Sun protection changes among diverse elementary schoolchildren participating in a sun safety intervention: A latent transition analysis of a randomized controlled trial.

Children are a priority population for skin cancer prevention as excessive sun exposure in childhood increases the risk of melanoma in adulthood. The complexity of sun protective behaviors has posed measurement challenges for trials testing intervention efficacy. The current study evaluated a sun safety intervention for schoolchildren using latent transition analysis (LTA) to examine patterns of sun protection behaviors over time. A three-armed randomized controlled trial was conducted between 2012 and 2016 with two intervention groups (N = 3368) and an observation-only control group (N = 342) among 4th and 5th graders from 24 public schools in Los Angeles County. Both interventions conditions were grouped and compared to controls. Five self-reported sun protective behaviors were measured at baseline and three-month follow-up: use of sunscreen, long sleeves, long pants, hats, and shade seeking. Participants comprised 3710 schoolchildren, mean age 9 years, 47% female and 69% Latino. At baseline, four patterns of sun protection behaviors were found: children who engaged in 1) all sun protective behaviors; 2) few protective behaviors; 3) protective clothing and shade only; and 4) hats only. Children in the control group were likely to remain in their baseline status or transition to a less protective status at three-month follow-up. By contrast, 30% of children in the intervention group transitioned to a more protective status at follow-up. In this RCT of a sun safety intervention, children in the intervention transitioned to more protective behaviors compared to controls. Using LTA enriches understanding of intervention efficacy by modeling the complexity of sun protection behaviors over time. TRIAL REGISTRATION: School-based Randomized Trial of SunSmart Interventions, ClinicalTrials.gov Identifier: NCT04176237 https://clinicaltrials.gov/ct2/show/NCT04176237?cond=School-based+Randomized+Trial+of+SunSmart+Interventions&draw=2&rank=1.

Predictors of mucosal melanoma survival in a population-based setting.

BACKGROUND: Mucosal melanomas are rare and aggressive neoplasms, with little published population-based data on predictors of survival. OBJECTIVE: We sought to assess the influences of race/ethnicity, sex, tumor stage, tumor thickness, and anatomic site on mucosal melanoma survival estimates. METHODS: We analyzed 132,751 cases of melanoma, including 1824 mucosal melanomas, diagnosed between 1994 and 2015 and reported to the California Cancer Registry. Kaplan-Meier survival analysis and Cox proportional hazards regression assessed the prognostic variables. RESULTS: The 5-year relative survival for mucosal melanomas (27.64% [95% confidence interval {CI} 25.42-29.91) was significantly lower than for cutaneous melanomas (76.28% [95% CI 76.03-76.53]). Stage independently influenced survival, and thickness did not predict survival for neoplasms of known depth. Less common anatomic sites conferred worse prognoses (hazard ratio 1.93 [95% CI 1.41-2.64]). LIMITATIONS: The lack of a standardized staging system may have resulted in misclassification of stage for some neoplasms. The influence of genetics is unknown because our database did not contain genetic characteristics. CONCLUSIONS: Stage and anatomic site, but not thickness (ie, Breslow depth), race, or ethnicity, determine the prognosis of mucosal melanomas. Considering the poor prognosis for all stages of mucosal melanoma, dermatologists should incorporate examination of the oropharynx and genitalia in the full body skin examination.

Prevalence of sun protection behaviors in Hispanic youth residing in a high ultraviolet light environment.

Although rates of late-stage melanoma are rising in Hispanics, particularly those living in high ultraviolet light environments, little is known about the prevalence of sun protective behaviors in Hispanic children. We analyzed baseline data including frequency of sunburn, sun protective behaviors, level of U.S. acculturation, and skin phototype from a cross-sectional survey of 2003 Hispanic elementary school children in Los Angeles, California, who participated in a skin cancer prevention intervention. Although the Hispanic children reported frequently engaging in some sun protective behaviors, they also had a high rate of sunburn (59%) that exceeded previous national estimates for non-Hispanic white children (43%). Fewer U.S.-acculturated children reported more frequent shade-seeking at home (P = .02), along with less shade-seeking at school (P = .001) and more sunscreen use at school (P = .02). The surprisingly high rate of sunburn in Hispanic children suggests that the way in which they are practicing sun protection is not preventing sunburns. Sun safety interventions should be targeted toward Hispanic youth to provide them with practical methods of effective sun protection, in addition to education on the risks of high sun exposure.

Mucosal melanomas in the racially diverse population of California.

BACKGROUND: Mucosal melanomas are rare, poorly understood neoplasms without a consensus standard of care. OBJECTIVE: We sought to define mucosal melanoma tumor characteristics and the racial/ethnic attributes of patients with mucosal melanomas. METHODS: We analyzed 130,920 cutaneous melanomas and 1919 mucosal melanomas recorded in the population-based California Cancer Registry from 1988 to 2013. RESULTS: Although only 1% of melanomas occurring in nonHispanic whites were mucosal, other racial/ethnic groups had a higher proportion of mucosal melanomas (15% for Asian/Pacific Islanders, 9% for nonHispanic blacks, and 4% for Hispanics). Anorectal mucosal melanomas were most common in female Asian/Pacific Islanders, whereas genitourinary mucosal melanomas were highest in nonHispanic whites, and head and neck tumors were most common among Hispanics. Stage at presentation was not uniform among racial/ethnic groups, with Asian/Pacific Islanders having the highest rates of metastasis. LIMITATIONS: The lack of a standardized staging system for mucosal melanomas confounds classification and knowledge regarding metastasis. Small sample size limits comparative analysis across race, stage, site, and depth. CONCLUSION: Mucosal melanomas differ by race/ethnicity with regard to anatomic site, stage, and depth. Because early detection offers the best chance of increased survival, greater awareness will aid clinicians who care for patients at risk for these aggressive tumors.

Correlates of sun protection behaviors among Hispanic children residing in a high UVR environment.

BACKGROUND/PURPOSE: Rates of melanoma are rising in Hispanics in the United States. Excessive sun exposure in childhood increases the risk of melanoma in adulthood, and little is known about the factors motivating sun protection behaviors among Hispanic youth. METHODS: Correlates of sun protection were examined among Hispanic children residing in Los Angeles, California (N = 1891). Associations between multiple constructs (psychosocial, familial, and cultural) and sun protection outcomes (use of sunscreen, protective clothing, and shade seeking/sun avoidance) were examined. RESULTS: Family variables were associated with more frequent sun protection among Hispanic children across outcomes, as were perceived peer norms, perceived self-efficacy, and fewer sun protection barriers. Skin cancer risk factors such as lighter skin and sunburn experience, and level of acculturation were not associated with greater sun protection. CONCLUSION: Family sun protection habits are instrumental to Hispanic children's sun safe behaviors, and interventions that engage the family may be most effective. Increasing risk communication to high-risk subgroups of Hispanic children (those with lighter, more sun reactive skin) is important when developing intervention strategies. However, there is overlap between Hispanic children's sun protection correlates and those observed among non-Hispanic white children, suggesting that interventions to improve sun protection may generalize across cultural contexts.

Dermatology Medical Education: A Multicenter Survey Study of the Undergraduate Perspective of the Dermatology Clinical Clerkship.

BACKGROUND/AIMS: Limited data are available regarding the undergraduate dermatology clinical clerkship curriculum in the United States. Our primaryaim is to assess medical students' perspectives of the dermatology clinical clerkship. METHODS: A multicenter survey study was conducted, which included four California dermatology academic programs. A 17-item questionnaire was designed to investigate medical student perception with regard tothe overall educational value of the various teaching aspects of the dermatology clinical clerkship. RESULTS: A total of 152 medical student surveys were completed. Over half of the medical students felt proficient in diagnosing the most commondermatologic conditions. Eighty-seven percent of medical students were very satisfied with the dermatology clerkship. Ninety-one percent of students felt the length of the clerkship was appropriate. CONCLUSIONS: The vast majority of medical students reported a high level of proficiency in the treatment and diagnosis of common skin disorders. In contrast, our findings suggest that medical students may not begaining sufficient hands-on experience in conducting certain dermatologic procedures following the dermatology clerkship. Overall, medical studentperception of the dermatology clinical clerkship was mostly positive.

Patterns of sun protective behaviors among Hispanic children in a skin cancer prevention intervention.

BACKGROUND: Invasive melanoma is becoming more common in U.S. Hispanics, yet little is known about the sun protection behaviors in this population, particularly children and adolescents who incur high ultraviolet (UV) exposures. METHODS: We used latent class analysis to examine patterns of sun protective behaviors in a cross-sectional survey of Hispanic elementary students participating in a sun safety intervention in Los Angeles from 2013- to 2014 (N=972). Five behavior indicators in two environments (school and home) representing multiple methods of sun protection were selected for the model. RESULTS: Results suggested a four-class model best fit the data. Classes were labeled in order of increasing risk as multiple protective behaviors (28%), clothing and shade (32%), pants only (15%), and low/inconsistent protective behaviors (25%). Children who reported high parental engagement with sun protection were significantly more likely to be classified in high overall protective categories (odds ratio (OR)=4.77). Girls were more likely than boys to be classified in the highest protecting class (OR=3.46), but were also more likely to be in the "pants only" class (OR=2.65). Sensitivity to sunburn was associated with less likelihood of being in the "clothing and shade" class (OR=0.53). CONCLUSION: The differences among these classes and their predictors reveal the heterogeneity and complexity of Hispanic children's sun protective behaviors. These findings have implications for the design and delivery of future sun protection interventions targeting Hispanic children, as strategies tailored to specific subgroups may be more effective in achieving meaningful behavioral changes.

Imaging of disorders affecting the bone and skin.

There are a variety of conditions that manifest not only in bone but also in skin. Bone and skin structures can share common embryologic origins, and genetic defects that occur early in cell differentiation may lead to disease in both organ systems. Alternatively, diseases of bone and skin may be caused by defects in genes that participate in directing or controlling both systems. Many diseases of bone and skin can manifest with atypical radiologic findings or mimic malignant bone lesions. Upon encountering such a disease process, a radiologist who is familiar with both aspects of the disorder and consequently looks for associated skin findings can greatly benefit the patient by making a definitive diagnosis. Similarly, a clinician who encounters suggestive skin lesions should be prompted to look for concomitant skeletal lesions. By synthesizing knowledge of bone and skin manifestations, radiologists and clinicians can help correctly diagnose a number of these disease processes, thereby helping patients avoid further, often nonspecific invasive workup and advancing patient care.

Integrated multi-omics profiling to dissect the spatiotemporal evolution of metastatic hepatocellular carcinoma.

Comprehensive molecular analyses of metastatic hepatocellular carcinoma (HCC) are lacking. Here, we generate multi-omic profiling of 257 primary and 176 metastatic regions from 182 HCC patients. Primary tumors rich in hypoxia signatures facilitated polyclonal dissemination. Genomic divergence between primary and metastatic HCC is high, and early dissemination is prevalent. The remarkable neoantigen intratumor heterogeneity observed in metastases is associated with decreased T cell reactivity, resulting from disruptions to neoantigen presentation. We identify somatic copy number alterations as highly selected events driving metastasis. Subclones without Wnt mutations show a stronger selective advantage for metastasis than those with Wnt mutations and are characterized by a microenvironment rich in activated fibroblasts favoring a pro-metastatic phenotype. Finally, metastases without Wnt mutations exhibit higher enrichment of immunosuppressive B cells that mediate terminal exhaustion of CD8+ T cells via HLA-E:CD94-NKG2A checkpoint axis. Collectively, our results provide a multi-dimensional dissection of the complex evolutionary process of metastasis.

Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance.

Combination approaches are needed to strengthen and extend the clinical response to KRASG12C inhibitors (KRASG12Ci). Here, we assessed the antitumor responses of KRASG12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRASG12C inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling. BI-3406 plus adagrasib treatment also delayed the emergence of acquired resistance and elicited antitumor responses from adagrasib-resistant models. Resistance to KRASG12Ci seemed to be driven by upregulation of MRAS activity, which both SOS1i and SHP2i were found to potently inhibit. Knockdown of SHOC2, a MRAS complex partner, partially restored response to KRASG12Ci treatment. These results suggest KRASG12C plus SOS1i to be a promising strategy for treating both KRASG12Ci naive and relapsed KRASG12C-mutant tumors.

Targeting immunosuppressive Ly6C+ classical monocytes reverses anti-PD-1/CTLA-4 immunotherapy resistance.

Introduction: Despite significant clinical advancement with the use of immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) there are still a major subset of patients that develop adaptive/acquired resistance. Understanding resistance mechanisms to ICB is critical to developing new therapeutic strategies and improving patient survival. The dynamic nature of the tumor microenvironment and the mutational load driving tumor immunogenicity limit the efficacy to ICB. Recent studies indicate that myeloid cells are drivers of ICB resistance. In this study we sought to understand which immune cells were contributing to resistance and if we could modify them in a way to improve response to ICB therapy. Results: Our results show that combination anti-PD-1/CTLA-4 produces an initial antitumor effect with evidence of an activated immune response. Upon extended treatment with anti-PD-1/CTLA-4 acquired resistance developed with an increase of the immunosuppressive populations, including T-regulatory cells, neutrophils and monocytes. Addition of anti-Ly6C blocking antibody to anti-PD-1/CTLA-4 was capable of completely reversing treatment resistance and restoring CD8 T cell activity in multiple KP lung cancer models and in the autochthonous lung cancer KrasLSL-G12D/p53fl/fl model. We found that there were higher classical Ly6C+ monocytes in anti-PD-1/CTLA-4 combination resistant tumors. B7 blockade illustrated the importance of dendritic cells for treatment efficacy of anti-Ly6C/PD-1/CTLA-4. We further determined that classical Ly6C+ monocytes in anti-PD-1/CTLA-4 resistant tumors are trafficked into the tumor via IFN-γ and the CCL2-CCR2 axis. Mechanistically we found that classical monocytes from ICB resistant tumors were unable to differentiate into antigen presenting cells and instead differentiated into immunosuppressive M2 macrophages or myeloid-derived suppressor cells (MDSC). Classical Ly6C+ monocytes from ICB resistant tumors had a decrease in both Flt3 and PU.1 expression that prevented differentiation into dendritic cells/macrophages. Conclusions: Therapeutically we found that addition of anti-Ly6C to the combination of anti-PD-1/CTLA-4 was capable of complete tumor eradication. Classical Ly6C+ monocytes differentiate into immunosuppressive cells, while blockade of classical monocytes drives dendritic cell differentiation/maturation to reinvigorate the anti-tumor T cell response. These findings support that immunotherapy resistance is associated with infiltrating monocytes and that controlling the differentiation process of monocytes can enhance the therapeutic potential of ICB.

In vivo metabolomics identifies CD38 as an emergent vulnerability in LKB1 -mutant lung cancer.

LKB1/STK11 is a serine/threonine kinase that plays a major role in controlling cell metabolism, resulting in potential therapeutic vulnerabilities in LKB1-mutant cancers. Here, we identify the NAD + degrading ectoenzyme, CD38, as a new target in LKB1-mutant NSCLC. Metabolic profiling of genetically engineered mouse models (GEMMs) revealed that LKB1 mutant lung cancers have a striking increase in ADP-ribose, a breakdown product of the critical redox co-factor, NAD + . Surprisingly, compared with other genetic subsets, murine and human LKB1-mutant NSCLC show marked overexpression of the NAD+-catabolizing ectoenzyme, CD38 on the surface of tumor cells. Loss of LKB1 or inactivation of Salt-Inducible Kinases (SIKs)-key downstream effectors of LKB1- induces CD38 transcription induction via a CREB binding site in the CD38 promoter. Treatment with the FDA-approved anti-CD38 antibody, daratumumab, inhibited growth of LKB1-mutant NSCLC xenografts. Together, these results reveal CD38 as a promising therapeutic target in patients with LKB1 mutant lung cancer. SIGNIFICANCE: Loss-of-function mutations in the LKB1 tumor suppressor of lung adenocarcinoma patients and are associated with resistance to current treatments. Our study identified CD38 as a potential therapeutic target that is highly overexpressed in this specific subtype of cancer, associated with a shift in NAD homeostasis.

A follow-up survey of the integrity of the dermatology National Resident Matching Program.

BACKGROUND: Our group's 2009 study of the integrity of the dermatology match revealed that some dermatology program directors violated National Resident Matching Program (NRMP) policy during their communications with applicants. Our group's article concluded with recommendations to change this behavior. OBJECTIVE: We repeated a survey of dermatology applicants to understand if dermatology program personnel behavior has changed since our group's 2009 study of the dermatology match. METHODS: We surveyed 2011 applicants to Department of Dermatology, Stanford University, Palo Alto, CA. The survey was anonymous and available online. RESULTS: Of applicants, 14% were asked to reveal how they intended to rank a program before match day. Of applicants, 32% felt pressured to reveal how they intended to rank programs. Of applicants, 90% were asked about interviews at other programs. Of applicants, 44% were asked about their marital status and 19% were asked if they had children or intended to have children. LIMITATIONS: The response rate for applicants was 53%. CONCLUSION: Although our previous study increased knowledge about the problems within the dermatology match, dermatology program personnel continue to violate NRMP policy. The most widespread violations are asking applicants where they will interview, asking applicants if they are married, and pressuring applicants to reveal how they intend to rank programs. We continue to recommend that programs avoid postinterview contact, and recommend that the NRMP create training videos for applicants and interviewers.

Calciphylaxis.

Calciphylaxis is a disease in which metastatic calcification affects small- and medium-sized vessels resulting in significant dermatologic manifestations. Lesions typically occur over areas of high fat content and progress to black leathery eschars. Calciphylaxis is associated with intense pain and markedly increased risk of infection, often leading to sepsis requiring hospitalization. Diagnosis is made by clinical history and skin biopsy. Management of calciphylaxis is interdisciplinary, emphasizing factors such as primary prevention, proper wound care, pain control, and hormone and mineral balance. Although calciphylaxis carries a high mortality rate, symptomatic treatment has shown promise as a method for controlling disease progression.

Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers.

Understanding resistance mechanisms to targeted therapies and immune checkpoint blockade in mutant KRAS lung cancers is critical to developing novel combination therapies and improving patient survival. Here, we show that MEK inhibition enhanced PD-L1 expression while PD-L1 blockade upregulated MAPK signaling in mutant KRAS lung tumors. Combined MEK inhibition with anti-PD-L1 synergistically reduced lung tumor growth and metastasis, but tumors eventually developed resistance to sustained combinatorial therapy. Multi-platform profiling revealed that resistant lung tumors have increased infiltration of Th17 cells, which secrete IL-17 and IL-22 cytokines to promote lung cancer cell invasiveness and MEK inhibitor resistance. Antibody depletion of IL-17A in combination with MEK inhibition and PD-L1 blockade markedly reduced therapy-resistance in vivo. Clinically, increased expression of Th17-associated genes in patients treated with PD-1 blockade predicted poorer overall survival and response in melanoma and predicated poorer response to anti-PD1 in NSCLC patients. Here we show a triple combinatorial therapeutic strategy to overcome resistance to combined MEK inhibitor and PD-L1 blockade.

The KRASG12C Inhibitor MRTX849 Reconditions the Tumor Immune Microenvironment and Sensitizes Tumors to Checkpoint Inhibitor Therapy.

KRASG12C inhibitors, including MRTX849, are promising treatment options for KRAS-mutant non-small cell lung cancer (NSCLC). PD-1 inhibitors are approved in NSCLC; however, strategies to enhance checkpoint inhibitor therapy (CIT) are needed. KRASG12C mutations are smoking-associated transversion mutations associated with high tumor mutation burden, PD-L1 positivity, and an immunosuppressive tumor microenvironment. To evaluate the potential of MRTX849 to augment CIT, its impact on immune signaling and response to CIT was evaluated. In human tumor xenograft models, MRTX849 increased MHC class I protein expression and decreased RNA and/or plasma protein levels of immunosuppressive factors. In a KrasG12C -mutant CT26 syngeneic mouse model, MRTX849 decreased intratumoral myeloid-derived suppressor cells and increased M1-polarized macrophages, dendritic cells, CD4+, and CD8+ T cells. Similar results were observed in lung KrasG12C -mutant syngeneic and a genetically engineered mouse (GEM) model. In the CT26 KrasG12C model, MRTX849 demonstrated marked tumor regression when tumors were established in immune-competent BALB/c mice; however, the effect was diminished when tumors were grown in T-cell-deficient nu/nu mice. Tumors progressed following anti-PD-1 or MRTX849 single-agent treatment in immune-competent mice; however, combination treatment demonstrated durable, complete responses (CRs). Tumors did not reestablish in the same mice that exhibited durable CRs when rechallenged with tumor cell inoculum, demonstrating these mice developed adaptive antitumor immunity. In a GEM model, treatment with MRTX849 plus anti-PD-1 led to increased progression-free survival compared with either single agent alone. These data demonstrate KRAS inhibition reverses an immunosuppressive tumor microenvironment and sensitizes tumors to CIT through multiple mechanisms.

Dual Inhibition of MEK and AXL Targets Tumor Cell Heterogeneity and Prevents Resistant Outgrowth Mediated by the Epithelial-to-Mesenchymal Transition in NSCLC.

The epithelial-to-mesenchymal transition (EMT) is a dynamic epigenetic reprogramming event that occurs in a subset of tumor cells and is an initiating step toward invasion and distant metastasis. The process is reversible and gives plasticity to cancer cells to survive under variable conditions, with the acquisition of cancer stem cell-like characteristics and features such as drug resistance. Therefore, understanding survival dependencies of cells along the phenotypic spectrum of EMT will provide better strategies to target the spatial and temporal heterogeneity of tumors and prevent their ability to bypass single-inhibitor treatment strategies. To address this, we integrated the data from a selective drug screen in epithelial and mesenchymal KRAS/p53 (KP)-mutant lung tumor cells with separate datasets including reverse-phase protein array and an in vivo shRNA dropout screen. These orthogonal approaches identified AXL and MEK as potential mesenchymal and epithelial cell survival dependencies, respectively. To capture the dynamicity of EMT, incorporation of a dual fluorescence EMT sensor system into murine KP lung cancer models enabled real-time analysis of the epigenetic state of tumor cells and assessment of the efficacy of single agent or combination treatment with AXL and MEK inhibitors. Both two- and three-dimensional culture systems and in vivo models revealed that this combination treatment strategy of MEK plus AXL inhibition synergistically killed lung cancer cells by specifically targeting each phenotypic subpopulation. In conclusion, these results indicate that cotargeting the specific vulnerabilities of EMT subpopulations can prevent EMT-mediated drug resistance, effectively controlling tumor cell growth and metastasis. SIGNIFICANCE: This study shows that a novel combination of MEK and AXL inhibitors effectively bypasses EMT-mediated drug resistance in KRAS/p53-mutant non-small cell lung cancer by targeting EMT subpopulations, thereby preventing tumor cell survival.

AXL Inhibition Induces DNA Damage and Replication Stress in Non-Small Cell Lung Cancer Cells and Promotes Sensitivity to ATR Inhibitors.

AXL, a TAM (TYRO3, AXL, and MERTK) family receptor tyrosine kinase, is increasingly being recognized as a key determinant of resistance to targeted therapies, as well as chemotherapy and radiation in non-small cell lung cancer (NSCLC) and other cancers. We further show here that high levels of AXL and epithelial-to-mesenchymal transition were frequently expressed in subsets of both treatment-naïve and treatment-relapsed NSCLC. Previously, we and others have demonstrated a role for AXL in mediating DNA damage response (DDR), as well as resistance to inhibition of WEE1, a replication stress response kinase. Here, we show that BGB324 (bemcentinib), a selective small-molecule AXL inhibitor, caused DNA damage and induced replication stress, indicated by ATR/CHK1 phosphorylation, more significantly in TP53-deficient NSCLC cell lines. Similar effects were also observed in large-cell neuroendocrine carcinoma (LCNEC) cell lines. High AXL protein levels were also associated with resistance to ATR inhibition. Combined inhibition of AXL and ATR significantly decreased cell proliferation of NSCLC and LCNEC cell lines. Mechanistically, combined inhibition of AXL and ATR significantly increased RPA32 hyperphosphorylation and DNA double-strand breaks and induced markers of mitotic catastrophe. Notably, NSCLC cell lines with low levels of SLFN11, a known predictive biomarker for platinum and PARP inhibitor sensitivity, were more sensitive to AXL/ATR cotargeting. These findings demonstrate a novel and unexpected role for AXL in replication stress tolerance, with potential therapeutic implications. IMPLICATIONS: These findings demonstrate that the combination of AXL and ATR inhibitors could be a promising therapeutic combination for NSCLC, LCNEC, and other cancers.

PD-1 inhibition therapy for advanced cutaneous squamous cell carcinoma: a retrospective analysis from the University of Southern California.

PURPOSE: Approximately 5% of patients with cutaneous squamous cell carcinoma (CSCC) may develop recurrent or metastatic disease. The management of such cases is challenging and requires multi-disciplinary care. Immunotherapy using PD-1 inhibition was approved to treat unresectable or metastatic CSCC in 2018. Given limited data regarding clinical outcomes outside of published trials, we describe our experience using this therapy. METHODS: We retrospectively reviewed all patients treated with PD-1 inhibition as therapy for locally advanced, regionally metastatic or distant metastatic CSCC at the University of Southern California. Clinicopathological characteristics, treatment data using PD-1 inhibitors, and outcomes were assessed. RESULTS: Among 26 patients treated with PD-1 inhibition, the objective response rate was 42.3%, with 19.2% of patients having partial response and 23.1% having complete response to therapy. The median progression-free survival was 5.4 months. Median tumor mutational burden (TMB) was higher among responders compared to non-responders (60 vs. 9 Mut/Mb, p = 0.04). Primary CSCC tumor location on the head/neck was also associated with response to PD-1 inhibition (p = 0.04). Two patients with mutations affecting mismatch repair deficiency were noted to have complete response to treatment. No other variables were associated with treatment outcomes. CONCLUSION: PD-1 inhibition produces durable responses among patients with advanced or metastatic CSCC. PD-1 inhibition therapy is well tolerated, but patients should be monitored closely for immune-related adverse events, particularly frail or immune-suppressed patients. Further investigation of potential biomarkers to help identify patients who will derive the most benefit from this therapeutic option is needed.

Dissecting spatial heterogeneity and the immune-evasion mechanism of CTCs by single-cell RNA-seq in hepatocellular carcinoma.

Little is known about the transcriptomic plasticity and adaptive mechanisms of circulating tumor cells (CTCs) during hematogeneous dissemination. Here we interrogate the transcriptome of 113 single CTCs from 4 different vascular sites, including hepatic vein (HV), peripheral artery (PA), peripheral vein (PV) and portal vein (PoV) using single-cell full-length RNA sequencing in hepatocellular carcinoma (HCC) patients. We reveal that the transcriptional dynamics of CTCs were associated with stress response, cell cycle and immune-evasion signaling during hematogeneous transportation. Besides, we identify chemokine CCL5 as an important mediator for CTC immune evasion. Mechanistically, overexpression of CCL5 in CTCs is transcriptionally regulated by p38-MAX signaling, which recruites regulatory T cells (Tregs) to facilitate immune escape and metastatic seeding of CTCs. Collectively, our results reveal a previously unappreciated spatial heterogeneity and an immune-escape mechanism of CTC, which may aid in designing new anti-metastasis therapeutic strategies in HCC.