Hematoxylin and Eosin Architecture Uncovers Clinically Divergent Niches in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) represents one of the only cancers with an increasing incidence rate and is often associated with intra- and peri-tumoral scarring, referred to as desmoplasia. This scarring is highly heterogeneous in extracellular matrix (ECM) architecture and plays complex roles in both tumor biology and clinical outcomes that are not yet fully understood. Using hematoxylin and eosin (H&E), a routine histological stain utilized in existing clinical workflows, we quantified ECM architecture in 85 patient samples to assess relationships between desmoplastic architecture and clinical outcomes such as survival time and disease recurrence. By utilizing unsupervised machine learning to summarize a latent space across 147 local (e.g., fiber length, solidity) and global (e.g., fiber branching, porosity) H&E-based features, we identified a continuum of histological architectures that were associated with differences in both survival and recurrence. Furthermore, we mapped H&E architectures to a CO-Detection by indEXing (CODEX) reference atlas, revealing localized cell- and protein-based niches associated with outcome-positive versus outcome-negative scarring in the tumor microenvironment. Overall, our study utilizes standard H&E staining to uncover clinically relevant associations between desmoplastic organization and PDAC outcomes, offering a translatable pipeline to support prognostic decision-making and a blueprint of spatial-biological factors for modeling by tissue engineering methods.

Spatial phenotyping of nodular lymphocyte predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma with sparse tumor B-cells and a favorable prognosis. Variant growth patterns of NLPHL, however, often show advanced stage, progression to T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) and a worse prognosis. We studied the tumor microenvironment (TME) of NLPHL and THRLBCL using highplex imaging and spatial profiling at the single cell level. Our findings show distinct differences in TME composition and spatial configuration that differ among typical and variant NLPHL and THRLBCL. Typical NLPHL show abundant helper T-cell subsets, while THRLBCL show abundant cytotoxic T-cells and macrophages. Tumor B-cell size and content is lowest in typical NLPHL, followed by variant NLPHL, and highest in THRLBCL, whereas an opposite trend characterized TME B-cells. CD4/CD8 double-positive T-cells are seen in all NLPHL but not in the majority of THRLBCL and are spatially distant from LP-cells and TFH-rosettes. The differences in macrophage/monocyte content in distinguishing NLPHL pattern E from THRLBCL is further corroborated in independent cohorts of cases. Our results validate the current approach to classification and in addition provide novel insights that could be leveraged to refine clinical management for patients with this spectrum of lymphomas.

Desmoplastic stromal signatures predict patient outcomes in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death. Hallmarks include desmoplasia with variable extracellular matrix (ECM) architecture and a complex microenvironment with spatially defined tumor, stromal, and immune populations. Nevertheless, the role of desmoplastic spatial organization in patient/tumor variability remains underexplored, which we elucidate using two technologies. First, we quantify ECM patterning in 437 patients, revealing architectures associated with disease-free and overall survival. Second, we spatially profile the cellular milieu of 78 specimens using codetection by indexing, identifying an axis of pro-inflammatory cell interactions predictive of poorer outcomes. We discover that clinical characteristics, including neoadjuvant chemotherapy status, tumor stage, and ECM architecture, correlate with differential stromal-immune organization, including fibroblast subtypes with distinct niches. Lastly, we define unified signatures that predict survival with areas under the receiver operating characteristic curve (AUCs) of 0.872-0.903, differentiating survivorship by 655 days. Overall, our findings establish matrix ultrastructural and cellular organizations of fibrosis linked to poorer outcomes.

Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin.

Cancer-associated fibroblasts (CAFs) are integral to the solid tumor microenvironment. CAFs were once thought to be a relatively uniform population of matrix-producing cells, but single-cell RNA sequencing has revealed diverse CAF phenotypes. Here, we further probed CAF heterogeneity with a comprehensive multiomics approach. Using paired, same-cell chromatin accessibility and transcriptome analysis, we provided an integrated analysis of CAF subpopulations over a complex spatial transcriptomic and proteomic landscape to identify three superclusters: steady state-like (SSL), mechanoresponsive (MR), and immunomodulatory (IM) CAFs. These superclusters are recapitulated across multiple tissue types and species. Selective disruption of underlying mechanical force or immune checkpoint inhibition therapy results in shifts in CAF subpopulation distributions and affected tumor growth. As such, the balance among CAF superclusters may have considerable translational implications. Collectively, this research expands our understanding of CAF biology, identifying regulatory pathways in CAF differentiation and elucidating therapeutic targets in a species- and tumor-agnostic manner.

Small Fiber Neuropathy Associated With the Moderna SARS-CoV-2 Vaccine.

Efforts of controlling viral transmission began soon after the first cases of coronavirus disease 2019 (COVID-19) infections were identified. Initial efforts were related to contact precautions, hand hygiene, and mask-wearing; however, it was soon evident that a robust global immunization drive was the most effective way to curb disease transmission. In the United States, the first doses of COVID-19 vaccines were rolled out soon after the FDA granted emergency use authorization for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. What this also meant was that many of the routine phases that any new drug or vaccine goes through before being released publicly were bypassed. Over the past two years, various side effects and reactions have been seen after COVID-19 vaccine administration, the most common being local injection site events (e.g., pain, redness, swelling) and systemic effects (e.g., fatigue, headaches, myalgias). We report the case of a 64-year-old female who developed bilateral lower extremity numbness and tingling within weeks of receiving the third dose of Moderna SARS-CoV-2 vaccine. The patient underwent extensive testing to ascertain the diagnosis. She had negative autonomic testing and normal nerve conduction study/electromyography (EMG), which did not reveal large fiber neuropathy. Eventually, the patient underwent a skin biopsy, which revealed small fiber neuropathy. This case report highlights the importance of keeping a broad differential for rare side effects, such as small fiber neuropathy, that are currently being seen and reported in the literature.

cPLA2 blockade attenuates S100A7-mediated breast tumorigenicity by inhibiting the immunosuppressive tumor microenvironment.

BACKGROUND: Molecular mechanisms underlying inflammation-associated breast tumor growth are poorly studied. S100A7, a pro-inflammatory molecule has been shown to enhance breast cancer growth and metastasis. However, the S100A7-mediated molecular mechanisms in enhancing tumor growth and metastasis are unclear. METHODS: Human breast cancer tissue and plasma samples were used to analyze the expression of S100A7, cPLA2, and PGE2. S100A7-overexpressing or downregulated human metastatic breast cancer cells were used to evaluate the S100A7-mediated downstream signaling mechanisms. Bi-transgenic mS100a7a15 overexpression, TNBC C3 (1)/Tag transgenic, and humanized patient-derived xenograft mouse models and cPLA2 inhibitor (AACOCF3) were used to investigate the role of S100A7/cPLA2/PGE2 signaling in tumor growth and metastasis. Additionally, CODEX, a highly advanced multiplexed imaging was employed to delineate the effects of S100A7/cPLA2 inhibition on the recruitment of various immune cells. RESULTS: In this study, we found that S100A7 and cPLA2 are highly expressed and correlate with decreased overall survival in breast cancer patients. Further mechanistic studies revealed that S100A7/RAGE signaling promotes the expression of cPLA2 to mediate its oncogenic effects. Pharmacological inhibition of cPLA2 suppressed S100A7-mediated tumor growth and metastasis in multiple pre-clinical models including transgenic and humanized patient-derived xenograft (PDX) mouse models. The attenuation of cPLA2 signaling reduced S100A7-mediated recruitment of immune-suppressive myeloid cells in the tumor microenvironment (TME). Interestingly, we discovered that the S100A7/cPLA2 axis enhances the immunosuppressive microenvironment by increasing prostaglandin E2 (PGE2). Furthermore, CO-Detection by indEXing (CODEX) imaging-based analyses revealed that cPLA2 inhibition increased the infiltration of activated and proliferating CD4+ and CD8+ T cells in the TME. In addition, CD163+ tumor associated-macrophages were positively associated with S100A7 and cPLA2 expression in malignant breast cancer patients. CONCLUSIONS: Our study provides new mechanistic insights on the cross-talk between S100A7/cPLA2 in enhancing breast tumor growth and metastasis by generating an immunosuppressive TME that inhibits the infiltration of cytotoxic T cells. Furthermore, our studies indicate that S100A7/cPLA2 could be used as novel prognostic marker and cPLA2 inhibitors as promising drugs against S100A7-overexpressing aggressive breast cancer.

Impact of COVID-19 Pandemic on Treatment of Pediatric Oncology Patients: Report from Resource-limited Setting.

The aim of this study was to determine how the COVID-19 pandemic impacted on the effective management; and the outcome of pediatric oncology patients in Shaukat Khanum Memorial Cancer Hospital & Research Centre, Lahore. Data was retrospectively reviewed from 15 March to 15 June 2020 after the approval of Institutional Review Board Committee. A total of 258 patients on active oncology treatment between the study period were included. The total number of patients whose treatment was affected were 118 (45.7%), while 140 (54.3%) patients received treatment in time. There was total 34 (13.2%) patients relapsed, 23 (67.6%) patients in which treatment delayed, and 11 (32.4%) patients in which their treatment not delayed; while, n=218 (84.5%) were in remission, and 6 (2.3%) patients absconded. COVID-19 pandemic caused a sudden impediment in the treatment of pediatric oncology patients, and is likely to affect the long-term survival outcome of pediatric oncology patients. Key Words: Chemotherapy, Radiotherapy, Surgery, Long term outcome.

Capacity building and mentorship among pan-Canadian early career researchers in community-based primary health care.

AIM: To describe activities and outcomes of a cross-team capacity building strategy that took place over a five-year funding period within the broader context of 12 community-based primary health care (CBPHC) teams. BACKGROUND: In 2013, the Canadian Institutes of Health Research funded 12 CBPHC Teams (12-Teams) to conduct innovative cross-jurisdictional research to improve the delivery of high-quality CBPHC to Canadians. This signature initiative also aimed to enhance CBPHC research capacity among an interdisciplinary group of trainees, facilitated by a collaboration between a capacity building committee led by senior researchers and a trainee-led working group. METHODS: After the committee and working group were established, capacity building activities were organized based on needs and interests identified by trainees of the CBPHC Teams. This paper presents a summary of the activities accomplished, as well as the outcomes reported through an online semistructured survey completed by the trainees toward the end of the five-year funding period. This survey was designed to capture the capacity building and mentorship activities that trainees either had experienced or would like to experience in the future. Descriptive and thematic analyses were conducted based on survey responses, and these findings were compared with the existing core competencies in the literature. FINDINGS: Since 2013, nine webinars and three online workshops were hosted by trainees and senior researchers, respectively. Many of the CBPHC Teams provided exposure for trainees to innovative methods, CBPHC content, and showcased trainee research. A total of 27 trainees from 10 of the 12-Teams responded to the survey (41.5%). Trainees identified key areas of benefit from their involvement in this initiative: skills training, networking opportunities, and academic productivity. Trainees identified gaps in research and professional skill development, indicating areas for further improvement in capacity building programs, particularly for trainees to play a more active role in their education and preparation.

Do family health clinics provide primary-level palliative care in Ontario and the eastern regions of Quebec?

OBJECTIVE: To explore the extent to which family health clinics in Ontario and the eastern regions of the province of Quebec provide palliative care. DESIGN: A cross-sectional survey. SETTING: Ontario and the eastern regions of Quebec. PARTICIPANTS: The clinic leads of a select group of family health clinics with patient enrolment models in Ontario and the eastern regions of Quebec. MAIN OUTCOME MEASURES: The types of palliative care services that the clinics provide, as well as the enablers of and barriers to providing palliative care within the 2 provinces. RESULTS: The overall response rate was 32%. Clinics in both provinces reported providing palliative care to ambulatory patients (83% of Ontario clinics and 74% of Quebec clinics). Only 29 of 102 (28%) Ontario clinics provided on-call services themselves, compared with 31 of 34 (91%) Quebec clinics, with the resulting effect being that more patients were directed to emergency departments in Ontario. Access to palliative care specialist teams for support was higher in Ontario than in Quebec (67% vs 41%, respectively). In Ontario, 56% of practices indicated that they had access to palliative care physicians who could take over the care of their patients with palliative care needs, but a lower number (44%) actually handed over care to these physicians. CONCLUSION: A group of clinics are providing full palliative care services to their own patients with palliative care needs, including "on-call" services and home visits, and these serve as role models. In Ontario in particular, substantial gaps still exist with respect to clinics providing their own after-hours coverage and home visits; many rely on other services to provide that care. In Quebec, lack of access to palliative care specialist teams appears to be a key challenge in the areas included in this survey. This survey could help policy makers and funders of health care services ensure that appropriate conditions are put in place for optimal palliative care provision in these clinics, such as coordinating access to on-call coverage and support from palliative care specialist teams, as well as providing education to all physicians and adequate remuneration.

Income inequalities in multimorbidity prevalence in Ontario, Canada: a decomposition analysis of linked survey and health administrative data.

BACKGROUND: The burden of multimorbidity is a growing clinical and health system problem that is known to be associated with socioeconomic status, yet our understanding of the underlying determinants of inequalities in multimorbidity and longitudinal trends in measured disparities remains limited. METHODS: We included all adult respondents from four cycles of the Canadian Community Health Survey (CCHS) (between 2005 to 2011/12), linked at the individual-level to health administrative data in Ontario, Canada (pooled n = 113,627). Multimorbidity was defined at each survey response as having ≥2 (of 17) high impact chronic conditions, based on claims data. Using a decomposition method of the Erreygers-corrected concentration index (CErreygers), we measured household income inequality and the contribution of the key determinants of multimorbidity (including socio-demographic, socio-economic, lifestyle and health system factors) to these disparities. Differences over time are described. We tested for statistically significant changes to measured inequality using the slope index (SII) and relative index of inequality (RII) with a 2-way interaction on pooled data. RESULTS: Multimorbidity prevalence in 2011/12 was 33.5% and the CErreygers was - 0.085 (CI: -0.108 to - 0.062), indicating a greater prevalence among lower income groups. In decomposition analyses, income itself accounted more than two-thirds (69%) of this inequality. Age (21.7%), marital status (15.2%) and physical inactivity (10.9%) followed, and the contribution of these factors increased from baseline (2005 CCHS survey) with the exception of age. Other lifestyle factors, including heavy smoking and obesity, had minimal contribution to measured inequality (1.8 and 0.4% respectively). Tests for trends (SII/RII) across pooled survey data were not statistically significant (p = 0.443 and 0.405, respectively), indicating no change in inequalities in multimorbidity prevalence over the study period. CONCLUSIONS: A pro-rich income gap in multimorbidity has persisted in Ontario from 2005 to 2011/12. These empirical findings suggest that to advance equality in multimorbidity prevalence, policymakers should target chronic disease prevention and control strategies focused on older adults, non-married persons and those that are physically inactive, in addition to addressing income disparities directly.

Integrated Care Planning for Cancer Patients: A Scoping Review.

INTRODUCTION: There has been a growing emphasis on the use of integrated care plans to deliver cancer care. However little is known about how integrated care plans for cancer patients are developed including featured core activities, facilitators for uptake and indicators for assessing impact. METHODS: Given limited consensus around what constitutes an integrated care plan for cancer patients, a scoping review was conducted to explore the components of integrated care plans and contextual factors that influence design and uptake. RESULTS: Five types of integrated care plans based on the stage of cancer care: surgical, systemic, survivorship, palliative and comprehensive (involving a transition between stages) are described in current literature. Breast, esophageal and colorectal cancers were common disease sites. Multi-disciplinary teams, patient needs assessment and transitional planning emerged as key features. Provider buy-in and training alongside informational technology support served as important facilitators for plan uptake. Provider-level measurement was considerably less robust compared to patient and system-level indicators. CONCLUSIONS: Similarities in design features, components and facilitators across the various types of integrated care plans indicates opportunities to leverage shared features and enable a management lens that spans the trajectory of a patient's journey rather than a phase-specific silo approach to care.