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Ki-67 is a nuclear protein associated with proliferation, and a strong potential biomarker in breast cancer, but is not routinely measured in current clinical management owing to a lack of standardization. Digital image analysis (DIA) is a promising technology that could allow high-throughput analysis and standardization. There is a dearth of data on the clinical reliability as well as intra- and interalgorithmic variability of different DIA methods. In this study, we scored and compared a set of breast cancer cases in which manually counted Ki-67 has already been demonstrated to have prognostic value (n = 278) to 5 DIA methods, namely Aperio ePathology (Lieca Biosystems), Definiens Tissue Studio (Definiens AG), Qupath, an unsupervised immunohistochemical color histogram algorithm, and a deep-learning pipeline piNET. The piNET system achieved high agreement (interclass correlation coefficient: 0.850) and correlation (R = 0.85) with the reference score. The Qupath algorithm exhibited a high degree of reproducibility among all rater instances (interclass correlation coefficient: 0.889). Although piNET performed well against absolute manual counts, none of the tested DIA methods classified common Ki-67 cutoffs with high agreement or reached the clinically relevant Cohen's κ of at least 0.8. The highest agreement achieved was a Cohen's κ statistic of 0.73 for cutoffs 20% and 25% by the piNET system. The main contributors to interalgorithmic variation and poor cutoff characterization included heterogeneous tumor biology, varying algorithm implementation, and setting assignments. It appears that image segmentation is the primary explanation for semiautomated intra-algorithmic variation, which involves significant manual intervention to correct. Automated pipelines, such as piNET, may be crucial in developing robust and reproducible unbiased DIA approaches to accurately quantify Ki-67 for clinical diagnosis in the future., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The Ki-67 proliferation index (PI) guides treatment decisions in breast cancer but suffers from poor inter-rater reproducibility. Although AI tools have been designed for Ki-67 assessment, their impact on pathologists' work remains understudied. 90 international pathologists were recruited to assess the Ki-67 PI of ten breast cancer tissue microarrays with and without AI. Accuracy, agreement, and turnaround time with and without AI were compared. Pathologists' perspectives on AI were collected. Using AI led to a significant decrease in PI error (2.1% with AI vs. 5.9% without AI, p < 0.001), better inter-rater agreement (ICC: 0.70 vs. 0.92; Krippendorff's α: 0.63 vs. 0.89; Fleiss' Kappa: 0.40 vs. 0.86), and an 11.9% overall median reduction in turnaround time. Most pathologists (84%) found the AI reliable. For Ki-67 assessments, 76% of respondents believed AI enhances accuracy, 82% said it improves consistency, and 83% trust it will improve efficiency. This study highlights AI's potential to standardize Ki-67 scoring, especially between 5 and 30% PI-a range with low PI agreement. This could pave the way for a universally accepted PI score to guide treatment decisions, emphasizing the promising role of AI integration into pathologist workflows., (© 2024. The Author(s).)

Tumor cells that preferentially enter circulation include the precursors of metastatic cancer. Previously, we characterized circulating tumor cells (CTC) from patients with breast cancer and identified a signature of genomic regions with recurrent copy-number gains. Through FISH, we now show that these CTC-associated regions are detected within the matched untreated primary tumors of these patients (21% to 69%, median 55.5%, n = 19). Furthermore, they are more prevalent in the metastases of patients who died from breast cancer after multiple rounds of treatment (70% to 100%, median 93%, samples n = 41). Diversity indices revealed that higher spatial heterogeneity for these regions within primary tumors is associated with increased dissemination and metastasis. An identified subclone with multiple regions gained (MRG clone) was enriched in a posttreatment primary breast carcinoma as well as multiple metastatic tumors and local breast recurrences obtained at autopsy, indicative of a distinct early subclone with the capability to resist multiple lines of treatment and eventually cause death. In addition, multiplex immunofluorescence revealed that tumor heterogeneity is significantly associated with the degree of infiltration of B lymphocytes in triple-negative breast cancer, a subtype with a large immune component. Collectively, these data reveal the functional potential of genetic subclones that comprise heterogeneous primary breast carcinomas and are selected for in CTCs and posttreatment breast cancer metastases. In addition, they uncover a relationship between tumor heterogeneity and host immune response in the tumor microenvironment. SIGNIFICANCE: As breast cancers progress, they become more heterogeneous for multiple regions amplified in circulating tumor cells, and intratumoral spatial heterogeneity is associated with the immune landscape., (©2021 The Authors; Published by the American Association for Cancer Research.)

We performed a post-occupancy assessment based on 500 occupant surveys in eight buildings using embedded radiant heating and cooling systems. This study follows-up on a quantitative assessment of 60 office buildings that found radiant and all-air buildings have comparable temperature and acoustic satisfaction with a tendency for increased temperature satisfaction in radiant buildings. Our objective was to investigate reasons of comfort and discomfort in the radiant buildings, and to relate these to building characteristics and operations strategies. The primary sources of thermal discomfort are lack of control over the thermal environment (both temperature and air movement) and slow system response, both of which were seen to be alleviated with fast-response adaptive opportunities such as operable windows and personal fans. There was no optimal radiant design or operation that maximized thermal comfort, and building operators were pleased with reduced repair and maintenance associated with radiant systems compared to all-air systems. Occupants reported low satisfaction with acoustics. This was primarily due to sound privacy issues in open-plan offices which may be exacerbated by highly reflective surfaces common in radiant spaces., Competing Interests: The authors have declared that no competing interests exist.

Background/objectives: To determine the effect of a proactive primary care program on acute hospitalization and aged-residential care placement for frail older people., Design: Controlled before and after, and controlled after only quasi-experimental studies, with a comparison group created via propensity score matching. One-year follow-up., Setting: Nine general practices in Auckland, New Zealand., Participants: Community-dwelling people aged 75 and older identified as at increased risk of hospitalization. One thousand and eighty five patients are compared with 3750 comparison patients matched by propensity score based on known risks., Intervention: Primary healthcare based, registered nurse-led, comprehensive geriatric assessment, goal-setting, care planning, and regular follow-up. Patients were also provided self-management education, health and social care navigation, and transitional care for hospital discharges. Practices received program support, workforce development, and mentoring of primary healthcare nurses by gerontology nurse specialists., Measurements: Outcomes from routinely collected administrative data. Primary: aged-residential care placement., Secondary Outcomes: acute hospitalization, mortality, and other health service utilization., Results: Aged-residential care placement (odds ratio [OR] 0.66, 95% confidence interval (CI) = 0.48-0.91) and mortality (OR 0.66, 95% CI = 0.49-0.88) were significantly lower over the first year in Kare patients compared with matched controls. There was no difference in acute hospitalization (+0.06 admissions per year, 95% CI = -0.01-0.13). Support service use (allied health therapists and assessment for social support) was increased, and emergency department use decreased., Conclusion: The Kare participants had lower aged-residential care placement and mortality in the first year, but no decrease in acute hospitalization. Because the design is nonexperimental caution is required in interpreting these results., (© 2021 The American Geriatrics Society.)