Digital pathology for reporting histopathology samples, including cancer screening samples - definitive evidence from a multisite study.

AIMS: To conduct a definitive multicentre comparison of digital pathology (DP) with light microscopy (LM) for reporting histopathology slides including breast and bowel cancer screening samples. METHODS: A total of 2024 cases (608 breast, 607 GI, 609 skin, 200 renal) were studied, including 207 breast and 250 bowel cancer screening samples. Cases were examined by four pathologists (16 study pathologists across the four speciality groups), using both LM and DP, with the order randomly assigned and 6 weeks between viewings. Reports were compared for clinical management concordance (CMC), meaning identical diagnoses plus differences which do not affect patient management. Percentage CMCs were computed using logistic regression models with crossed random-effects terms for case and pathologist. The obtained percentage CMCs were referenced to 98.3% calculated from previous studies. RESULTS: For all cases LM versus DP comparisons showed the CMC rates were 99.95% [95% confidence interval (CI) = 99.90-99.97] and 98.96 (95% CI = 98.42-99.32) for cancer screening samples. In speciality groups CMC for LM versus DP showed: breast 99.40% (99.06-99.62) overall and 96.27% (94.63-97.43) for cancer screening samples; [gastrointestinal (GI) = 99.96% (99.89-99.99)] overall and 99.93% (99.68-99.98) for bowel cancer screening samples; skin 99.99% (99.92-100.0); renal 99.99% (99.57-100.0). Analysis of clinically significant differences revealed discrepancies in areas where interobserver variability is known to be high, in reads performed with both modalities and without apparent trends to either. CONCLUSIONS: Comparing LM and DP CMC, overall rates exceed the reference 98.3%, providing compelling evidence that pathologists provide equivalent results for both routine and cancer screening samples irrespective of the modality used.

The use of Vaccinia Immune Globulin in the Treatment of Severe Mpox. Virus Infection in Human Immunodeficiency Virus/AIDS.

We report a case of progressive, severe mpox virus (MPXV) infection in a patient with AIDS despite a standard course of tecovirimat. He significantly improved after administration of vaccinia immune globulin intravenous (VIGIV) highlighting its use as an adjunct for severe disease in immunocompromised hosts.

Trends in pathology diagnoses during 10 years of a colorectal cancer screening programme.

AIMS: We report pathology findings from the first 10 years of the faecal-occult blood-based Northern Ireland Bowel Cancer Screening Programme, presenting summary data and trends in pathology diagnoses and clinicopathological features of screen-detected cancers. METHODS AND RESULTS: Data were analysed from a comprehensive polyp-level pathology database representing all endoscopy specimens from programme inception in 2010 until 2021. A total of 9800 individuals underwent 13 472 endoscopy procedures, yielding 25 967 pathology specimens and 32 119 diagnoses. Index specimen diagnoses (4.1%) and index colonoscopies (10.4%) yielded a diagnosis of colorectal cancer, representing 1045 cancers from 1020 individuals (25 with synchronous cancers). A further 13 index cancers were identified via computed tomography colonography; 65.3% of cancer diagnoses were in males; 41.7% were stage I, 23.1% stage II, 25.8% stage III and 1.8% stage IV (7.6% unstaged). Of 233 pT1 cancers diagnosed within local excision specimens, 79 (33.9%) had completion surgery. Ten-year trends showed a steady decline in the proportion of index colonoscopies that yielded a diagnosis of cancer (14.7% in year 1; 4.8% in year 11) or advanced colorectal polyp. There was a strong upward trend in diagnoses of sessile serrated lesions, which overtook hyperplastic polyps in proportions of total index diagnoses by the end of the study time-frame (8.7% compared to 8.5%). CONCLUSIONS: Over the first 10 years of a population colorectal cancer screening programme, 'real world' pathology data demonstrate success in the form of reduced diagnoses of cancer and advanced colorectal polyp with passage of successive screening rounds. Interesting trends with respect to serrated polyp diagnoses are also evident, probably related to pathologist and endoscopist behaviour.

Spin-Flip Diffusion Length in 5d Transition Metal Elements: A First-Principles Benchmark.

Little is known about the spin-flip diffusion length l_{sf}, one of the most important material parameters in the field of spintronics. We use a density-functional-theory based scattering approach to determine values of l_{sf} that result from electron-phonon scattering as a function of temperature for all 5d transition metal elements. l_{sf} does not decrease monotonically with the atomic number Z but is found to be inversely proportional to the density of states at the Fermi level. By using the same local current methodology to calculate the spin Hall angle Θ_{sH} that characterizes the efficiency of the spin Hall effect, we show that the products ρ(T)l_{sf}(T) and Θ_{sH}(T)l_{sf}(T) are constant.

Late Development of Metastatic Ovarian Mucinous Adenocarcinoma From Primary Gallblader Adenocarcinoma and High-grade Dysplasia.

The ovary is a common site of metastatic mucinous adenocarcinoma. In most, but not all, cases the presence of a primary neoplasm elsewhere is already known and the metastasis is picked up at diagnosis or is discovered a relatively short time following the diagnosis of the primary neoplasm. We report 2 cases of metastatic gallbladder adenocarcinoma involving the ovaries of women aged 65 and 59 after long time periods of 8 and 5 yr following diagnosis of high-grade dysplasia or early adenocarcinoma of the gallbladder, respectively. In both cases, a review of the original operative notes suggested the possibility of intraoperative gallbladder rupture or bile leakage suggesting that the metastatic disease may have developed secondary to "seeding." In both cases, p53 immunohistochemistry revealed identical null mutation-type immunoreactivity within the gallbladder and ovarian neoplasms, assisting in confirming the ovarian disease as a metastasis from the gallbladder. The possibility of late ovarian metastasis of gallbladder dysplasia or adenocarcinoma secondary to rupture/bile leakage should be borne in mind.

Non-inferiority randomised phase 3 trial comparing two radiation schedules (single vs. five fractions) in malignant spinal cord compression.

BACKGROUND: The optimal EBRT schedule for MSCC is undetermined. Our aim was to determine whether a single fraction (SF) was non-inferior to five daily fractions (5Fx), for functional motor outcome. METHODS: Patients not proceeding with surgical decompression in this multicentre non-inferiority, Phase 3 trial were randomised to 10 Gy/SF or 20 Gy/5Fx. A change in mobility from baseline to 5 weeks for each patient, was evaluated by a Modified Tomita score: 1 = 'Walk unaided', 2 = 'With walking aid' and 3 = 'Bed-bound'. The margin used to establish non-inferiority was a detrimental change of -0.4 in the mean difference between arms. RESULTS: One-hundred and twelve eligible patients were enrolled. Seventy-three patients aged 30-87 were evaluated for the primary analysis. The 95% CI for the difference in the mean change in mobility scores between arms was -0.12 to 0.6. Since -0.4 is not included in the interval, there is evidence that 10 Gy/SF is non-inferior to 20 Gy/5Fx. One grade 3 AE was reported in the 5Fx arm. Twelve (26%) patients in the 5Fx arm had a Grade 2-3 AE compared with six (11%) patients in the SF arm (p = 0.093). CONCLUSION: For mobility preservation, one 10-Gy fraction is non-inferior to 20 Gy in five fractions, in patients with MSCC not proceeding with surgical decompression. CLINICAL TRIAL REGISTRATION: Cancer Trials Ireland ICORG 05-03; NCT00968643; EU-20952.

Disorder Dependence of Interface Spin Memory Loss.

The discontinuity of a spin-current through an interface caused by spin-orbit coupling is characterized by the spin memory loss (SML) parameter δ. We use first-principles scattering theory and a recently developed local current scheme to study the SML for Au|Pt, Au|Pd, Py|Pt, and Co|Pt interfaces. We find a minimal temperature dependence for nonmagnetic interfaces and a strong dependence for interfaces involving ferromagnets that we attribute to the spin disorder. The SML is larger for Co|Pt than for Py|Pt because the interface is more abrupt. Lattice mismatch and interface alloying strongly enhance the SML that is larger for a Au|Pt than for a Au|Pd interface. The effect of the proximity-induced magnetization of Pt is negligible.

Primary Ovarian High-grade Neuroendocrine Carcinoma With Merkel Cell-like Immunophenotype Arising in a Teratoma.

Ovarian high-grade neuroendocrine carcinomas (NECs) (small cell and large cell NEC) are rare neoplasms. They may arise in association with other ovarian tumors, most commonly epithelial neoplasms and rarely teratomas. We report a case of an 19-yr-old female with bilateral ovarian teratomas with a high-grade NEC (immunohistochemically positive with chromogranin, synaptophysin, and CD56 and MIB1 proliferation index in excess of 90%) arising within one of these. Although CK20 was negative, the NEC exhibited an immunophenotype suggestive of a Merkel cell carcinoma with diffuse positive staining with FLI-1, SATB2 and neurofilament, markers which are preferentially expressed in Merkel cell carcinoma compared with other NECs. There was also diffuse staining for SALL4. Immunohistochemistry and molecular studies for Merkel cell polyomavirus were negative. Immunohistochemical staining for CK20, FLI-1, SATB2, neurofilament, and SALL4 was performed in 6 additional primary ovarian high-grade NECs; One, 5, 5, 1, and 0 cases were positive for CK20, FLI-1, SATB2, neurofilament, and SALL4, respectively, usually with very focal immunoreactivity. Pathologists should be aware of these potential unexpected staining patterns in ovarian NECs as positivity may result in consideration of other neoplasms.

Human Papillomavirus (HPV)-associated Lymphoepithelioma-like Carcinoma of the Vagina and Anal Canal: A Rare Variant of Squamous Cell Carcinoma.

Lymphoepithelioma-like carcinoma (LELC) is an uncommon variant of squamous cell carcinoma, which is histologically identical to lymphoepithelial carcinoma of the nasopharynx. LELCs have been reported at a variety of sites, including the stomach, salivary gland, thymus, cervix, endometrium, breast, skin, bladder, and lung. We report 2 LELCs of the vagina and 1 of the anal canal, the first report of LELC at the latter site. All 3 neoplasms were diffusely positive with p16 (block-type immunoreactivity) and the anal canal lesion contained high-risk human papillomavirus type 16; the 2 vaginal neoplasms underwent human papillomavirus testing but were unsuitable for analysis. All cases were Epstein-Barr virus negative. In reporting these cases, we highlight the potential for misdiagnosis and suggest an association with human papillomavirus infection similar to LELCs in the uterine cervix.

Back to the future: routine morphological assessment of the tumour microenvironment is prognostic in stage II/III colon cancer in a large population-based study.

AIMS: Both morphological and molecular approaches have highlighted the biological and prognostic importance of the tumour microenvironment in colorectal cancer (CRC). Despite this, microscopic assessment of the tumour microenvironment has not been adopted into routine practice. The study aim was to identify those tumour microenvironmental features that are most likely to provide prognostic information and be feasible to use in routine pathology reporting practice. METHODS AND RESULTS: On the basis of existing evidence, we selected specific morphological features relating to peritumoral inflammatory and stromal responses, agreed criteria for scoring, and assessed these in representative haematoxylin and eosin (H&E)-stained whole tumour sections from a population-based cohort of 445 stage II/III colon cancer cases. Moderate/severe peritumoral diffuse lymphoid inflammation and Crohn's disease-like reaction were associated with significantly reduced risks of CRC-specific death [adjusted hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.31-0.76, and HR 0.60, 95% CI 0.42-0.84, respectively]. The presence of >50% tumour stromal percentage, as assessed by global evaluation of tumour area, was associated with a significantly increased risk of CRC-specific death (HR 1.60 95% CI 1.06-2.41). A composite 'fibroinflammatory score' (0-3), combining dichotomized scores of these three features, showed a highly significant association with survival outcomes. Those with a score of ≥2 had an almost 2.5-fold increased risk of CRC-specific death (HR 2.44, 95% CI 1.56-3.81) as compared with those scoring zero. These associations were stronger in microsatellite instability (MSI)-high tumours, potentially identifying a subset of MSI-high colon cancers that lack characteristic morphological features and have an associated worse prognosis. CONCLUSIONS: In summary, reporting on H&E staining of selected microscopic features of the tumour microenvironment, independently or in combination, offers valuable prognostic information in stage II/III colon cancer, and may allow morphological correlation with developing molecular classifications of prognostic and predictive relevance.

Z_{2} Invariance of Germanene on MoS_{2} from First Principles.

We present a low energy Hamiltonian generalized to describe how the energy bands of germanene (Ge[over ¯]) are modified by interaction with a substrate or a capping layer. The parameters that enter the Hamiltonian are determined from first-principles relativistic calculations for Ge[over ¯]|MoS_{2} bilayers and MoS_{2}|Ge[over ¯]|MoS_{2} trilayers and are used to determine the topological nature of the system. For the lowest energy, buckled germanene structure, the gap depends strongly on how germanene is oriented with respect to the MoS_{2} layer(s). Topologically nontrivial gaps for bilayers and trilayers can be almost as large as for a freestanding germanene layer.

Giant Room Temperature Interface Spin Hall and Inverse Spin Hall Effects.

The spin Hall angle (SHA) is a measure of the efficiency with which a transverse spin current is generated from a charge current by the spin-orbit coupling and disorder in the spin Hall effect (SHE). In a study of the SHE for a Pt|Py (Py=Ni_{80}Fe_{20}) bilayer using a first-principles scattering approach, we find a SHA that increases monotonically with temperature and is proportional to the resistivity for bulk Pt. By decomposing the room temperature SHE and inverse SHE currents into bulk and interface terms, we discover a giant interface SHA that dominates the total inverse SHE current with potentially major consequences for applications.

A comparison of endoscopy versus pathology sizing of colorectal adenomas and potential implications for surveillance colonoscopy.

BACKGROUND AND AIMS: The aim of this study was to compare endoscopy and pathology sizing in a large population-based series of colorectal adenomas and to evaluate the implications for patient stratification into surveillance colonoscopy. METHODS: Endoscopy and pathology sizes available from intact adenomas removed at colonoscopies performed as part of the Northern Ireland Bowel Cancer Screening Programme, from 2010 to 2015, were included in this study. Chi-squared tests were applied to compare size categories in relation to clinicopathologic parameters and colonoscopy surveillance strata according to current American Gastroenterology Association and British Society of Gastroenterology guidelines. RESULTS: A total of 2521 adenomas from 1467 individuals were included. There was a trend toward larger endoscopy than pathology sizing in 4 of the 5 study centers, but overall sizing concordance was good. Significantly greater clustering with sizing to the nearest 5 mm was evident in endoscopy versus pathology sizing (30% vs 19%, P < .001), which may result in lower accuracy. Applying a 10-mm cut-off relevant to guidelines on risk stratification, 7.3% of all adenomas and 28.3% of those 8 to 12 mm in size had discordant endoscopy and pathology size categorization. Depending on which guidelines are applied, 4.8% to 9.1% of individuals had differing risk stratification for surveillance recommendations, with the use of pathology sizing resulting in marginally fewer recommended surveillance colonoscopies. CONCLUSIONS: Choice of pathology or endoscopy approaches to determine adenoma size will potentially influence surveillance colonoscopy follow-up in 4.8% to 9.1% of individuals. Pathology sizing appears more accurate than endoscopy sizing, and preferential use of pathology size would result in a small, but clinically important, decreased burden on surveillance colonoscopy demand. Careful endoscopy sizing is required for adenomas removed piecemeal.

Tuning ferromagnetism at interfaces between insulating perovskite oxides.

We use density functional theory calculations to show that the LaAlO3|SrTiO3 interface between insulating perovskite oxides is borderline in satisfying the Stoner criterion for itinerant ferromagnetism and explore other oxide combinations with a view to satisfying it more amply. The larger lattice parameter of a LaScO3|BaTiO3 interface is found to be less favorable than the greater interface distortion of LaAlO3|CaTiO3. Compared to LaAlO3|SrTiO3, the latter is predicted to exhibit robust magnetism with a larger saturation moment and a higher Curie temperature. Our results provide support for a "two phase" picture of coexistent superconductivity and ferromagnetism.

Gilbert damping in noncollinear ferromagnets.

The precession and damping of a collinear magnetization displaced from its equilibrium are well described by the Landau-Lifshitz-Gilbert equation. The theoretical and experimental complexity of noncollinear magnetizations is such that it is not known how the damping is modified by the noncollinearity. We use first-principles scattering theory to investigate transverse domain walls (DWs) of the important ferromagnetic alloy Ni80Fe20 and show that the damping depends not only on the magnetization texture but also on the specific dynamic modes of Bloch and Néel DWs in ways that were not theoretically predicted. Even in the highly disordered Ni80Fe20 alloy, the damping is found to be remarkably nonlocal.

Interface enhancement of Gilbert damping from first principles.

The enhancement of Gilbert damping observed for Ni_{80}Fe_{20} (Py) films in contact with the nonmagnetic metals Cu, Pd, Ta, and Pt is quantitatively reproduced using first-principles scattering calculations. The "spin-pumping" theory that qualitatively explains its dependence on the Py thickness is generalized to include a number of extra factors known to be important for spin transport through interfaces. Determining the parameters in this theory from first principles shows that interface spin flipping makes an essential contribution to the damping enhancement. Without it, a much shorter spin-flip diffusion length for Pt would be needed than the value we calculate independently.

"Aberrant" expression of skeletal muscle markers in neuroendocrine carcinomas: a significant diagnostic pitfall.

In this study, we investigate the expression of muscle markers, including the specific skeletal muscle markers myogenin and myoD1, in neuroendocrine carcinomas (NECs). The study included 23 NECs from various sites (14 small cell NECs and 9 large cell NECs). These were stained with desmin, myogenin and myoD1. Positive staining with at least one muscle marker was observed in 14 cases (61%). 8 (35%), 8 (35%) and 11 (48%) of the cases were positive with desmin, myogenin and myoD1 respectively. In most, but not all, cases positive staining was focal generally involving < 10% of tumour cells. Expression of muscle markers is not uncommon in NECs. This represents an important diagnostic pitfall of which pathologists should be aware. In reporting this phenomenon, we speculate on the pathogenesis of this "aberrant" expression of muscle markers.

Experiences implementing a Radiation therapist-led oncology prehabilitation program during COVID-19.

•Multi-modal prehabilitation prior to radiotherapy is valuable and achievable.•Radiation Therapists can be instrumental in developing prehab programs.•Multi-disciplinary care influences the patient's experience of cancer.•Validated screening tools can be easily incorporated into pre-radiotherapy assessments.•Online delivery of a prehabilitation program is feasible and safe.

What factors influence cellular pathologists' confidence in case reporting?

Histopathology is a challenging interpretive discipline, and the level of confidence a pathologist has in their diagnosis is known to vary, which is conveyed descriptively in pathology reports. There has been little study to accurately quantify pathologists' diagnostic confidence or the factors that influence it. In this study involving sixteen pathologists from six NHS trusts, we assessed diagnostic confidence across multiple variables and four specialties. Each case was reported by four pathologists, with each pathologist reporting each case twice (on light microscopy (LM) and digital pathology (DP)). For each diagnosis, pathologists recorded their confidence on a 7-point Likert scale. This provided 16,187 diagnoses and associated confidence scores for analysis. All variables investigated were found to be significantly predictive of diagnostic confidence, except level of pathologist experience. Confidence was lower for difficult to report cases, cases where there was inter- and intra-pathologist variation in the diagnosis, and cases where the pathologist made an incorrect diagnosis. Confidence was higher, although nominally, for LM diagnoses than DP (rate ratio 1.09 (95% CI 1.01-1.18), p = 0.035), although results indicate pathologists are confident to report on DP. Lowest confidence scores were seen in areas of known diagnostic complexity and cases with quality issues. High confidence in incorrect diagnoses were almost invariably attributed to interpretive diagnostic differences which occurred across both rare and common lesions. The results highlight the value of external quality control schemes and the benefits of selective peer review when reporting.

A Rare Case of Septic Ovarian Thrombophlebitis Caused by Tissierella praeacuta.

We report a case of Tissierella praeacuta bacteremia and septic thrombophlebitis of the ovarian vein as a rare puerperal complication in a young patient. She was successfully managed with subcutaneous low molecular weight heparin (LMWH) and intravenous (IV) antibiotics before transitioning to a prolonged course of oral antibiotics at discharge.