Spatial Architecture of Myeloid and T Cells Orchestrates Immune Evasion and Clinical Outcome in Lung Cancer.

Understanding the role of the tumour microenvironment (TME) in lung cancer is critical to improving patient outcome. We identified four histology-independent archetype TMEs in treatment-naive early-stage lung cancer using imaging mass cytometry in the TRACERx study (n=81 patients/198 samples/2.3million cells). In immune-hot adenocarcinomas, spatial niches of T cells and macrophages increased with clonal neoantigen burden, whereas such an increase was observed for niches of plasma and B cells in immune-excluded squamous cell carcinomas (LUSC). Immune-low TMEs were associated with fibroblast barriers to immune infiltration. The fourth archetype, characterised by sparse lymphocytes and high tumour-associated neutrophil (TAN) infiltration, had tumour cells spatially separated from vasculature and exhibited low spatial intratumour heterogeneity. TAN-High LUSC had frequent PIK3CA mutations. TAN-High tumours harboured recently expanded and metastasis-seeding subclones and had a shorter disease-free survival independent of stage. These findings delineate genomic, immune and physical barriers to immune surveillance and implicate neutrophil-rich TMEs in metastasis.

Guide to tinted sunscreens in skin of color.

Disorders of hyperpigmentation, such as melasma and post-inflammatory hyperpigmentation, disproportionately affect skin of color and have a profound impact on quality of life. Exposure to ultraviolet light (UVL) is a well-documented factor in these disorders. However, recent studies show that visible light (VL) is a significant and underrecognized contributor to hyperpigmentation, especially in skin of color. Our objective is to review the role of VL in disorders of hyperpigmentation and that of tinted sunscreens in protecting against VL. Tinted sunscreens containing iron oxides should be recommended over nontinted sunscreens for patients prone to disorders of hyperpigmentation, as iron oxides protect against VL in addition to UVL. Tinted sunscreens are more effective than nontinted sunscreens in preventing melasma relapses and reducing hyperpigmentation, and they may also enhance the depigmenting efficacy of topical hydroquinone. In the search for an ideal tinted sunscreen for a particular patient, several factors must be considered, including a broad spectrum with adequate coverage of both UVL and VL, tint, formulation texture, active ingredients, and cost. VL is increasingly recognized as a major contributor of hyperpigmentation, and adequate treatment for disorders of hyperpigmentation should include protection against VL. Tinted sunscreens are ideal but require consideration of cosmesis, efficacy, and affordability.

Dermoscopic features associated with 3-GEP PLA: LINC00518, PRAME, and TERT expression in suspicious pigmented lesions.

Utilization of dermoscopy and novel molecular triage technologies augments visual triage of pigmented skin lesions, promoting early detection of melanoma. One emerging in vivo genomic test, 3-GEP pigmented lesion assay (3-GEP PLA) aids in pigmented lesion triage by noninvasively detecting the presence of three genes associated with melanoma: LINC00518, PRAME, and TERT. The purpose of our retrospective case-control study was to identify dermoscopic features uniquely associated with the presence of LINC00518, PRAME, or TERT in the stratum corneum as determined by 3-GEP PLA testing. Images of suspicious pigmented lesions that had undergone 3-GEP PLA testing and received a definitive positive or negative result (n = 393) were evaluated for the presence of specific clinical and dermoscopic features associated with melanoma. We found that asymmetry of color was a significant predictor for PRAME expression (Odds Ratio (OR) 5.5, 95% Confidence Interval (CI) 1.6-34.5, p = 0.004), blue color and negative pigment network were significant predictors for LINC00518 expression (adjusted OR 2.7, 95% CI 1.2-5.5, p = 0.014 and adjusted OR 5.4, 95% CI 1.6-16.9, p = 0.010, respectively), and atypical polymorphous vessels present in a pigmented skin lesion were a significant predictor for TERT promoter mutations (OR 5.8, 95% CI 1.3-23.4, p = 0.022). The results presented suggest a hierarchy in the significance of these dermoscopic features and may help guide evaluation and management of pigmented skin lesions.

Evolutionary characterization of lung adenocarcinoma morphology in TRACERx.

Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly high-grade pattern tumors exhibited higher proliferation and lower clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade tumors, while purely undifferentiated solid-pattern tumors had a higher frequency of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumors tend to evolve toward higher-grade patterns. The presence of micropapillary pattern and 'tumor spread through air spaces' were associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform patterns, necrosis and preoperative circulating tumor DNA detection, which were associated with extra-thoracic recurrence. These data provide insights into the relationship between LUAD morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk.

The evolution of lung cancer and impact of subclonal selection in TRACERx.

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.

Lung adenocarcinoma promotion by air pollutants.

A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 µm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1ß. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for  PM2.5 air pollutants  and provide impetus for public health policy initiatives to address air pollution to reduce disease burden.

The role of mobile teledermoscopy in skin cancer triage and management during the COVID-19 pandemic.

The unprecedented onset of the COVID-19 crisis poses a significant challenge to all fields of medicine, including dermatology. Since the start of the coronavirus outbreak, a stark decline in new skin cancer diagnoses has been reported by countries worldwide. One of the greatest challenges during the pandemic has been the reduced access to face-to-face dermatologic evaluation and non-urgent procedures, such as biopsies or surgical excisions. Teledermatology is a well-integrated alternative when face-to-face dermatological assistance is not available. Teledermoscopy, an extension of teledermatology, comprises consulting dermoscopic images to improve the remote assessment of pigmented and non-pigmented lesions when direct visualisation of lesions is difficult. One of teledermoscopy's greatest strengths may be its utility as a triage and monitoring tool, which is critical in the early detection of skin cancer, as it can reduce the number of unnecessary referrals, wait times, and the cost of providing and receiving dermatological care. Mobile teledermoscopy may act as a communication tool between medical practitioners and patients. By using their smartphone (mobile phone) patients can monitor a suspicious skin lesion identified by their medical practitioner, or alternatively self-detect concerning lesions and forward valuable dermoscopic images for remote medical evaluation. Several mobile applications that allow users to photograph suspicious lesions with their smartphones and have them evaluated using artificial intelligence technology have recently emerged. With the growing popularity of mobile apps and consumer-involved healthcare, this will likely be a key component of skin cancer screening in the years to come. However, most of these applications apply artificial intelligence technology to assess clinical images rather than dermoscopic images, which may lead to lower diagnostic accuracy. Incorporating the direct-to-consumer mobile dermoscopy model in combination with mole-scanning artificial intelligence as a mobile app may be the future of skin cancer detection.

Clinical Utility of Dermoscopy and 31-Gene Expression Profiling by Dermatology Providers in Melanoma Management Care.

OBJECTIVE: A 31-gene expression profile (31-GEP) test that predicts metastatic risk in patients with cutaneous malignant melanoma (CMM) has previously been validated and is available for clinical use. The test dichotomizes patients into lower risk and higher risk groups based on differences that correspond to unique genetic expression patterns. Although the impact of such a test on dermatology providers' clinical decision-making has been studied, little is known about whether there exists an association between certain clinical features, such as dermoscopy, and 31-GEP results. METHODS: In this retrospective analysis of 31-GEP test results ordered by dermatologists, we evaluated the frequency of dermoscopic features, using a modified dermoscopy three-point checklist, in 17 cases (n=17) and compared these findings to other key clinicopathologic features including tumor thickness, ulceration, and mitotic rate to 31-GEP results. Additionally, we evaluated the dermatologist's perspective and incorporation of GEP testing as part of patient discussion on melanoma management. RESULTS: 31-GEP stratified patients into 4 groups; groups 1A and 1B are considered low risk of metastasis or recurrence, while 2A and 2B are considered high risk. Of the 17 cases, we had fifteen group 1A (88.23%), one 1B (5.88%), and one 2B (5.88%) result. Overall frequency of dermoscopic features is as follows; 100% of lesions presented with asymmetry, 47% with round structures, and 70.6% with blue-white color. The average time providers spent explaining and ordering the test was 15 minutes, with a range of 10 to 20 minutes. CONCLUSIONS: This study represents our experience and understanding of the dermatologist’s role ordering 31-GEP in the care pathway of melanoma patients and we recommend that dermatology providers consider ordering the test for newly diagnosed CMM patients. J Drugs Dermatol. 2022;21(12): doi:10.36849/JDD.6889.

Potential Limitations in the Clinical Adoption of 3-GEP Pigmented Lesion Assay for Melanoma Triage by Dermatologists and Advanced Practice Practitioners.

Background A pigmented lesion assay (PLA) is used to non-invasively detect the presence of three genes associated with melanoma (LINC00518, PRAME, and TERT) using adhesive patch testing and has the potential to reduce unnecessary biopsies. However, few studies have evaluated the clinical applicability of PLA testing and its potential limitations in real-world practice. We aim to identify possible barriers that inhibit the clinical utility of PLA testing by dermatologists. Methods Retrospective case-control study analyzing the PLA testing by two pigmented-lesion specialists that underwent PLA testing as part of clinical management. Data was collected from April 2021 to April 2022 from an academic tertiary-level center. Results The total cohort consists of 472 lesions. Genetic analysis failure for LINC00518 and PRAME occurred in 12.5% of cases and in 70.9% of cases for TERT. In 38.5% of cases, PLA results were discrepant with histopathology. The additional time associated with PLA use independent from the patient's visit was 15 min on average. Conclusion The high proportion of non-actionable results and discrepant cases highlights potential barriers to the widespread adoption of PLA testing. The high proportion of genetic analysis failure seen for TERT and limited influence on the proposed risk suggests TERT does not offer significant clinical value.

Long-Term Intensive Care Unit (ICU) Stays Can Lead to Long-Term Cognitive Impairment (LTCI): Neurosurgery Nursing Strategies to Minimize Risk.

Long-term cognitive impairment (LTCI) is a phenomenon predominantly seen in patients within intensive care units (ICU) that causes chronic dysfunction, defined as new or worsening deficits in memory, attention, mental processing speed, executive function, intellectual function, and visual-spatial abilities for over 12 months, inhibiting the necessary return to baseline function without appropriate intervention. Our objective is to provide a guideline of nursing strategies to reduce LTCI through different studies that evaluate pharmacological and non-pharmacological methods. Current literature demonstrates that pharmacotherapy focused on neuronal protection as well as robust physical therapy regimens and regulated sleep schedules show promise in strengthening cognitive function and reducing LTCI. Future studies regarding LTCI should focus on the efficacy of specific pharmacological regimens, large-scale assessments of the implementation of physical therapy to reduce LTCI, as well as, specific interventions to reduce the incidence of delirium in the ICU.