Brentuximab vedotin for skin involvement in refractory diffuse cutaneous systemic sclerosis, an open-label trial.

OBJECTIVE: We explored the efficacy and safety of brentuximab vedotin, a chimeric anti-CD30 antibody drug conjugate, in patients with severe active diffuse cutaneous systemic sclerosis (dcSSc). METHODS: This phase II proof-of-concept, single center, open-label, single arm, investigator-initiated trial included patients ≥18 years, with dcSSc, modified Rodnan skin score (mRSS) ≥15 with <5 years since the first non-Raynaud's symptom and/or skin worsening despite immunosuppression who were treated with intravenous brentuximab vedotin 0.6 mg/Kg q3 weeks for 45 weeks. The primary end point was a decrease in mRSS of ≥ 8 points at 48 weeks. RESULTS: Eleven patients were treated with brentuximab vedotin, with 9 completing the study. The mean mRSS reduction at week 48 was 11.3 (95% CI 6.9, 15.8; p= 0.001), meeting the primary end point in the intention to treat analysis (7/11 had a decrease in mRSS ≥8). The % forced vital capacity increased by 7.8% (12.5). The Composite Response Index in dcSSc (CRISS) suggested a beneficial treatment effect (86% ≥0.6). Most adverse events were mild. No SAEs were attributed to brentuximab vedotin. CONCLUSION: In dcSSc, brentuximab vedotin improved skin and FVC; without safety concerns. A placebo-controlled trial is warranted to corroborate these initial findings.

Ten Years of Pathology on Twitter (X): Landscape and Evolution of Pathology on Twitter From 2012 to 2023.

CONTEXT.­: Social media is a powerful tool in pathology education and professional networking that connects pathologists and pathology trainees from around the world. Twitter (X) appears to be the most popular social media platform pathologists use to share pathology-related content and connect with other pathologists. Although there has been some published research on pathology-related activity on Twitter during short time frames, to date there has not been published research examining pathology-related Twitter activity in totality from its earliest days of activity to recently. OBJECTIVE.­: To comprehensively evaluate the use of pathology on Twitter (X) during the last 10 years. DESIGN.­: Pathology-related tweets were systematically scraped from Twitter from January 2012 to January 2023 using pathology hashtags as a surrogate measure for all pathology content on Twitter. COVID-related tweets were approximated by tweets containing the term "COVID." RESULTS.­: There were 591 812 unique pathology-related tweets identified during the time period, with #pathology being the most common hashtag used and #PathTwitter becoming more popular since 2020. There has been positive annual growth of pathology Twitter, with peaks in use during major pathology conferences. During the initial phases of the COVID-19 pandemic a sustained increase in pathology tweets was observed. CONCLUSIONS.­: Pathology Twitter has grown during the last 10 years and has become increasingly popular for pathology education and networking. With the changing landscape of social media platforms this study provides an understanding of how pathology medical education and professional networking uses of social media are used and evolve over time.

SMARCA4-Deficient Undifferentiated Tumor of the Esophagus: Diagnostic Pitfalls in Immunohistochemical Profiles.

SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) are a newly described entity and are typically seen in the thoracic cavity. However, these tumors have been described in other body sites, including the esophagus. These tumors are rare, aggressive neoplasms, characterized by the loss of protein product of SMARCA4 (Brahma-related gene-1) and the preservation of INI1 (SMARCB1) expression. Here, we present two tumors of SMARCA4-UT of the esophagus with its microscopic appearance and immunohistochemical profile. We also include a literature review of SMARCA4-deficient tumors of the tubular gastrointestinal tract with their immunohistochemical and mismatch repair profiles for each specimen. Due to its non-specific histologic appearance and variable staining in expanded immunohistochemical panels, this tumor frequently overlaps with other tumor types, making the diagnosis of SMARCA4-UT challenging. These tumors are often associated with intestinal metaplasia of the esophagus and are thought to represent a high-grade undifferentiated transformation of a conventional esophageal adenocarcinoma. These tumors are typically associated with poor clinical outcomes and have poor response to conventional therapies. Currently, there are no standard guidelines for treatment of these tumors; however, palliative radiotherapy and systemic chemotherapy may provide benefit. More recently, immunotherapy and novel therapeutic targets have shown some promise for these patients.

The genomic and evolutionary landscapes of anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.

Assessment of Pathology Domain-Specific Knowledge of ChatGPT and Comparison to Human Performance.

CONTEXT.­: Artificial intelligence algorithms hold the potential to fundamentally change many aspects of society. Application of these tools, including the publicly available ChatGPT, has demonstrated impressive domain-specific knowledge in many areas, including medicine. OBJECTIVES.­: To understand the level of pathology domain-specific knowledge for ChatGPT using different underlying large language models, GPT-3.5 and the updated GPT-4. DESIGN.­: An international group of pathologists (n = 15) was recruited to generate pathology-specific questions at a similar level to those that could be seen on licensing (board) examinations. The questions (n = 15) were answered by GPT-3.5, GPT-4, and a staff pathologist that recently passed their Canadian pathology licensing exams. Participants were instructed to score answers on a 5-point scale and to predict which answer was written by ChatGPT. RESULTS.­: GPT-3.5 performed at a similar level to the staff pathologist, while GPT-4 outperformed both. The overall score for both GPT-3.5 and GPT-4 was within the range of meeting expectations for a trainee writing licensing examinations. In all but one question, the reviewers were able to correctly identify the answers generated by GPT-3.5. CONCLUSIONS.­: By demonstrating the ability of ChatGPT to answer pathology-specific questions at a level similar to (GPT-3.5) or exceeding (GPT-4) a trained pathologist, this study highlights the potential of large language models to be transformative in this space. In the future, more advanced iterations of these algorithms with increased domain-specific knowledge may have the potential to assist pathologists and enhance pathology resident training.

HPV-negative head and neck cancers with adverse pathological features carry specific molecular changes that are associated with survival.

BACKGROUND: Adverse pathological features following surgery in head and neck squamous cell carcinoma (HNSCC) are strongly associated with survival and guide adjuvant therapy. We investigated molecular changes associated with these features. METHODS: We downloaded data from the Cancer Genome Atlas and Cancer Proteome Atlas HNSCC cohorts. We compared tumors positive versus negative for perineural invasion (PNI), lymphovascular invasion (LVI), extracapsular spread (ECS), and positive margins (PSM), with multivariable analysis. RESULTS: All pathological features were associated with poor survival, as were the following molecular changes: low cyclin E1 (HR = 1.7) and high PKC-alpha (HR = 1.8) in tumors with PNI; six of 13 protein abundance changes with LVI; greater tumor hypoxia and high Raptor (HR = 2.0) and Rictor (HR = 1.6) with ECS; and low p38 (HR = 2.3), high fibronectin (HR = 1.6), low annexin A1 (HR = 3.1), and high caspase-9 (HR = 1.6) abundances with PSM. CONCLUSIONS: Pathological features in HNSCC carry specific molecular changes that may explain their poor prognostic associations.

Evolving educational landscape in pathology: a comprehensive bibliometric and visual analysis including digital teaching and learning resources.

AIMS: Pathology education is a core component of medical training, and its literature is critical for refining educational modalities. We performed a cross-sectional bibliometric analysis to explore publications on pathology education, focusing on new medical education technologies. METHODS: The analysis identified 64 pathology journals and 53 keywords. Relevant articles were collected using a web application, PaperScraper, developed to accelerate literature search. Citation data were collected from multiple sources. Descriptive statistics, with time period analysis, were performed using Microsoft Excel and visualised with Flourish Studio. Two article groups were further investigated with a bibliometric software, VOSViewer, to establish co-authorship and keyword relationships. RESULTS: 8946 citations were retrieved from 905 selected articles. Most articles were published in the last decade (447, 49.4%). The top journals were Archives of Pathology & Laboratory Medicine (184), Human Pathology (122) and the American Journal of Clinical Pathology (117). The highest number of citations was found for Human Pathology (2120), followed by Archives of Pathology & Laboratory Medicine (2098) and American Journal of Clinical Pathology (1142). Authors with different backgrounds had the greatest number of articles and citations. 12 co-authorship, 3 keyword and 8 co-citation clusters were found for the social media/online resources group, 8 co-authorship, 4 keyword and 7 co-citation clusters for the digital pathology/virtual microscopy/mobile technologies group. CONCLUSIONS: The analysis revealed a significant increase in publications over time. The emergence of digital teaching and learning resources played a major role in this growth. Overall, these findings underscore the transformative potential of technology in pathology education.

Clinical Presentation and Genomic Analysis of HPV-Related Squamous Cell Carcinoma of the Larynx in Two Young Female Patients.

Laryngeal cancer most frequently develops in males aged 60-70 years with a history of tobacco and/or alcohol use, while fewer cases occur in young patients in which tobacco and alcohol are often absent or less significant, highlighting the importance of other etiologies. We present cases of human papillomavirus (HPV)-associated laryngeal cancer in two previously healthy young women. A retrospective case review was carried out for both patients. DNA was extracted from the primary tumors and matched to normal tissue or blood, HPV genotype was determined by PCR and whole exome sequencing was carried out. Genomic results were pooled with laryngeal cancer patients from the cancer genome atlas (TCGA) dataset. The first patient was an 18-year-old female who underwent laryngectomy followed by adjuvant radiation. The second was a 24-year-old female who received chemoradiation. The first patient has remained disease-free for 16 years and the second for two years; both continue to be monitored. One tumor was positive for HPV45 and had mutations in FAT1 and FAT2; the other was positive for HPV31 and had mutations at NOTCH1, MAPK1, and HIST1H2AK. Both tumors had wild-type TP53 alleles. We bring attention to HPV as an etiology of laryngeal carcinoma in young patients, which may have implications for the treatment and prognosis of similar patients.

Double Duty: Complete Pathologic Response of Two Colonic Primaries with Mosaicism of a Novel MLH1 Mutation to Neoadjuvant Pembrolizumab.

We present a fascinating case of a 57-year-old male with a novel mutation in MLH1 (MLH1:c.1288G > T, p.(Glu430*)), who presented with two synchronous colonic tumours, initially deemed unresectable, and experienced a complete pathological response on neoadjuvant pembrolizumab. Extensive genetic testing revealed post-zygotic mosaicism from the novel mutation.

Loss of LRP1B expression drives acquired chemo and radio-resistance in HPV-positive head and neck cancer.

OBJECTIVES: Although human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) patients typically experience excellent survival, 15-20 % of patients recur after treatment with chemotherapy and radiation. Therefore, there is a need for biomarkers of treatment failure to guide treatment intensity. MATERIALS AND METHODS: Whole genome sequencing was carried out on HPV+OPSCC patients who were primarily treated with concurrent chemotherapy (cisplatin) and radiation. We then explored whether the loss of LRP1Bwas sufficient to drive an aggressive phenotype, and promote a resistance to cisplatin and radiation therapy both in vitro using HPV+ cell lines (93VU147T, UMSCC47, UWO37 and UWO23) and in vivo. RESULTS: Through integrative genomic analysis of three HPV+OPSCC tumour datasets, we identified that deletion of LRP1B was enriched in samples that recurred following chemo-radiation. Knockdown using siRNA in four HPV+ cell lines (UWO23, UWO37, UMSCC47 and 93VU147T) resulted in increased proliferation of all cases. CRISPR/Cas9 deletion of LRP1B in the same cell line panel demonstrated increased proliferation, clonogenic growth and migration, as well as resistance to both cisplatin and radiation in LRP1B deleted cells compared to their respective non-targeting control cells. Cell line derived xenograft studies indicated that the LRP1B knockout tumours were more resistant to cisplatin and radiation therapy compared to their controls invivo. CONCLUSION: Taken together, our work implicates LRP1B deletion as a potential biomarker for identifying treatment resistant HPV+ OPSCC cases.

The protective role of postoperative radiation therapy in low and intermediate grade major salivary gland malignancies: A study of the Canadian Head and Neck Collaborative Research Initiative.

BACKGROUND: The objective of this study was to examine the utility of postoperative radiation for low and intermediate grade cancers of the parotid and submandibular glands. METHODS: The authors conducted a retrospective, Canadian-led, international, multi-institutional analysis of a patient cohort with low or intermediate grade salivary gland cancer of the parotid or submandibular gland who were treated from 2010 until 2020 with or without postoperative radiation therapy. A multivariable, marginal Cox proportional hazards regression analysis was performed to quantify the association between locoregional recurrence (LRR) and receipt of postoperative radiation therapy while accounting for patient-level factors and the clustering of patients by institution. RESULTS: In total, 621 patients across 14 tertiary care centers were included in the study; of these, 309 patients (49.8%) received postoperative radiation therapy. Tumor histologies included 182 (29.3%) acinic cell carcinomas, 312 (50.2%) mucoepidermoid carcinomas, and 137 (20.5%) other low or intermediate grade primary salivary gland carcinomas. Kaplan-Meier LRR-free survival at 10 years was 89.0% (95% confidence interval [CI], 84.9%-93.3%). In multivariable Cox regression analysis, postoperative radiation therapy was independently associated with a lower hazard of LRR (adjusted hazard ratio, 0.53; 95% CI, 0.29-0.97). The multivariable model estimated that the marginal probability of LRR within 10 years was 15.4% without radiation and 8.8% with radiation. The number needed to treat was 16 patients (95% CI, 14-18 patients). Radiation therapy had no benefit in patients who had early stage, low-grade salivary gland cancer without evidence of nodal disease and negative margins. CONCLUSIONS: Postoperative radiation therapy may reduce LLR in some low and intermediate grade salivary gland cancers with adverse features, but it had no benefit in patients who had early stage, low-grade salivary gland cancer with negative margins.

Molecular profiling of solid tumors by next-generation sequencing: an experience from a clinical laboratory.

Background: Personalized targeted therapies have transformed management of several solid tumors. Timely and accurate detection of clinically relevant genetic variants in tumor is central to the implementation of molecular targeted therapies. To facilitate precise molecular testing in solid tumors, targeted next-generation sequencing (NGS) assays have emerged as a valuable tool. In this study, we provide an overview of the technical validation, diagnostic yields, and spectrum of variants observed in 3,164 solid tumor samples that were tested as part of the standard clinical diagnostic assessment in an academic healthcare institution over a period of 2 years. Methods: The Ion Ampliseq™ Cancer Hotspot Panel v2 assay (ThermoFisher) that targets ~2,800 COSMIC mutations from 50 oncogenes and tumor suppressor genes was validated, and a total of 3,164 tumor DNA samples were tested in 2 years. A total of 500 tumor samples were tested by the comprehensive panel containing all the 50 genes. Other samples, including 1,375 lung cancer, 692 colon cancer, 462 melanoma, and 135 brain cancer, were tested by tumor-specific targeted subpanels including a few clinically actionable genes. Results: Of 3,164 patient samples, 2,016 (63.7%) tested positive for at least one clinically relevant variant. Of 500 samples tested by a comprehensive panel, 290 had a clinically relevant variant with TP53, KRAS, and PIK3CA being the most frequently mutated genes. The diagnostic yields in major tumor types were as follows: breast (58.4%), colorectal (77.6%), lung (60.4%), pancreatic (84.6%), endometrial (72.4%), ovary (57.1%), and thyroid (73.9%). Tumor-specific targeted subpanels also demonstrated high diagnostic yields: lung (69%), colon (61.2%), melanoma (69.7%), and brain (20.7%). Co-occurrence of mutations in more than one gene was frequently observed. Conclusions: The findings of our study demonstrate the feasibility of integrating an NGS-based gene panel screen as part of a standard diagnostic protocol for solid tumor assessment. High diagnostic rates enable significant clinical impact including improved diagnosis, prognosis, and clinical management in patients with solid tumors.

Stereotactic ablative radiotherapy before resection to avoid delay for early-stage lung cancer or oligometastases during the COVID-19 pandemic: Pathologic outcomes from the SABR-BRIDGE protocol.

BACKGROUND: During coronavirus disease 2019 (COVID-19)-related operating room closures, some multidisciplinary thoracic oncology teams adopted a paradigm of stereotactic ablative radiotherapy (SABR) as a bridge to surgery, an approach called SABR-BRIDGE. This study presents the preliminary surgical and pathological results. METHODS: Eligible participants from four institutions (three in Canada and one in the United States) had early-stage presumed or biopsy-proven lung malignancy that would normally be surgically resected. SABR was delivered using standard institutional guidelines, with surgery >3 months following SABR with standardized pathologic assessment. Pathological complete response (pCR) was defined as absence of viable cancer. Major pathologic response (MPR) was defined as ≤10% viable tissue. RESULTS: Seventy-two patients underwent SABR. Most common SABR regimens were 34 Gy/1 (29%, n = 21), 48 Gy/3-4 (26%, n = 19), and 50/55 Gy/5 (22%, n = 16). SABR was well-tolerated, with one grade 5 toxicity (death 10 days after SABR with COVID-19) and five grade 2-3 toxicities. Following SABR, 26 patients underwent resection thus far (13 pending surgery). Median time-to-surgery was 4.5 months post-SABR (range, 2-17.5 months). Surgery was reported as being more difficult because of SABR in 38% (n = 10) of cases. Thirteen patients (50%) had pCR and 19 (73%) had MPR. Rates of pCR trended higher in patients operated on at earlier time points (75% if within 3 months, 50% if 3-6 months, and 33% if ≥6 months; p = .069). In the exploratory best-case scenario analysis, pCR rate does not exceed 82%. CONCLUSIONS: The SABR-BRIDGE approach allowed for delivery of treatment during a period of operating room closure and was well-tolerated. Even in the best-case scenario, pCR rate does not exceed 82%.

Using deep learning to predict tumor mutational burden from scans of H&E-stained multicenter slides of lung squamous cell carcinoma.

Purpose: A high tumor mutational burden (TMB) is a promising biomarker for identifying lung squamous cell carcinoma (SqCC) patients who are more likely to benefit from risky but potentially highly beneficial immunotherapy, but it is not available in most clinics. It has been shown that it is possible to predict TMB from standard-of-care cancer histology slides using deep learning for various cancer sites. Our goal is to build a model that can do this specifically for lung SqCC and to validate it on a held-out test set from centers on which the model was not trained. Approach: We obtained scans of diagnostic slides from 50 lung SqCC patients, with one slide per-patient, from 35 different centers. We held out 20 slides from 15 centers for testing and used the rest for training and validation, ensuring that no center was represented in more than one set. Using transfer learning, we explored several neural network architectures and training parameters to choose an optimal model. Results: Using the training and validation sets, we found the optimal model to be VGG16. The per-patient AUC for this model on the held-out test set was 0.65, with an accuracy of 65%, true positive rate of 77%, and true negative rate of 43%. Conclusions: A deep learning model can predict TMB from scans of H&E-stained slides of lung SqCC resections on an independent test set containing images only from centers on which the model was not trained. With further development and external validation, such a system can act as an alternative to traditional genetic sequencing for patients with SqCC; this will help physicians determine, with more accuracy, whether patients should be given immunotherapy. This will more effectively give access to immunotherapy drugs to those who need them and help spare others the toxicities associated with them.

Digital Quantification of Tumor Cellularity as a Novel Prognostic Feature of Non-Small Cell Lung Carcinoma.

Non-small cell lung carcinoma is currently staged based on the size and involvement of other structures. Tumor size may be a surrogate measure of the total number of tumor cells. A recently revised reporting system for adenocarcinoma incorporates high-risk histologic patterns, which may have increased cellular density. Modern digital image analysis tools can be utilized to automate the quantification of cells. In this study, we tested the hypothesis that tumor cellularity can be used as a novel prognostic tool for lung cancer. Digital slides from The Cancer Genome Atlas lung adenocarcinoma (ADC) data set (n = 213) and lung squamous cell carcinoma (SCC) data set (n = 90) were obtained and analyzed using QuPath. The number of tumor cells was normalized with the surface area of the tumor to provide a measure of tumor cell density. Tumor cellularity was calculated by multiplying the size of the tumor with the cell density. Major histologic patterns and grade were compared with the tumor density of the lung ADC and lung SCC cases. The overall and progression-free survival were compared between groups of high and low tumor cellularity. High-grade histologic patterns in the ADC and SCC cases were associated with greater tumor densities compared with low-grade patterns. Cases with lower tumor cellularity had improved overall and progression-free survival compared with cases with higher cellularity. These results support tumor cellularity as a novel prognostic tool for non-small cell lung carcinoma that considers tumor stage and grade elements.

Tumor-Infiltrating T Cells in EBV-Associated Gastric Carcinomas Exhibit High Levels of Multiple Markers of Activation, Effector Gene Expression, and Exhaustion.

Epstein-Barr virus (EBV) is a gamma-herpesvirus associated with 10% of all gastric cancers (GCs) and 1.5% of all human cancers. EBV-associated GCs (EBVaGCs) are pathologically and clinically distinct entities from EBV-negative GCs (EBVnGCs), with EBVaGCs exhibiting differential molecular pathology, treatment response, and patient prognosis. However, the tumor immune landscape of EBVaGC has not been well explored. In this study, a systemic and comprehensive analysis of gene expression and immune landscape features was performed for both EBVaGC and EBVnGC. EBVaGCs exhibited many aspects of a T cell-inflamed phenotype, with greater T and NK cell infiltration, increased expression of immune checkpoint markers (BTLA, CD96, CTLA4, LAG3, PD1, TIGIT, and TIM3), and multiple T cell effector molecules in comparison with EBVnGCs. EBVaGCs also displayed a higher expression of anti-tumor immunity factors (PDL1, CD155, CEACAM1, galectin-9, and IDO1). Six EBV-encoded miRNAs (miR-BARTs 8-3p, 9-5p, 10-3p, 22, 5-5p, and 14-3p) were strongly negatively correlated with the expression of immune checkpoint receptors and multiple markers of anti-tumor immunity. These profound differences in the tumor immune landscape between EBVaGCs and EBVnGCs may help explain some of the observed differences in pathological and clinical outcomes, with an EBV-positive status possibly being a potential biomarker for the application of immunotherapy in GC.

Sclerosing Pneumocytoma With Pulmonary Sarcoidosis: A Case Report.

Pulmonary sclerosing pneumocytoma, formally named pulmonary sclerosing hemangioma, is a rare benign tumor with malignant potential often identified as solid pulmonary nodules. Sarcoidosis is an inflammatory, multisystemic disease of unknown cause with a wide range of clinical manifestations. The disorder is characterized by the formation of noncaseating granulomas in virtually any organ in the body. We present a case of a patient presenting with fever, weight loss, and respiratory symptoms found to have both a sclerosing pneumocytoma and pulmonary sarcoidosis. A diagnosis was made following the lobectomy. The patient was followed for two years with stable lymphadenopathy while remaining asymptomatic.

Immune-based classification of HPV-associated oropharyngeal cancer with implications for biomarker-driven treatment de-intensification.

BACKGROUND: There is significant interest in treatment de-escalation for human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) patients given the generally favourable prognosis. However, 15-30% of patients recur after primary treatment, reflecting a need for improved risk-stratification tools. We sought to develop a molecular test to risk stratify HPV+ OPSCC patients. METHODS: We created an immune score (UWO3) associated with survival outcomes in six independent cohorts comprising 906 patients, including blinded retrospective and prospective external validations. Two aggressive radiation de-escalation cohorts were used to assess the ability of UWO3 to identify patients who recur. Multivariate Cox models were used to assess the associations between the UWO3 immune class and outcomes. FINDINGS: A three-gene immune score classified patients into three immune classes (immune rich, mixed, or immune desert) and was strongly associated with disease-free survival in six datasets, including large retrospective and prospective datasets. Pooled analysis demonstrated that the immune rich group had superior disease-free survival compared to the immune desert (HR = 9.0, 95% CI: 3.2-25.5, P = 3.6 × 10-5) and mixed (HR = 6.4, 95% CI: 2.2-18.7, P = 0.006) groups after adjusting for age, sex, smoking status, and AJCC8 clinical stage. Finally, UWO3 was able to identify patients from two small treatment de-escalation cohorts who remain disease-free after aggressive de-escalation to 30 Gy radiation. INTERPRETATION: With additional prospective validation, the UWO3 score could enable biomarker-driven clinical decision-making for patients with HPV+ OPSCC based on robust outcome prediction across six independent cohorts. Prospective de-escalation and intensification clinical trials are currently being planned. FUNDING: CIHR, European Union, and the NIH.

The spatial transcriptomic landscape of non-small cell lung cancer brain metastasis.

Brain metastases (BrMs) are a common occurrence in lung cancer with a dismal outcome. To understand the mechanism of metastasis to inform prognosis and treatment, here we analyze primary and metastasized tumor specimens from 44 non-small cell lung cancer patients by spatial RNA sequencing, affording a whole transcriptome map of metastasis resolved with morphological markers for the tumor core, tumor immune microenvironment (TIME), and tumor brain microenvironment (TBME). Our data indicate that the tumor microenvironment (TME) in the brain, including the TIME and TBME, undergoes extensive remodeling to create an immunosuppressive and fibrogenic niche for the BrMs. Specifically, the brain TME is characterized with reduced antigen presentation and B/T cell function, increased neutrophils and M2-type macrophages, immature microglia, and reactive astrocytes. Differential gene expression and network analysis identify fibrosis and immune regulation as the major functional modules disrupted in both the lung and brain TME. Besides providing systems-level insights into the mechanism of lung cancer brain metastasis, our study uncovers potential prognostic biomarkers and suggests that therapeutic strategies should be tailored to the immune and fibrosis status of the BrMs.

A Case of Li-Fraumeni Associated Thymoma.

Thymomas are among the most common cancers of the anterior mediastinum. They rarely occur in patients with Li-Fraumeni syndrome (LFS), a hereditary syndrome that predisposes individuals to cancer and is characterized by mutations in the tumor suppressor encoding gene TP53. Here we describe a case of primary thymoma in a woman diagnosed with LFS. We cover the initial presentation and diagnosis, radiological findings, histopathological examination, and management of thymoma. In addition, we review p53 physiology and LFS pathophysiology to explore how TP53 expression might differ between the majority of thymomas and in thymomas associated with LFS. This altered pathophysiology may affect management and prognosis due to emerging evidence of increased resistance to conventional treatment, which suggests a need for close monitoring and consideration of novel treatment strategies such as programmed death-ligand 1 (PD-L1) inhibitors.