI: 94.5%, 97.0%) for OA/US and 98.6% (4680/4746, 99% CI: 97.8%, 99.1%) for US (P < .0001). The negative likelihood ratio of 0.094 for OA/US indicates a negative examination can reduce a maximum US-assigned pretest probability of 17.8% (low BI-RADS 4B) to a posttest probability of 2% (BI-RADS 3). Conclusion OA/US increases the specificity of breast mass assessment compared with the device internal grayscale US alone. Online supplemental material is available for this article. © RSNA, 2017.

Effect of age on breast cancer screening using tomosynthesis in combination with digital mammography.

PURPOSE: To determine the effect of tomosynthesis imaging as a function of age for breast cancer screening. METHODS: Screening performance metrics from 13 institutions were examined for 12 months prior to introduction of tomosynthesis (period 1) and compared to those after introduction of tomosynthesis (period 2, range 3-22 months). Screening metrics for women ages 40-49, 50-59, 60-69, and 70+ , included rates per 1000 screens for recalls, biopsies, cancers, and invasive cancers detected. RESULTS: Performance parameters were compared for women screened with digital mammography alone (n = 278,908) and digital mammography + tomosynthesis (n = 173,414). Addition of tomosynthesis to digital mammography produced significant reductions in recall rates for all age groups and significant increases in cancer detection rates for women 40-69. Largest recall rate reduction with tomosynthesis was for women 40-49, decreasing from 137 (95% CI 117-156) to 115 (95% CI 95-135); difference, -22 (95% CI -26 to -18; P < .001). Simultaneous increase in invasive cancer detection rate for women 40-49 from 1.6 (95% CI 1.2-1.9) to 2.7 (95% CI 2.2-3.1) with tomosynthesis (difference, 1.1; 95% CI 0.6-1.6; P < .001) was observed. CONCLUSIONS: Addition of tomosynthesis to digital mammography increased invasive cancer detection rates for women 40-69 and decreased recall rates for all age groups with largest performance gains seen in women 40-49. The similar performance seen with tomosynthesis screening for women in their 40s compared to digital mammography for women in their 50s argues strongly for commencement of mammography screening at age 40 using tomosynthesis.