Getting Rigor Right: A Framework for Methodological Choice in Adaptive Monitoring and Evaluation.

The field of global development has embraced the idea that programs require agile, adaptive approaches to monitoring, evaluation, and learning. But considerable debate still exists around which methods are most appropriate for adaptive learning. Researchers have a range of proven and novel tools to promote a culture of adaptation and learning. These tools include lean testing, rapid prototyping, formative research, and structured experimentation, all of which can be utilized to generate responsive feedback (RF) to improve social change programs. With such an extensive toolkit, how should one decide which methods to employ? In our experience, the level of rigor used should be responsive to the team's level of certainty about the program design being investigated-how certain-or confident-are we that a program design will produce its intended results? With less certainty, less rigor is needed; with more certainty, more rigor is needed. In this article, we present a framework for getting rigor right and illustrate its use in 3 case studies. For each example, we describe the feedback methods used and why, how the approach was implemented (including how we conducted cocreation and ensured buy-in), and the results of each engagement. We conclude with lessons learned from these examples and how to use the right kind of RF mechanism to improve social change programs.

Upgrade Rate and Predictive Factors Associated With Breast Papillary Lesions on Core Biopsy: A Canadian Experience.

Background: Papillary lesions of the breast are a heterogeneous group, encompassing a wide range of lesions. The histologic distinction between papillary breast lesions remains challenging, especially on core biopsy specimens. Aim: This study aimed to determine the rate of upgrade to atypia or malignancy of biopsy-proven papillary lesions on surgical follow-up and to assess for factors associated with an upgrade in Greater Vancouver, BC, Canada. Materials and Methods: This is a retrospective population-based study of all breast papillary lesions diagnosed on core biopsy between 2017 and 2019 in the Fraser Health Authority in Greater Vancouver, Canada. Patients were retrieved from the laboratory information system. Patient demographics, histopathologic, and radiologic findings were analyzed. Results: A total of 269 specimens from 269 patients (mean 61.1 years), including 265 female and 4 male patients, were included in the study. Of the 269 specimens, 129 (48%) were intraductal papillomas and 140 (52%) were atypical papillary lesions. The overall upgrade rate among papillomas was 11.6% (15 of 129) on final excision. The mean age of patients diagnosed with papilloma on core biopsy was significantly younger than those with atypical papillary lesions (55.6 vs 66.1 years, P < .0001). Lesion size in patients with papillomas on core biopsy was significantly smaller than those with atypical papillary lesions (11.1 vs 15.1 mm, P = .001). The upgrade rates in patients <55 and ≥55 years were 4.9% and 13.2%. Size (P = .004) and atypia on core biopsy (P = .009) were significantly associated with upgrade. Older age (>55 years) (OR = 5.3, 95% CI: 1.04-27.08) was an independent predictor of upgrade among papillomas. Size, location, and Breast Imaging-Reporting and Data System (BI-RADS) radiologic categories in our study were not associated with predicting the upgrade of papillomas. Conclusion: Our data suggest that the risk of upgrade to atypia or malignancy is sufficient to warrant the excision of benign papillomas of any size in patients aged ≥55 years. In patients younger than 55 years, observation with close clinical and radiological follow-up without surgery may be sufficient. Our findings also support surgical excision of papillomas diagnosed on core biopsy when associated with atypia.

Variability in endometrial carcinoma pathology practice: opportunities for improvement with molecular classification.

We assessed the landscape of diagnostic pathology practice and how molecular classification could potentially impact management of patients with endometrial cancer by collecting patient samples, clinicopathologic data, and patient outcomes from EC patients diagnosed in 2016 at 10 Canadian tertiary cancer centers and 19 community hospitals. ProMisE molecular subtype (POLEmut, MMRd, p53abn, No Specific Molecular Profile (NSMP)) was assigned retrospectively. 1357 patients were fully evaluable including 85 POLEmut (6.3%), 380 MMRd (28.0%), 643 NSMP (47.4%), and 249 p53abn ECs (18.3%). Immunohistochemistry (IHC) for MMR proteins was undertaken at the time of primary diagnosis in 2016 in only 42% of the cohort (570/1357; range 3.5-95.4%/center). p53 IHC had only been performed in 21.1% of the cohort (286/1357; range 10.1-41.9%/center). Thus, based on the retrospective molecular subtype assignment, 54.7% (208/380) of MMRd EC had not been tested with MMR IHC (or MSI) and 48.2% (120/249) of p53abn ECs were not tested with p53 IHC in 2016. Molecular subtype diversity within histotypes was profound; most serous carcinomas were p53abn (91.4%), but only 129/249 (51.8%) p53abn EC were serous. Low-grade (Gr1-2) endometrioid carcinomas were mostly NSMP (589/954, 61.7%) but included all molecular subtypes, including p53abn (19/954, 2.0%). Molecular subtype was significantly associated with clinical outcomes (p < 0.001) even in patients with stage I disease (OS p = 0.006, DSS p < 0.001, PFS p < 0.001). Assessment of national pathologic practice in 2016 shows highly variable use of MMR and p53 IHC and demonstrates significant opportunities to improve and standardize biomarker reporting. Inconsistent, non-reflexive IHC resulted in missed opportunities for Hereditary Cancer Program referral and Lynch Syndrome diagnosis, and missed potential therapeutic implications (e.g., chemotherapy in p53abn EC, immune blockade for MMRd EC). Routine integration of molecular subtyping into practice can improve the consistency of EC pathology assessment and classification.

TRPS1, GATA3, and SOX10 expression in triple-negative breast carcinoma.

A diagnostic dilemma can be encountered when primary triple-negative breast carcinoma (TNBC) without an in situ component or metastatic TNBCs lose the currently used organ-specific marker such as GATA3, raising concerns about metastatic carcinoma from other sites. In the current study, we compared the newly identified breast marker TRPS1 with currently used breast markers GATA3 and SOX10 in whole-tissue sections from 315 cases of various subtypes of TNBC. TRPS1 was highly expressed in 100% of triple-negative primary and metastatic invasive lobular carcinomas, 99% of triple-negative primary and metastatic invasive breast carcinoma of no special type (IBC-NST), and 95% of metaplastic breast carcinomas. In contrast, GATA3 and SOX10 were expressed in 94% and 0% of invasive lobular carcinomas, 63% and 74% of IBC-NST, and 50% and 49% of metaplastic breast carcinomas, respectively. For special-type TNBCs, both TRPS1 and GATA3 were negative in acinic cell carcinomas, most cribriform adenoid cystic carcinomas, and neuroendocrine carcinomas, but positive in secretory carcinomas. Triple-negative apocrine carcinoma was the only subtype of TNBC with positive GATA3 but negative TRPS1. These data indicate that TRPS1 is a highly sensitive marker for TNBCs with positivity not only in GATA3/SOX10-positive TNBCs but also in almost all GATA3/SOX10-negative TNBCs.

Histological subtype is associated with PD-L1 expression and CD8+ T-cell infiltrates in triple-negative breast carcinoma.

Assessment of programmed death-ligand 1 (PD-L1) expression and CD8+ lymphocyte infiltrates in triple-negative breast carcinoma (TNBC) can provide valuable prognostic and predictive information. Knowledge of clinical and pathological factors that predict the status of these two markers is needed to better select patients likely to respond to immunotherapy. We aim to assess the association between histological subtypes of TNBC and tumor microenvironment type, defined here as each tumor's PD-L1 status and the percentage of CD8+ cells in its tumor-associated lymphocyte population. Tissue microarrays consisting of 72 TNBC cases (28 conventional invasive ductal carcinomas (IDCs), 21 basal-like IDCs, 18 apocrine carcinomas, and five metaplastic carcinomas) were evaluated for PD-L1 expression using the SP142 and 22C3 immunohistochemical (IHC) assays. The percentages of CD8+ and CD4+ intra-tumoral stromal lymphocytes in each case were analyzed using QuPath (open-source software platform) on CD8 and CD4 IHC-stained digital slides of the TMAs. Tumor-infiltrating lymphocytes (TILs) were also assessed on representative H&E-stained whole-tissue sections and compared to CD8+ and CD4+ lymphocyte percentages, and to the CD4/CD8 ratio of intra-tumoral lymphocytes for each case. Cases were then separated into four tumor microenvironment groups (PD-L1+/CD8+, PD-L1+/CD8-, PD-L1-/CD8+, and PD-L1-/CD8-). Basal-like IDCs were most often PD-L1-/CD8- (71.4%/61.9% of cases with SP142/22C3, respectively), while conventional IDCs were more distributed among PD-L1+ and PD-L1- microenvironments (35.7% PD-L1+/CD8+ and 42.9% PD-L1-/CD8- with the 22C3 assay). Apocrine carcinomas tended to be PD-L1-/CD8- (83.3% of cases with both SP142 and 22C3 antibodies). Metaplastic carcinomas were PD-L1-/CD8- in 60% of cases with both 22C3 and SP142. A CD8+ lymphocyte percentage ≥5% strongly predicted PD-L1 positivity (positive predictive value using the 22C3 assay: 0.75). Our data suggest that some histological subtypes of TNBC are predictive of PD-L1 status and CD8+ T-cell infiltrate levels.

Correct diagnosis of childhood pneumonia in public facilities in Tanzania: a randomised comparison of diagnostic methods.

OBJECTIVE: This study compares two methods for clinical diagnosis of childhood pneumonia that aim to estimate rates of underdiagnosis and overdiagnosis of childhood pneumonia by examining the sensitivity of Integrated Management of Childhood Diseases implementation in routine care against lung ultrasound (LUS) diagnosis. SETTING: We conducted observations in 83 public health facilities (dispensaries, health centres and district hospitals) in Pwani, Dodoma and Tabora, Tanzania between October and December 2017. METHODS: We used a novel method to estimate rates of underdiagnosis and overdiagnosis of childhood pneumonia by comparing directly observed public provider diagnoses to the results of diagnoses made by trained clinicians using Mindray DP-10 ultrasound machines. We perform multivariate analysis to identify confounding effects and robustness checks to bound the result. We also explore a number of observable characteristics correlated with higher rates of agreement between provider diagnoses and ultrasound diagnoses. RESULTS: We observed 93 providers conducting exams on patients aged 2 months-5 years who presented respiratory symptoms or were given a respiratory diagnosis by the provider. Of these 957 patients, 110 were excluded from analysis resulting in a final sample of 847.17.6% of cases identified as pneumonia via LUS examinations in our sample were diagnosed as pneumonia by providers, suggesting that a significant number of pneumonia cases for which care is sought in the public sector go undiagnosed. Provider knowledge of breath counting and years of experience are positively correlated with higher agreement. While clinical examination rates are not statistically correlated with agreement, it is notable that providers conducted a clinical examination on only about one-third of patients in the sample. CONCLUSION: Our results suggest that provider training and knowledge of clinical examination protocols for pneumonia diagnosis are predictive of correct diagnosis of pneumonia and should be further explored in future research as a tool for improving quality of care.

CD146 immunohistochemical staining for the separation of benign from malignant mesothelial proliferations.

The separation of benign from malignant mesothelial cells is often a challenging problem. Some studies have suggested that immunohistochemical staining of CD146 can be used to make this distinction, but there are marked differences in the reported results. Here, we assessed CD146 expression in tissue microarray specimens of 32 epithelioid reactive mesothelial hyperplasias, 17 spindle cell reactive mesothelial proliferations, 43 epithelioid mesotheliomas, and 31 sarcomatoid mesotheliomas. We found that, although the specificity of CD146 for epithelioid mesotheliomas versus reactive epithelial mesothelial proliferations was high (94%), staining intensity and extent was usually low and sensitivity was poor (23%). For sarcomatoid mesotheliomas versus reactive spindle cell mesothelial processes, both measures (33% sensitivity, 76% specificity) were inadequate. Furthermore, strong staining of endothelial cells and fibroblasts often created difficulties in interpretation. In comparison, BAP1 was lost in 21/43 (49%) epithelioid and 9/31 (29%) sarcomatoid mesotheliomas and methylthioadenosine phosphorylase (MTAP) was lost in 9/40 (23%) epithelioid and 7/29 (24%) sarcomatoid mesotheliomas from these TMAs. There was no association between CD146 staining and BAP1 or MTAP retention/loss. We conclude that CD146 staining is probably not useful for separating malignant from benign mesothelial proliferations.

Immunoreactive Acellular Keratin in Sentinel Lymph Nodes From a Patient With Endometrioid Carcinoma of the Endometrium With Squamous Differentiation: A Case Report of a Potential Diagnostic Pitfall.

Sentinel lymph node biopsy is gaining increasing acceptance as a less morbid way to assess lymph node status in patients with endometrial carcinoma, compared with full pelvic node dissection. The sentinel nodes are usually subjected to ultrastaging, with sections taken at multiple levels from each block and immunstaining for keratin performed, in order to detect micrometastses. We report a case of an 80-yr-old woman who underwent a right sentinel lymph node biopsy at the time of surgery for clinically and radiologically apparent stage I endometrial endometrioid adenocarcinoma. The immunostains for AE1/AE3 performed on the 2 right pelvic sentinel lymph nodes were positive, corresponding to subcapsular acellular keratin on hematoxylin and eosin; however, carcinoma cells could not be identified on the hematoxylin and eosin-stained slides. Immunomarkers for Ber-EP4 and EMA, both of which were strongly expressed in the endometrial carcinoma cells, were negative on the nodal tissue, and we concluded that the sentinel lymph nodes were negative for metastatic carcinoma, despite the positive keratin immunostains. To our knowledge, this unusual finding is not described in the literature; recognition of this phenomenon and study of additional cases is warranted.

Synthesis of diagnostic quality cancer pathology images by generative adversarial networks.

Deep learning-based computer vision methods have recently made remarkable breakthroughs in the analysis and classification of cancer pathology images. However, there has been relatively little investigation of the utility of deep neural networks to synthesize medical images. In this study, we evaluated the efficacy of generative adversarial networks to synthesize high-resolution pathology images of 10 histological types of cancer, including five cancer types from The Cancer Genome Atlas and the five major histological subtypes of ovarian carcinoma. The quality of these images was assessed using a comprehensive survey of board-certified pathologists (n = 9) and pathology trainees (n = 6). Our results show that the real and synthetic images are classified by histotype with comparable accuracies and the synthetic images are visually indistinguishable from real images. Furthermore, we trained deep convolutional neural networks to diagnose the different cancer types and determined that the synthetic images perform as well as additional real images when used to supplement a small training set. These findings have important applications in proficiency testing of medical practitioners and quality assurance in clinical laboratories. Furthermore, training of computer-aided diagnostic systems can benefit from synthetic images where labeled datasets are limited (e.g. rare cancers). We have created a publicly available website where clinicians and researchers can attempt questions from the image survey (http://gan.aimlab.ca/). © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.