A multi-modal exploration of heterogeneous physico-chemical properties of DCIS breast microcalcifications.

Ductal carcinoma in situ (DCIS) is frequently associated with breast calcification. This study combines multiple analytical techniques to investigate the heterogeneity of these calcifications at the micrometre scale. X-ray diffraction, scanning electron microscopy and Raman and Fourier-transform infrared spectroscopy were used to determine the physicochemical and crystallographic properties of type II breast calcifications located in formalin fixed paraffin embedded DCIS breast tissue samples. Multiple calcium phosphate phases were identified across the calcifications, distributed in different patterns. Hydroxyapatite was the dominant mineral, with magnesium whitlockite found at the calcification edge. Amorphous calcium phosphate and octacalcium phosphate were also identified close to the calcification edge at the apparent mineral/matrix barrier. Crystallographic features of hydroxyapatite also varied across the calcifications, with higher crystallinity centrally, and highest carbonate substitution at the calcification edge. Protein was also differentially distributed across the calcification and the surrounding soft tissue, with collagen and ß-pleated protein features present to differing extents. Combination of analytical techniques in this study was essential to understand the heterogeneity of breast calcifications and how this may link crystallographic and physicochemical properties of calcifications to the surrounding tissue microenvironment.

Fair shares: building and benefiting from healthcare AI with mutually beneficial structures and development partnerships.

Artificial intelligence (AI) algorithms are used in an increasing range of aspects of our lives. In particular, medical applications of AI are being developed and deployed, including many in image analysis. Deep learning methods, which have recently proved successful in image classification, rely on large volumes of clinical data generated by healthcare institutions. Such data is collected from their served populations. In this opinion article, using digital mammographic screening as an example, we briefly consider the background to AI development and some issues around its deployment. We highlight the importance of high quality clinical data as fundamental to these technologies, and question how the ownership of resultant tools should be defined. Though many of the ethical issues concerning the development and use of medical AI technologies continue to be discussed, the value of the data on which they rely remains a subject that is seldom considered. This potentially controversial issue can and should be addressed in a way which is beneficial to all parties, particularly the population in general and the patients we serve.

UK Guidelines on the Diagnosis and Treatment of Breast Implant-Associated Anaplastic Large Cell Lymphoma on behalf of the Medicines and Healthcare products Regulatory Agency Plastic, Reconstructive and Aesthetic Surgery Expert Advisory Group.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon T-cell non-Hodgkin Lymphoma (NHL) associated with breast implants. Raising awareness of the possibility of BIA-ALCL in anyone with breast implants and new breast symptoms is crucial to early diagnosis. The tumour begins on the inner aspect of the peri-implant capsule causing an effusion, or less commonly a tissue mass to form within the capsule, which may spread locally or to more distant sites in the body. Diagnosis is usually made by cytological, immunohistochemical and immunophenotypic evaluation of the aspirated peri-implant fluid: pleomorphic lymphocytes are characteristically anaplastic lymphoma kinase (ALK)-negative and strongly positive for CD30. BIA-ALCL is indolent in most patients but can progress rapidly. Surgical removal of the implant with the intact surrounding capsule (total en-bloc capsulectomy) is usually curative. Late diagnosis may require more radical surgery and systemic therapies and although these are usually successful, poor outcomes and deaths have been reported. By adopting a structured approach, as suggested in these guidelines, early diagnosis and successful treatment will minimise the need for systemic treatments, reduce morbidity and the risk of poor outcomes.

Calcification Microstructure Reflects Breast Tissue Microenvironment.

Microcalcifications are important diagnostic indicators of disease in breast tissue. Tissue microenvironments differ in many aspects between normal and cancerous cells, notably extracellular pH and glycolytic respiration. Hydroxyapatite microcalcification microstructure is also found to differ between tissue pathologies, including differential ion substitutions and the presence of additional crystallographic phases. Distinguishing between tissue pathologies at an early stage is essential to improve patient experience and diagnostic accuracy, leading to better disease outcome. This study explores the hypothesis that microenvironment features may become immortalised within calcification crystallite characteristics thus becoming indicators of tissue pathology. In total, 55 breast calcifications incorporating 3 tissue pathologies (benign - B2, ductal carcinoma in-situ - B5a and invasive malignancy - B5b) from archive formalin-fixed paraffin-embedded core needle breast biopsies were analysed using X-ray diffraction. Crystallite size and strain were determined from 548 diffractograms using Williamson-Hall analysis. There was an increased crystallinity of hydroxyapatite with tissue malignancy compared to benign tissue. Coherence length was significantly correlated with pathology grade in all basis crystallographic directions (P < 0.01), with a greater difference between benign and in situ disease compared to in-situ disease and invasive malignancy. Crystallite size and non-uniform strain contributed to peak broadening in all three pathologies. Furthermore, crystallite size and non-uniform strain normal to the basal planes increased significantly with malignancy (P < 0.05). Our findings support the view that tissue microenvironments can influence differing formation mechanisms of hydroxyapatite through acidic precursors, leading to differential substitution of carbonate into the hydroxide and phosphate sites, causing significant changes in crystallite size and non-uniform strain.

Has integrated 18F FDG PET/CT improved staging, reduced early recurrence or increased survival in oesophageal cancer?

BACKGROUND: Survival in oesophageal cancer remains poor with high post-operative recurrence rates. PET/CT was introduced to the Three-Counties Cancer Network (3CCN) in 2006 to detect 'occult' metastatic disease not seen with conventional staging modalities. This study aims to determine whether the introduction of Integrated fluorodeoxyglucose (18F) Positron Emission Tomography (PET/CT) has changed the management, improved survival or reduced the rate of early post-operative recurrence in patients with operable oesophageal cancer. METHODS: A retrospective review was undertaken of all patients diagnosed with oesophageal cancer in the 3CCN from 2005 to 2009. Early recurrence was defined as proven recurrence locally or at a distant site within one year of resection. RESULTS: 725 patients were identified. 200 (27.6%) patients underwent staging PET/CT. PET/CT altered treatment intent in 19 (9.5%) patients. 128 (17.7%) patients underwent oesophageal resection, 90 (70.3%) of which had a staging PET/CT. No significant difference was noted in post-operative mortality (4.4% Vs 5.3%, p = 0.8) or early recurrence where PET/CT was performed when adjusted for age, sex, stage or neo-adjuvant chemotherapy (p = 0.761, OR 1.136[95% CI 0.499-2.585]). PET/CT had no significant effect on survival (log-rank test; Chi-square 0.710, p = 0.4). CONCLUSION: PET/CT has improved the accuracy of oesophageal cancer staging avoiding potentially unnecessary surgery. Ultimately however, its use has had no effect on early recurrence or survival rates. Inaccurate identification of occult metastatic disease prior to the introduction of staging PET/CT does not appear to be the primary cause of early recurrence in patients with oesophageal cancer.

Adult Presentation of Cutaneous Langerhans Cell Histiocytosis: 18 F-FDG PET/CT Detection of Systemic Disease.

ABSTRACT: Langerhans cell histiocytosis (LCH) is a rare hematological disease, more common in pediatric populations. A 26-year-old man with biopsy-proven cutaneous LCH underwent 18 F-FDG PET/CT systemic staging. 18 F-FDG PET/CT highlighted multiple sites of avid cutaneous disease within the natal cleft. Additional characteristic cystic lung disease was seen on the CT component and focal uptake in the pituitary stalk/hypothalamic region noted, a common but occult site of disease in this patient. Because of the rarity of adult-onset cutaneous LCH, guidance on management and staging is lacking. 18 F-FDG PET/CT is critical to baseline evaluation of systemic disease, as illustrated here.

Translating microcalcification biomarker information into the laboratory: A preliminary assessment utilizing core biopsies obtained from sites of mammographic calcification.

Rationale and objectives: The potential of breast microcalcification chemistry to provide clinically valuable intelligence is being increasingly studied. However, acquisition of crystallographic details has, to date, been limited to high brightness, synchrotron radiation sources. This study, for the first time, evaluates a laboratory-based system that interrogates histological sections containing microcalcifications. The principal objective was to determine the measurement precision of the laboratory system and assess whether this was sufficient to provide potentially clinical valuable information. Materials and methods: Sections from 5 histological specimens from breast core biopsies obtained to evaluate mammographic calcification were examined using a synchrotron source and a laboratory-based instrument. The samples were chosen to represent a significant proportion of the known breast tissue, mineralogical landscape. Data were subsequently analysed using conventional methods and microcalcification characteristics such as crystallographic phase, chemical deviation from ideal stoichiometry and microstructure were determined. Results: The crystallographic phase of each microcalcification (e.g., hydroxyapatite, whitlockite) was easily determined from the laboratory derived data even when a mixed phase was apparent. Lattice parameter values from the laboratory experiments agreed well with the corresponding synchrotron values and, critically, were determined to precisions that were significantly greater than required for potential clinical exploitation. Conclusion: It has been shown that crystallographic characteristics of microcalcifications can be determined in the laboratory with sufficient precision to have potential clinical value. The work will thus enable exploitation acceleration of these latent microcalcification features as current dependence upon access to limited synchrotron resources is minimized.

Diffuse peritoneal carcinomatosis and Sister Mary Joseph nodule in ovarian carcinoma - exquisite demonstration of the peritoneal reflections on [18F]FDG PET/CT.

A case involving a 64-year-old woman with ovarian carcinoma on maintenance therapy who underwent 18-fluorodeoxyglucose positron emission tomography with computed tomography ([18F]FDG PET/CT) restaging due to rapid cancer antigen 125 (Ca-125) rise. This revealed recurrent disease within the pelvis and large volume, peritoneal carcinomatosis including an avid umbilical deposit, consistent with the rarely seen Sister Mary Joseph nodule (SMJN). This case elegantly demonstrates not only the anatomy of the peritoneal surfaces through avid disease deposition but also highlights the sensitive depiction of disease burden in peritoneal carcinomatosis, including the detection of rare manifestations such as SMJN.

Multimodality Appearances of Marginal Zone Lymphoma Masquerading as Cryptogenic Organizing Pneumonia-serial Chest Radiograph and High-resolution Computed Tomography Appearances: (18F) Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Staging Utility.

Marginal zone lymphoma (MZL) is a group of low-grade, indolent, non-Hodgkin lymphomas rarely manifesting in the lungs. A 46-year-old man presenting with shortness of breath and cough was investigated and treated over 10 months for an atypical pattern of lung disease in keeping with cryptogenic organizing pneumonia (COP). Initial lung biopsies were nondiagnostic - repeat sampling eventually showed MZL. Staging whole-body (18F) fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) demonstrated multisystem stage IV disease with intensely avid widespread pulmonary changes resembling COP. The case elegantly illustrates that pulmonary MZL can present insidiously masquerading as COP and shows the value of (18F) FDG PET/CT to stage extranodal MZL.

Exploration of utility of combined optical photothermal infrared and Raman imaging for investigating the chemical composition of microcalcifications in breast cancer.

Microcalcifications play an important role in cancer detection. They are evaluated by their radiological and histological characteristics but it is challenging to find a link between their morphology, their composition and the nature of a specific type of breast lesion. Whilst there are some mammographic features that are either typically benign or typically malignant often the appearances are indeterminate. Here, we explore a large range of vibrational spectroscopic and multiphoton imaging techniques in order to gain more information about the composition of the microcalcifications. For the first time, we validated the presence of carbonate ions in the microcalcifications by O-PTIR and Raman spectroscopy at the same time, the same location and the same high resolution (0.5 µm). Furthermore, the use of multiphoton imaging allowed us to create stimulated Raman histology (SRH) images which mimic histological images with all chemical information. In conclusion, we established a protocol for efficiently analysing the microcalcifications by iteratively refining the area of interest.

Lessons learned from independent external validation of an AI tool to detect breast cancer using a representative UK data set.

OBJECTIVE: To pilot a process for the independent external validation of an artificial intelligence (AI) tool to detect breast cancer using data from the NHS breast screening programme (NHSBSP). METHODS: A representative data set of mammography images from 26,000 women attending 2 NHS screening centres, and an enriched data set of 2054 positive cases were used from the OPTIMAM image database. The use case of the AI tool was the replacement of the first or second human reader. The performance of the AI tool was compared to that of human readers in the NHSBSP. RESULTS: Recommendations for future external validations of AI tools to detect breast cancer are provided. The tool recalled different breast cancers to the human readers. This study showed the importance of testing AI tools on all types of cases (including non-standard) and the clarity of any warning messages. The acceptable difference in sensitivity and specificity between the AI tool and human readers should be determined. Any information vital for the clinical application should be a required output for the AI tool. It is recommended that the interaction of radiologists with the AI tool, and the effect of the AI tool on arbitration be investigated prior to clinical use. CONCLUSION: This pilot demonstrated several lessons for future independent external validation of AI tools for breast cancer detection. ADVANCES IN KNOWLEDGE: Knowledge has been gained towards best practice procedures for performing independent external validations of AI tools for the detection of breast cancer using data from the NHS Breast Screening Programme.

Microcalcification crystallography as a potential marker of DCIS recurrence.

Ductal carcinoma in-situ (DCIS) accounts for 20-25% of all new breast cancer diagnoses. DCIS has an uncertain risk of progression to invasive breast cancer and a lack of predictive biomarkers may result in relatively high levels (~ 75%) of overtreatment. To identify unique prognostic biomarkers of invasive progression, crystallographic and chemical features of DCIS microcalcifications have been explored. Samples from patients with at least 5-years of follow up and no known recurrence (174 calcifications in 67 patients) or ipsilateral invasive breast cancer recurrence (179 microcalcifications in 57 patients) were studied. Significant differences were noted between the two groups including whitlockite relative mass, hydroxyapatite and whitlockite crystal maturity and, elementally, sodium to calcium ion ratio. A preliminary predictive model for DCIS to invasive cancer progression was developed from these parameters with an AUC of 0.797. These results provide insights into the differing DCIS tissue microenvironments, and how these impact microcalcification formation.

Bilateral Avid Axillary Nodes on FDG PET/CT Due to Concurrent Booster COVID-19 Immunization and Seasonal Influenza Vaccination.

ABSTRACT: In an attempt to protect the high-risk demographic and reduce burden on health care systems, concomitant administration of COVID-19 and influenza vaccines has been recommended by health bodies. The ComFluCOV trial indicates this is well tolerated with no reduction in immune response to either vaccine. A 48-year-old woman with right oropharyngeal squamous cell carcinoma underwent postradiotherapy FDG PET/CT, which demonstrated complete metabolic response. Incidental avid bilateral axillary lymphadenopathy of benign configuration was noted and concluded to be reactive in response to recent Pfizer-BioNTech booster and influenza vaccination. This is expected to be seen more frequently over the coming months.

Incidental [18F]PSMA-1007 Appendiceal Uptake Mimicking Nodal Disease.

ABSTRACT: When interpreting an [18F]prostate specific membrane antigen (PSMA)-1007 PET/CT, it is important to understand the normal biodistribution of the tracer. A 73-year-old man with prostate cancer underwent [18F]PSMA-1007 PET/CT for biochemical recurrence. There was no abnormal uptake in the prostatectomy bed, but PSMA-avid pelvic nodal disease was found. Incidental intense focal uptake was also noted corresponding to the tip of the appendix, which was concluded to be physiological. This is an example of an uncommon site of physiological uptake of [18F]PSMA-1007 in the appendix.

Features of Systemic Immune Response From COVID-19 Vaccination on 18F-FDG PET/CT.

ABSTRACT: The rapid rollout of COVID-19 vaccination is accompanied by incidental findings on 18F-FDG PET/CT. Most cases describe reactive axillary lymphadenopathy. A 46-year-old woman with previous history of stage 3A breast cancer underwent follow-up 18F-FDG PET/CT, which demonstrated avid left axillary nodes and intense diffuse splenic uptake and moderate diffuse bone marrow uptake. She had been administered COVID-19 vaccination in the left deltoid 1 week earlier and required hospitalization for 24 hours due to fever. Symptoms settled with supportive treatment. One month after the PET/CT scan, she remained well. Sites of uptake were taken to relate to a systemic immune response.

Systemic Immune Response Syndrome After COVID-19 Immunization-Initial and Follow-up 18F-FDG PET/CT Imaging Appearances.

ABSTRACT: A 46-year-old woman with previous history of breast cancer had follow-up 18F-FDG PET/CT 5 days after COVID-19 vaccination. In addition to avid axillary nodes, a well-documented feature, the scan demonstrated diffuse splenic and marrow uptake. Clinical history, laboratory, and scan findings were in keeping with SIRS (systemic inflammatory response). The patient recovered with supportive management. On follow-up, 18F-FDG PET/CT imaging 3 months later features had resolved. SIRS after vaccination may be observed on 18F-FDG PET/CT.

[18F]FDG-PET/CT Demonstration of Young Adult Onset Stills Disease Mimicking Lymphoma.

Adult-onset Still's disease (AOSD) is an inflammatory disease of unknown aetiology, with no specific diagnostic tests. A 17-year-old female presented with fevers, night sweats and weight loss. Markedly FDG avid lymphadenopathy, and diffuse marrow and splenic uptake were demonstrated on [18F]FDG-PET/CT, most suggestive of lymphoma. After extensive investigations, the working diagnosis of AOSD was made. Other conditions, such AOSD, in addition to lymphoproliferative disorders, should be considered in the differential diagnosis of widespread avid lymphadenopathy in a teenager/young adult.

Breast calcification micromorphology classification.

OBJECTIVES: The importance of consistent terminology in describing the appearance of breast calcifications in mammography is well recognised. Imaging of calcifications using electron microscopy is a globally growing field of research. We therefore suggest that the time is ripe to develop a lexicon of terms for classifying the micromorphology of breast calcifications. METHODS: Calcifications within a wide range of histological sections of breast tissue, both benign and malignant, were imaged by Scanning Electron Microscopy (SEM). These images were examined, and the micromorphology of calcifications present was grouped to create a classification system. RESULTS: Based on the appearance of the calcifications observed, we propose five main categories for classification of the micromorphology of breast calcifications, namely, Dense Homogenous, Punctulate, Banded, Spongy and Aggregate. CONCLUSIONS: Use of the descriptive categories outlined here will help to ensure consistency and comparability of published observations on the micromorphology of breast calcifications. ADVANCES IN KNOWLEDGE: This is the first time a lexicon and classification system has been proposed for the micromorphology of breast calcifications, as observed by scanning electron microscopy of histological sections. This will facilitate comparability of observed relationships between micromorphology, mammographic appearance, chemistry and pathology.