SpatialCells: automated profiling of tumor microenvironments with spatially resolved multiplexed single-cell data.

Cancer is a complex cellular ecosystem where malignant cells coexist and interact with immune, stromal and other cells within the tumor microenvironment (TME). Recent technological advancements in spatially resolved multiplexed imaging at single-cell resolution have led to the generation of large-scale and high-dimensional datasets from biological specimens. This underscores the necessity for automated methodologies that can effectively characterize molecular, cellular and spatial properties of TMEs for various malignancies. This study introduces SpatialCells, an open-source software package designed for region-based exploratory analysis and comprehensive characterization of TMEs using multiplexed single-cell data. The source code and tutorials are available at https://semenovlab.github.io/SpatialCells. SpatialCells efficiently streamlines the automated extraction of features from multiplexed single-cell data and can process samples containing millions of cells. Thus, SpatialCells facilitates subsequent association analyses and machine learning predictions, making it an essential tool in advancing our understanding of tumor growth, invasion and metastasis.

Cancer Type and Histology Influence Cutaneous Immunotherapy Toxicities: A Multi-Institutional Cohort Study.

BACKGROUND: Cutaneous immune-related adverse events (cirAEs) are the most common toxicities to occur in the setting of immune checkpoint inhibitor (ICI) therapy. Identifying patients who are at increased risk of developing cirAEs may improve quality of life and outcomes. OBJECTIVE: To investigate the influence of cancer type and histology on the development of cirAEs in the setting of ICI therapy and survival outcomes. METHODS: This retrospective cohort study included patients between December 1, 2011, and October 30, 2020. They received ICIs from 2011-2020 with follow-up of outcomes through October 2021. We identified 3,668 ICI recipients who were seen at Mass General Brigham and Dana-Farber. Of these, 669 developed cirAEs. Records that were incomplete or categories of insufficient sample size were excluded from the study cohort. Multivariate Cox proportional hazards models were utilized to investigate the impact of cancer organ system and histology on cirAE development, after adjusting for demographics, Charlson Comorbidity Index, ICI type, cancer stage at ICI initiation, and year of ICI initiation. Time-varying Cox proportional hazards modeling was utilized to examine the impact of cirAE development on mortality. RESULTS: Compared to other non-epithelial cancers (neuroendocrine, leukemia, lymphoma, myeloma, sarcoma, and central nervous system malignancies), cutaneous squamous cell carcinoma (cSCC) (HR = 3.57, p < 0.001), melanoma (HR = 2.09, p < 0.001), head and neck adenocarcinoma (HR = 2.13, p = 0.009), genitourinary transitional cell carcinoma (HR = 2.15, p < 0.001), and genitourinary adenocarcinoma (HR = 1.53, p = 0.037) were at significantly higher risk of cirAEs in multivariate analyses. The increased risk of cirAEs translated into an adjusted survival benefit for melanoma (HR = 0.37, p < 0.001) and cSCC (HR = 0.51, p = 0.011). CONCLUSIONS: The highest rate of cirAEs and subsequent survival benefits were observed in cutaneous malignancies treated with ICIs. This study improves our understanding of patients who are at highest risk of developing cirAEs and would, therefore, benefit from appropriate counseling and closer monitoring by their oncologists and dermatologists throughout their ICI therapy. Limitations include its retrospective nature and cohort from one geography.

[Identification of breast cancer subtypes based on graph convolutional network].

Identification of molecular subtypes of malignant tumors plays a vital role in individualized diagnosis, personalized treatment, and prognosis prediction of cancer patients. The continuous improvement of comprehensive tumor genomics database and the ongoing breakthroughs in deep learning technology have driven further advancements in computer-aided tumor classification. Although the existing classification methods based on gene expression omnibus database take the complexity of cancer molecular classification into account, they ignore the internal correlation and synergism of genes. To solve this problem, we propose a multi-layer graph convolutional network model for breast cancer subtype classification combined with hierarchical attention network. This model constructs the graph embedding datasets of patients' genes, and develops a new end-to-end multi-classification model, which can effectively recognize molecular subtypes of breast cancer. A large number of test data prove the good performance of this new model in the classification of breast cancer subtypes. Compared to the original graph convolutional neural networks and two mainstream graph neural network classification algorithms, the new model has remarkable advantages. The accuracy, weight-F1-score, weight-recall, and weight-precision of our model in seven-category classification has reached 0.851 7, 0.823 5, 0.851 7 and 0.793 6 respectively. In the four-category classification, the results are 0.928 5, 0.894 9, 0.928 5 and 0.865 0 respectively. In addition, compared with the latest breast cancer subtype classification algorithms, the method proposed in this paper also achieved the highest classification accuracy. In summary, the model proposed in this paper may serve as an auxiliary diagnostic technology, providing a reliable option for precise classification of breast cancer subtypes in the future and laying the theoretical foundation for computer-aided tumor classification.

Development and validation of time-to-event models to predict metastatic recurrence of localized cutaneous melanoma.

BACKGROUND: The recent expansion of immunotherapy for stage IIB/IIC melanoma highlights a growing clinical need to identify patients at high risk of metastatic recurrence and, therefore, most likely to benefit from this therapeutic modality. OBJECTIVE: To develop time-to-event risk prediction models for melanoma metastatic recurrence. METHODS: Patients diagnosed with stage I/II primary cutaneous melanoma between 2000 and 2020 at Mass General Brigham and Dana-Farber Cancer Institute were included. Melanoma recurrence date and type were determined by chart review. Thirty clinicopathologic factors were extracted from electronic health records. Three types of time-to-event machine-learning models were evaluated internally and externally in the distant versus locoregional/nonrecurrence prediction. RESULTS: This study included 954 melanomas (155 distant, 163 locoregional, and 636 1:2 matched nonrecurrences). Distant recurrences were associated with worse survival compared to locoregional/nonrecurrences (HR: 6.21, P < .001) and to locoregional recurrences only (HR: 5.79, P < .001). The Gradient Boosting Survival model achieved the best performance (concordance index: 0.816; time-dependent AUC: 0.842; Brier score: 0.103) in the external validation. LIMITATIONS: Retrospective nature and cohort from one geography. CONCLUSIONS: These results suggest that time-to-event machine-learning models can reliably predict the metastatic recurrence from localized melanoma and help identify high-risk patients who are most likely to benefit from immunotherapy.

SpatialCells: Automated Profiling of Tumor Microenvironments with Spatially Resolved Multiplexed Single-Cell Data.

Background: Cancer is a complex cellular ecosystem where malignant cells coexist and interact with immune, stromal, and other cells within the tumor microenvironment. Recent technological advancements in spatially resolved multiplexed imaging at single-cell resolution have led to the generation of large-scale and high-dimensional datasets from biological specimens. This underscores the necessity for automated methodologies that can effectively characterize the molecular, cellular, and spatial properties of tumor microenvironments for various malignancies. Results: This study introduces SpatialCells, an open-source software package designed for region-based exploratory analysis and comprehensive characterization of tumor microenvironments using multiplexed single-cell data. Conclusions: SpatialCells efficiently streamlines the automated extraction of features from multiplexed single-cell data and can process samples containing millions of cells. Thus, SpatialCells facilitates subsequent association analyses and machine learning predictions, making it an essential tool in advancing our understanding of tumor growth, invasion, and metastasis.

Pre-Existing Inflammatory Disease Predicts Cutaneous Immunotherapy Toxicity Development: A Multi-Institutional Cohort Study.

Background: Relationships between pre-existing inflammatory diseases (pIDs) and cutaneous immune-related adverse events (cirAEs) have not been well-studied. This study is to investigate associations between pIDs and cirAEs among immune-checkpoint inhibitor (ICI) recipients at the Mass General Brigham healthcare system. Methods: Electronic health records were reviewed to ascertain cirAE status. Patients' pID status was determined using International Classification of Diseases (ICD) codes. Cox proportional hazard, logistic regression, and linear regression models were performed. Results: Among 3607 ICI recipients, 1354 had pIDs, and 672 developed cirAEs. After covariate adjustments, patients with cutaneous pIDs (HR:1.56, p<0.001) or both cutaneous and non-cutaneous pIDs (HR:1.76, p<0.001) had increased cirAE risk in contrast to patients with non-cutaneous pIDs alone (HR:1.01, p=0.9). In adjusted ordinal logistic regression modeling, cutaneous pIDs (OR:1.55, p<0.0001) and the presence of both cutaneous pIDs and non-cutaneous pIDs (OR:1.71, p=0.002) were associated with increased cirAE severity. The time to cirAE onset was different between the cutaneous pID group and the non-cutaneous pID group (Mean: 98 vs. 146 days, p=0.021; Beta: -0.11, p=0.033). Conclusions: ICI recipients with cutaneous pIDs should have increased clinical monitoring due to their increased risk of cirAE development, severity, and earlier onset.

A Polygenic Risk Score for Predicting Racial and Genetic Susceptibility to Prurigo Nodularis.

Prurigo nodularis (PN) is an understudied inflammatory skin disease characterized by pruritic, hyperkeratotic nodules. Identifying the genetic factors underlying PN could help to better understand its etiology and guide the development of therapies. In this study, we developed a polygenic risk score that predicts a diagnosis of PN (OR = 1.41, P = 1.6 × 10-5) in two independent and continentally distinct populations. We also performed GWASs, which uncovered genetic variants associated with PN, including one near PLCB4 (rs6039266: OR = 3.15, P = 4.8 × 10-8) and others near TXNRD1 (rs34217906: OR = 1.71, P = 6.4 × 10-7; rs7134193: OR = 1.57, P = 1.1 × 10-6). Finally, we discovered that Black patients have over a two-times greater genetic risk of developing PN (OR = 2.63, P = 7.8 × 10-4). Combining the polygenic risk score and self-reported race together was significantly predictive of PN (OR = 1.32, P = 4.7 × 10-3). Strikingly, this association was more significant with race than after adjusting for genetic ancestry. Because race is a sociocultural construct and not a genetically bound category, our findings suggest that genetics, environmental influence, and social determinants of health likely affect the development of PN and may contribute to clinically observed racial disparities.

Increased risk of cutaneous immune-related adverse events in patients treated with talimogene laherparepvec and immune checkpoint inhibitors: A multi-hospital cohort study.

BACKGROUND: Previous studies have shown that combining immune checkpoint inhibitors (ICIs) with talimogene laherparepvec (TVEC) may improve antitumor responses. However, the risk of developing cutaneous immune-related adverse events (cirAEs) in patients treated with ICI and TVEC has not been studied. OBJECTIVE: To evaluate the differences in cirAE development between patients treated with ICI alone and both ICI and TVEC (ICI + TVEC). METHODS: Patients with cutaneous malignancy receiving ICI with or without TVEC therapy at the Massachusetts General Brigham healthcare system were included. CirAE development, time from ICI initiation to cirAE, cirAE grade, cirAE morphology, and survival were analyzed. Pearson's χ2 test or Fisher's exact test for categorical variables and t test or Kruskal-Wallis test for continuous variables were used. To account for immortal time bias, we performed adjusted time-varying Cox proportional hazards modeling. RESULTS: The rate of cirAE development was 32.3% and 38.7% for ICI only and ICI + TVEC, respectively. After adjusting for covariates, ICI + TVEC was associated with a 2-fold increased risk of cirAE development (hazard ratio: 2.03, P = .006) compared to patients receiving ICI therapy alone. LIMITATIONS: The retrospective nature and limited sample size from a tertiary-level academic center. CONCLUSION: These findings underscore potential opportunities for dermatologists and oncologists in counseling and monitoring patients.

Cutaneous immune-related adverse events are associated with longer overall survival in advanced cancer patients on immune checkpoint inhibitors: A multi-institutional cohort study.

BACKGROUND: Cutaneous immune-related adverse events (cirAEs) occur in up to 40% of immune checkpoint inhibitor (ICI) recipients. However, the association of cirAEs with survival remains unclear. OBJECTIVE: To investigate the association of cirAEs with survival among ICI recipients. METHODS: ICI recipients were identified from the Mass General Brigham healthcare system and Dana-Farber Cancer Institute. Patient charts were reviewed for cirAE development within 2 years after ICI initiation. Multivariate time-varying Cox proportional hazards models, adjusted for age, sex, race/ethnicity, Charlson Comorbidity Index, ICI type, cancer type, and year of ICI initiation were utilized to investigate the impact of cirAE development on overall survival. RESULTS: Of the 3731 ICI recipients, 18.1% developed a cirAE. Six-month landmark analysis and time-varying Cox proportional hazards models demonstrated that patients who developed cirAEs were associated with decreased mortality (hazardratio [HR] = 0.87, P = .027), particularly in patients with melanoma (HR = 0.67, P = .003). Among individual morphologies, lichenoid eruption (HR = 0.51, P < .001), psoriasiform eruption (HR = 0.52, P = .005), vitiligo (HR = 0.29, P = .007), isolated pruritus without visible manifestation of rash (HR = 0.71, P = .007), acneiform eruption (HR = 0.34, P = .025), and non-specific rash (HR = 0.68, P < .001) were significantly associated with better survival after multiple comparisons adjustment. LIMITATIONS: Retrospective design; single geography. CONCLUSION: CirAE development is associated with improved survival among ICI recipients, especially patients with melanoma.

Influence of melanoma type on incidence and downstream implications of cutaneous immune-related adverse events in the setting of immune checkpoint inhibitor therapy.

BACKGROUND: Emerging evidence suggests that cutaneous immune-related adverse events (cirAEs) are associated with a survival benefit in the setting of advanced melanoma treated with immune checkpoint inhibitor (ICI) therapy. Previous studies have not examined the role of melanoma subtypes on cirAE development and downstream therapeutic outcomes. OBJECTIVE: Examine the impact of melanoma subtypes on cirAE onset and survival among ICI recipients. METHODS: Retrospective multi-institutional cohort study. Multivariate time-series regressions were utilized to assess relationships between melanoma subtype, cirAE development, and survival. RESULTS: Among 747 ICI recipients, 236 (31.6%) patients developed a cirAE. Patients with acral melanoma were less likely to develop a cirAE (hazard ratio [HR] = 0.41, P = .016) compared to patients with nonacral cutaneous melanoma. Across all melanoma subtypes, cirAEs were associated with reduced mortality (HR = 0.76, P = .042). Patients with acral (HR = 2.04, P = .005), mucosal (HR = 2.30, P < .001), and uveal (HR = 4.09, P < .001) primaries exhibited the worst survival. LIMITATIONS: Retrospective cohort study. CONCLUSION: This is the first study to demonstrate differences in cirAE development among melanoma subtypes. The presence of cirAEs was associated with better survival. Further, the lower incidence of cirAEs may be a marker of immunotherapy response, which is reflected in the association between acral melanoma and mortality.

Cutaneous immune-related adverse events are associated with longer overall survival in advanced cancer patients on immune checkpoint inhibitors: a multi-institutional cohort study.

Background: Cutaneous immune-related adverse events (cirAEs) occur in up to 40% of immune checkpoint inhibitor (ICI) recipients. However, the association of cirAEs with survival remains unclear. Objective: To investigate the association of cirAEs with survival among ICI recipients. Methods: ICI recipients were identified from the Mass General Brigham healthcare system (MGB) and Dana-Farber Cancer Institute (DFCI). Patient charts were reviewed for cirAE development within 2 years after ICI initiation. Multivariate time-varying Cox proportional hazards models, adjusted for age, sex, race/ethnicity, Charlson Comorbidity Index, ICI type, cancer type, and year of ICI initiation were utilized to investigate the impact of cirAE development on overall survival. Results: Of the 3,731 ICI recipients, 18.1% developed a cirAE. 6-month landmark analysis and time-varying Cox proportional hazards models demonstrated that patients who developed cirAEs were associated with decreased mortality (HR=0.87,p=0.027), particularly in melanoma patients (HR=0.67,p=0.003). Among individual morphologies, lichenoid eruption (HR=0.51,p<0.001), psoriasiform eruption (HR=0.52,p=0.005), vitiligo (HR=0.29,p=0.007), isolated pruritus without visible manifestation of rash (HR=0.71,p=0.007), acneiform eruption (HR =0.34,p=0.025), and non-specific rash (HR=0.68, p<0.001) were significantly associated with better survival after multiple comparisons adjustment. Limitations: Retrospective design; single geography. Conclusion: CirAE development is associated with improved survival among ICI recipients, especially melanoma patients. Capsule Summary: Patients on immune checkpoint inhibitors (ICIs) who developed cutaneous immune-related adverse events (cirAEs) had favorable outcomes. This was especially notable for melanoma patients who had cirAEs, both those with vitiligo and other morphologies.Development of cirAEs in ICI-treated patients can be used to prognosticate survival and guide treatment decisions.