Respiratory viral infection promotes the awakening and outgrowth of dormant metastatic breast cancer cells in lungs.

Breast cancer is the second most common cancer globally. Most deaths from breast cancer are due to metastatic disease which often follows long periods of clinical dormancy1. Understanding the mechanisms that disrupt the quiescence of dormant disseminated cancer cells (DCC) is crucial for addressing metastatic progression. Infection with respiratory viruses (e.g. influenza or SARS-CoV-2) is common and triggers an inflammatory response locally and systemically2,3. Here we show that influenza virus infection leads to loss of the pro-dormancy mesenchymal phenotype in breast DCC in the lung, causing DCC proliferation within days of infection, and a greater than 100-fold expansion of carcinoma cells into metastatic lesions within two weeks. Such DCC phenotypic change and expansion is interleukin-6 (IL-6)-dependent. We further show that CD4 T cells are required for the maintenance of pulmonary metastatic burden post-influenza virus infection, in part through attenuation of CD8 cell responses in the lungs. Single-cell RNA-seq analyses reveal DCC-dependent impairment of T-cell activation in the lungs of infected mice. SARS-CoV-2 infected mice also showed increased breast DCC expansion in lungs post-infection. Expanding our findings to human observational data, we observed that cancer survivors contracting a SARS-CoV-2 infection have substantially increased risks of lung metastatic progression and cancer-related death compared to cancer survivors who did not. These discoveries underscore the significant impact of respiratory viral infections on the resurgence of metastatic cancer, offering novel insights into the interconnection between infectious diseases and cancer metastasis.

Pilot Curriculum for Continued Professional Development of Radiation Oncology Nurses.

Purpose: Limited structured educational programs are available for the continued professional development of radiation oncology nurses. In this study, we evaluated a pilot curriculum focusing on clinical workflow and toxicity management for radiation oncology nurses at a single university-affiliated medical center network. Methods and Materials: Based on a previous multi-institutional needs assessment, a targeted curriculum on clinical workflow and toxicity management was developed, including didactic lectures, written disease-specific toxicity management guidelines, and standardized medication/laboratory order preference lists in the electronic health record. An anonymized survey was circulated to all participants pre- and postcurriculum. The survey was composed of Likert-type subjective questions and 11 objective knowledge-based questions (KBQs). Paired Likert-type data were analyzed using Wilcoxon signed ranks test. Objective question data were compared with the McNamar's mid P test. Results: Thirteen nurses participated in the pilot curriculum and 100% completed pre- and post curriculum surveys. After the didactics, nurses reported a significant increase in their understanding of the responsibilities of a nurse and overall process of care and their ability to explain computed tomography simulation, as well as their ability to assess, manage, and grade radiation-related toxicities (P < .01). There was significant improvement in the percent of correct answers on objective KBQs from a baseline of 52% to 80% after the curriculum (P < .01). Qualitatively, 70% (9/13) of nurses rated the curriculum as "extremely useful" and 30% (4/13) as "quite useful." Conclusions: Our pilot curriculum using a combination of in-person formal didactics, toxicity management guidelines, and electronic health record based order preference lists was well-received and showed promising results on KBQ assessment. This work may be used to guide the development of larger curricula for nurse onboarding and continuing education in a multicenter setting.

Instrumental variable analysis for cost outcome: Application to the effect of primary care visit on medical cost among low-income adults.

Medical cost data often consist of zero values as well as extremely right-skewed positive values. A two-part model is a popular choice for analyzing medical cost data, where the first part models the probability of a positive cost using logistic regression and the second part models the positive cost using a lognormal or Gamma distribution. To address the unmeasured confounding in studies on cost outcome under two-part models, two instrumental variable (IV) methods, two-stage residual inclusion (2SRI) and two-stage prediction substitution (2SPS) are widely applied. However, previous literature demonstrated that both the 2SRI and the 2SPS could fail to consistently estimate the causal effect among compliers under standard IV assumptions for binary and survival outcomes. Our simulation studies confirmed that it continued to be the case for a two-part model, which is another nonlinear model. In this article, we develop a model-based IV approach, Instrumental Variable with Two-Part model (IV2P), to obtain a consistent estimate of the causal effect among compliers for cost outcome under standard IV assumptions. In addition, we develop sensitivity analysis approaches to allow the evaluation of the sensitivity of the causal conclusions to potential quantified violations of the exclusion restriction assumption and the randomization of IV assumption. We apply our method to a randomized cash incentive study to evaluate the effect of a primary care visit on medical cost among low-income adults newly covered by a primary care program.

Integrated variant allele frequency analysis pipeline and R package: easyVAF.

Somatic sequence variants are associated with cancer diagnosis, prognostic stratification, and treatment response. Variant allele frequency (VAF), the percentage of sequence reads with a specific DNA variant over the read depth at that locus, has been used as a metric to quantify mutation rates in these applications. VAF has the potential for feature detection by reflecting changes in tumor clonal composition across treatments or time points. Although there are several packages, including Genome Analysis Toolkit and VarScan, designed for variant calling and rare mutation identification, there is no readily available package for comparing VAFs among and between groups to identify loci of interest. To this end, we have developed the R package easyVAF, which includes parametric and nonparametric tests to compare VAFs among multiple groups. It is accompanied by an interactive R Shiny app. With easyVAF, the investigator has the option between three statistical tests to maximize power while maintaining an acceptable type I error rate. This paper presents our proposed pipeline for VAF analysis, from quality checking to group comparison. We evaluate our method in a wide range of simulated scenarios and show that choosing the appropriate test to limit the type I error rate is critical. For situations where data is sparse, we recommend comparing VAFs with the beta-binomial likelihood ratio test over Fisher's exact test and Pearson's χ2 test.

Interferon hyperactivity impairs cardiogenesis in Down syndrome via downregulation of canonical Wnt signaling.

Congenital heart defects (CHDs) are frequent in children with Down syndrome (DS), caused by trisomy of chromosome 21. However, the underlying mechanisms are poorly understood. Here, using a human-induced pluripotent stem cell (iPSC)-based model and the Dp(16)1Yey/+ (Dp16) mouse model of DS, we identified downregulation of canonical Wnt signaling downstream of increased dosage of interferon (IFN) receptors (IFNRs) genes on chromosome 21 as a causative factor of cardiogenic dysregulation in DS. We differentiated human iPSCs derived from individuals with DS and CHDs, and healthy euploid controls into cardiac cells. We observed that T21 upregulates IFN signaling, downregulates the canonical WNT pathway, and impairs cardiac differentiation. Furthermore, genetic and pharmacological normalization of IFN signaling restored canonical WNT signaling and rescued defects in cardiogenesis in DS in vitro and in vivo. Our findings provide insights into mechanisms underlying abnormal cardiogenesis in DS, ultimately aiding the development of therapeutic strategies.

Safety and Efficacy of Tucatinib, Letrozole, and Palbociclib in Patients with Previously Treated HR+/HER2+ Breast Cancer.

PURPOSE: To overcome resistance to antihormonal and HER2-targeted agents mediated by cyclin D1-CDK4/6 complex, we proposed an oral combination of the HER2 inhibitor tucatinib, aromatase inhibitor letrozole, and CDK4/6 inhibitor palbociclib (TLP combination) for treatment of HR+/HER2+ metastatic breast cancer (MBC). PATIENTS AND METHODS: Phase Ib/II TLP trial (NCT03054363) enrolled patients with HR+/HER2+ MBC treated with ≥2 HER2-targeted agents. The phase Ib primary endpoint was safety of the regimen evaluated by NCI CTCAE version 4.3. The phase II primary endpoint was efficacy by median progression-free survival (mPFS). RESULTS: Forty-two women ages 22 to 81 years were enrolled. Patients received a median of two lines of therapy in the metastatic setting, 71.4% had visceral disease, 35.7% had CNS disease. The most common treatment-emergent adverse events (AE) of grade ≥3 were neutropenia (64.3%), leukopenia (23.8%), diarrhea (19.0%), and fatigue (14.3%). Tucatinib increased AUC10-19 hours of palbociclib 1.7-fold, requiring palbociclib dose reduction from 125 to 75 mg daily. In 40 response-evaluable patients, mPFS was 8.4 months, with similar mPFS in non-CNS and CNS cohorts (10.0 months vs. 8.2 months; P = 0.9). Overall response rate was 44.5%, median duration of response was 13.9 months, and clinical benefit rate was 70.4%; 60% of patients were on treatment for ≥6 months, 25% for ≥1 year, and 10% for ≥2 years. In the CNS cohort, 26.6% of patients remained on study for ≥1 year. CONCLUSIONS: TLP combination was safe and tolerable. AEs were expected and manageable with supportive therapy and dose reductions. TLP showed excellent efficacy for an all-oral chemotherapy-free regimen warranting further testing. See related commentary by Huppert and Rugo, p. 4993.

The programmed death ligand 1 interactome demonstrates bidirectional signaling coordinating immune suppression and cancer progression in head and neck squamous cell carcinoma.

BACKGROUND: The programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) are validated cancer targets; however, emerging mechanisms and impact of PD-L1 intracellular signaling on cancer behavior are poorly understood. METHODS: We investigated the cancer cell intrinsic role of PD-L1 in multiple patient-derived models in vitro and in vivo. PD-L1 overexpression, knockdown, and PD-L1 intracellular domain (PD-L1-ICD) deletion (Δ260-290PD-L1) models were assessed for key cancer properties: clonogenicity, motility, invasion, and immune evasion. To determine how PD-L1 transduces signals intracellularly, we used the BioID2 platform to identify the PD-L1 intracellular interactome. Both human papillomavirus-positive and negative patient-derived xenografts were implanted in NOD-scid-gamma and humanized mouse models to investigate the effects of recombinant PD-1, anti-PD-L1, and anti-signal transducer and activator of transcription 3 (STAT3) in vivo. RESULTS: PD-L1 intracellular signaling increased clonogenicity, motility, and invasiveness in multiple head and neck squamous cell carcinoma (HNSCC) models, and PD-1 binding enhanced these effects. Protein proximity labeling revealed the PD-L1 interactome, distinct for unbound and bound PD-1, which initiated cancer cell-intrinsic signaling. PD-L1 binding partners interleukin enhancer binding factors 2 and 3 (ILF2-ILF3) transduced their effect through STAT3. Δ260-290PD-L1 disrupted signaling and reversed pro-growth properties. In humanized HNSCC in vivo models bearing T-cells, PD-1 binding triggered PD-L1 signaling, and dual PD-L1 and STAT3 inhibition were required to achieve tumor control. CONCLUSIONS: Upon PD-1 binding, the PD-L1 extracellular and intracellular domains exert a synchronized effect to promote immune evasion by inhibiting T-cell function while simultaneously enhancing cancer cell-invasive properties.

CCR4-IL2 bispecific immunotoxin is more effective than brentuximab for targeted therapy of cutaneous T-cell lymphoma in a mouse CTCL model.

Cutaneous T-cell lymphoma (CTCL) encompasses two main subtypes: mycosis fungoides and Sezary syndrome. Global response rates for the systemic treatment of mycosis fungoides and Sezary syndrome are approximately 30%, and none of these treatments are thought to be curative. C-C chemokine receptor type 4 (CCR4) and CD25 are encouraging targets for the treatment of CTCL and are individually targeted by mogamulizumab and denileukin diftitox, respectively. We developed a novel CCR4-IL2 bispecific immunotoxin (CCR4-IL2 IT) targeting both CCR4 and CD25. CCR4-IL2 IT demonstrated superior efficacy against CCR4+ CD25+ CD30+ CTCL in an immunodeficient NSG mouse tumor model. Investigative New Drug-enabling studies of CCR4-IL2 IT are ongoing, including Good Manufacturing Practice production and toxicology studies. In this study, we compared the in vivo efficacy of CCR4-IL2 IT versus the US Food and Drug Administration-approved drug, brentuximab, using an immunodeficient mouse CTCL model. We demonstrated that CCR4-IL2 IT was significantly more effective in prolonging survival than brentuximab, and combination treatment of CCR4-IL2 IT and brentuximab was more effective than brentuximab or CCR4-IL2 IT alone in an immunodeficient NSG mouse CTCL model. Thus, CCR4-IL2 IT is a promising novel therapeutic drug candidate for CTCL treatment.

Significant increase of high-risk chromosome 1q gain and 6q loss at recurrence in posterior fossa group A ependymoma: A multicenter study.

BACKGROUND: Ependymoma (EPN) posterior fossa group A (PFA) has the highest rate of recurrence and the worst prognosis of all EPN molecular groups. At relapse, it is typically incurable even with re-resection and re-irradiation. The biology of recurrent PFA remains largely unknown; however, the increasing use of surgery at first recurrence has now provided access to clinical samples to facilitate a better understanding of this. METHODS: In this large longitudinal international multicenter study, we examined matched samples of primary and recurrent disease from PFA patients to investigate the biology of recurrence. RESULTS: DNA methylome derived copy number variants (CNVs) revealed large-scale chromosome gains and losses at recurrence in PFA. CNV changes were dominated by chromosome 1q gain and/or 6q loss, both previously identified as high-risk factors in PFA, which were present in 23% at presentation but increased to 61% at first recurrence. Multivariate survival analyses of this cohort showed that cases with 1q gain or 6q loss at first recurrence were significantly more likely to recur again. Predisposition to 1q+/6q- CNV changes at recurrence correlated with hypomethylation of heterochromatin-associated DNA at presentation. Cellular and molecular analyses revealed that 1q+/6q- PFA had significantly higher proportions of proliferative neuroepithelial undifferentiated progenitors and decreased differentiated neoplastic subpopulations. CONCLUSIONS: This study provides clinically and preclinically actionable insights into the biology of PFA recurrence. The hypomethylation predisposition signature in PFA is a potential risk-classifier for trial stratification. We show that the cellular heterogeneity of PFAs evolves largely because of genetic evolution of neoplastic cells.

Comparison of first-line radiosurgery for small-cell and non-small cell lung cancer brain metastases (CROSS-FIRE).

INTRODUCTION: Historical reservations regarding stereotactic radiosurgery (SRS) for small-cell lung cancer (SCLC) brain metastases include concerns for short-interval and diffuse central nervous system (CNS) progression, poor prognoses, and increased neurological mortality specific to SCLC histology. We compared SRS outcomes for SCLC and non-small cell lung cancer (NSCLC) where SRS is well established. METHODS: Multicenter first-line SRS outcomes for SCLC and NSCLC from 2000 to 2022 were retrospectively collected (n = 892 SCLC, n = 4785 NSCLC). Data from the prospective Japanese Leksell Gamma Knife Society (JLGK0901) clinical trial of first-line SRS were analyzed as a comparison cohort (n = 98 SCLC, n = 814 NSCLC). Overall survival (OS) and CNS progression were analyzed using Cox proportional hazard and Fine-Gray models, respectively, with multivariable adjustment for cofactors including age, sex, performance status, year, extracranial disease status, and brain metastasis number and volume. Mutation-stratified analyses were performed in propensity score-matched retrospective cohorts of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) positive NSCLC, mutation-negative NSCLC, and SCLC. RESULTS: OS was superior for patients with NSCLC compared to SCLC in the retrospective dataset (median OS = 10.5 vs 8.6 months; P < .001) and in the JLGK0901 dataset. Hazard estimates for first CNS progression favoring NSCLC were similar in both datasets but reached statistical significance in the retrospective dataset only (multivariable hazard ratio = 0.82, 95% confidence interval = 0.73 to 0.92, P = .001). In the propensity score-matched cohorts, there were continued OS advantages for NSCLC patients (median OS = 23.7 [EGFR and ALK positive NSCLC] vs 13.6 [mutation-negative NSCLC] vs 10.4 months [SCLC], pairwise P values < 0.001), but no statistically significant differences in CNS progression were observed in the matched cohorts. Neurological mortality and number of lesions at CNS progression were similar for NSCLC and SCLC patients. Leptomeningeal progression was increased in patients with NSCLC compared to SCLC in the retrospective dataset only (multivariable hazard ratio = 1.61, 95% confidence interval = 1.14 to 2.26, P = .007). CONCLUSIONS: After SRS, SCLC histology was associated with shorter OS compared to NSCLC. CNS progression occurred earlier in SCLC patients overall but was similar in patients matched on baseline factors. SCLC was not associated with increased neurological mortality, number of lesions at CNS progression, or leptomeningeal progression compared to NSCLC. These findings may better inform clinical expectations and individualized decision making regarding SRS for SCLC patients.

CTLA4 mRNA is downregulated by miR-155 in regulatory T cells, and reduced blood CTLA4 levels are associated with poor prognosis in metastatic melanoma patients.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is an immune checkpoint expressed in regulatory T (Treg) cells and activated T lymphocytes. Despite its potential as a treatment strategy for melanoma, CTLA-4 inhibition has limited efficacy. Using data from The Cancer Genome Atlas (TCGA) melanoma database and another dataset, we found that decreased CTLA4 mRNA was associated with a poorer prognosis in metastatic melanoma. To investigate further, we measured blood CTLA4 mRNA in 273 whole-blood samples from an Australian cohort and found that it was lower in metastatic melanoma than in healthy controls and associated with worse patient survival. We confirmed these findings using Cox proportional hazards model analysis and another cohort from the US. Fractionated blood analysis revealed that Treg cells were responsible for the downregulated CTLA4 in metastatic melanoma patients, which was confirmed by further analysis of published data showing downregulated CTLA-4 surface protein expression in Treg cells of metastatic melanoma compared to healthy donors. Mechanistically, we found that secretomes from human metastatic melanoma cells downregulate CTLA4 mRNA at the post-transcriptional level through miR-155 while upregulating FOXP3 expression in human Treg cells. Functionally, we demonstrated that CTLA4 expression inhibits the proliferation and suppressive function of human Treg cells. Finally, miR-155 was found to be upregulated in Treg cells from metastatic melanoma patients compared to healthy donors. Our study provides new insights into the underlying mechanisms of reduced CTLA4 expression observed in melanoma patients, demonstrating that post-transcriptional silencing of CTLA4 by miRNA-155 in Treg cells may play a critical role. Since CTLA-4 expression is downregulated in non-responder melanoma patients to anti-PD-1 immunotherapy, targeting miRNA-155 or other factors involved in regulating CTLA4 expression in Treg cells without affecting T cells could be a potential strategy to improve the efficacy of immunotherapy in melanoma. Further research is needed to understand the molecular mechanisms regulating CTLA4 expression in Treg cells and identify potential therapeutic targets for enhancing immune-based therapies.

Phase II trial of fulvestrant plus enzalutamide in ER+/HER2- advanced breast cancer.

This clinical trial combined fulvestrant with the anti-androgen enzalutamide in women with metastatic ER+/HER2- breast cancer (BC). Eligible patients were women with ECOG 0-2, ER+/HER2- measurable or evaluable metastatic BC. Prior fulvestrant was allowed. Fulvestrant was administered at 500 mg IM on days 1, 15, 29, and every 4 weeks thereafter. Enzalutamide was given at 160 mg po daily. Fresh tumor biopsies were required at study entry and after 4 weeks of treatment. The primary efficacy endpoint of the trial was the clinical benefit rate at 24 weeks (CBR24). The median age was 61 years (46-87); PS 1 (0-1); median of 4 prior non-hormonal and 3 prior hormonal therapies for metastatic disease. Twelve had prior fulvestrant, and 91% had visceral disease. CBR24 was 25% (7/28 evaluable). Median progression-free survival (PFS) was 8 weeks (95% CI: 2-52). Adverse events were as expected for hormonal therapy. Significant (p < 0.1) univariate relationships existed between PFS and ER%, AR%, and PIK3CA and/or PTEN mutations. Baseline levels of phospho-proteins in the mTOR pathway were more highly expressed in biopsies of patients with shorter PFS. Fulvestrant plus enzalutamide had manageable side effects. The primary endpoint of CBR24 was 25% in heavily pretreated metastatic ER+/HER2- BC. Short PFS was associated with activation of the mTOR pathway, and PIK3CA and/or PTEN mutations were associated with an increased hazard of progression. Thus, a combination of fulvestrant or other SERD plus AKT/PI3K/mTOR inhibitor with or without AR inhibition warrants investigation in second-line endocrine therapy of metastatic ER+ BC.

Ordered Van der Waals Hetero-nanoribbon from Pressure-Induced Topochemical Polymerization of Azobenzene.

Pressure-induced topochemical polymerization of molecular crystals with various stackings is a promising way to synthesize materials with different co-existing sub-structures. Here, by compressing the azobenzene crystal containing two kinds of intermolecular stacking, we synthesized an ordered van der Waals carbon nanoribbon (CNR) heterostructure in one step. Azobenzene polymerizes via a [4 + 2] hetero-Diels-Alder (HDA) reaction of phenylazo-phenyl in layer A and a para-polymerization reaction of phenyl in layer B at 18 GPa, as evidenced by in situ Raman and IR spectroscopies, X-ray diffraction, as well as gas chromatography-mass spectrometry and the solid-state nuclear magnetic resonance of the recovered products. The theoretical calculation shows that the obtained CNR heterostructure has a type II (staggered) band gap alignment. Our work highlights a high-pressure strategy to synthesize bulk CNR heterostructures.

Equivocal end-of-therapy imaging findings do not predict a higher risk of local relapse after definitive radiotherapy in pediatric Ewing sarcoma and rhabdomyosarcoma.

BACKGROUND: Posttherapy imaging studies can provide reassurance or induce anxiety regarding risk of recurrence for patients and their families. In some cases, it is difficult to determine if imaging findings represent posttreatment changes or residual disease. Equivocal radiographic findings can occur due to therapy-related inflammation or residual, inactive soft tissue masses, but it is unknown if such findings indicate an increased likelihood of local recurrence. The aim of this study was to assess the value of initial posttherapy scans for predicting local relapse in patients with Ewing sarcoma (EWS) or rhabdomyosarcoma (RMS) who received radiotherapy (RT) for local control. These findings are critical to inform clinicians' surveillance recommendations and ability to accurately counsel patients and their families. PROCEDURE: The primary endpoint was time to local progression (LP). Patients were classified as having posttherapy scans that were "positive" (residual disease within the RT field), "negative" (no evidence of residual disease within the RT field), or "equivocal" (no determination could be made). The value of initial posttreatment scans for predicting LP was assessed using positive predictive value (PPV) and negative predictive value (NPV). RESULTS: Negative imaging findings (n = 51) had an NPV of 88%, and positive imaging findings (n = 1) had a PPV of 100%. When equivocal findings (n = 16) were categorized with negative results (i.e., positive vs. equivocal/negative), the NPV was 90%. When equivocal findings were categorized with positive results (equivocal/positive vs. negative), the PPV was 12%. CONCLUSION: Equivocal findings within the RT field on end-of-therapy imaging studies indicate no higher risk of local recurrence than negative findings. These results may contribute to appropriate surveillance schedules and accurate counseling of patients with RMS and EWS who have received RT for local control.

Multicenter analysis of stereotactic radiosurgery for multiple brain metastases from EGFR and ALK driven non-small cell lung cancer.

INTRODUCTION: Patients with brain metastases (BrMs) arising from EGFR and ALK driven non-small cell lung cancer (NSCLC) have favorable prognoses and evolving treatment options. We evaluated multicenter outcomes for stereotactic radiosurgery (SRS) to multiple (≥4) BrMs, where randomized data remain limited. METHODS: Data were collected retrospectively from 5 academic centers on EGFR and ALK NSCLC who received SRS to ≥4 BrMs with their first SRS treatment between 2008 and 2018. Analyzed endpoints included overall survival (OS), freedom from CNS progression (FFCNSP), and freedom from whole-brain radiotherapy (FFWBRT). RESULTS: Eighty-nine patients (50 EGFR, 39 ALK) received a total of 159 SRS treatments to 1,080 BrMs, with a median follow up of 51.3 months. The median number of BrMs treated with SRS treatment-1 was 6 (range 4-26) and median for all treatments was 9 (range 4-47). Sixteen patients (18 %) had received WBRT prior to SRS treatment-1. The median OS was 24.2, 21.2, and 33.2 months for all patients, EGFR, and ALK subsets, respectively. After multivariable adjustment, only receipt of a next-generation tyrosine kinase inhibitor was associated with OS (HR 0.40, p = 0.005). No differences in OS were observed based on number of BrMs treated. The median FFCNSP was 9.4, 11.6, and 7.5 months, for all patients, EGFR, and ALK subsets, respectively. After multivariable adjustment, the number of BrMs (continuous) treated during treatment-1 was the only negative prognostic factor associated with FFCNSP (HR 1.071, p = 0.045). The 5-year FFWBRT was 73.6 %. CONCLUSIONS: This multicenter analysis over a >10-year period demonstrated favorable OS, FFCNSP, and FFWBRT, in patients with EGFR and ALK driven NSCLC receiving SRS to ≥4 BrMs. These data support SRS as an option in the upfront and salvage setting for higher burden CNS disease in this population.

Targeting MDSC Differentiation Using ATRA: A Phase I/II Clinical Trial Combining Pembrolizumab and All-Trans Retinoic Acid for Metastatic Melanoma.

PURPOSE: A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in patients with stage IV melanoma. PATIENTS AND METHODS: Anti-PD-1 naïve patients with stage IV melanoma were treated with pembrolizumab plus supplemental ATRA for three days surrounding each of the first four pembrolizumab infusions. The primary objective was to establish the MTD and recommended phase II dose (RP2D) of the combination. The secondary objectives were to describe the safety and toxicity of the combined treatment and to assess antitumor activity in terms of (i) the reduction in circulating myeloid-derived suppressor cell (MDSC) frequency and (ii) progression-free survival (PFS). RESULTS: Twenty-four patients were enrolled, 46% diagnosed with M1a and 29% with M1c stage disease at enrollment. All patients had an ECOG status ≤1, and 75% had received no prior therapies. The combination was well tolerated, with the most common ATRA-related adverse events being headache, fatigue, and nausea. The RP2D was established at 150 mg/m2 ATRA + 200 mg Q3W pembrolizumab. Median PFS was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response, and the 1-year overall survival was 80%. The combination effectively lowered the frequency of circulating MDSCs. CONCLUSIONS: With a favorable tolerability and high response rate, this combination is a promising frontline treatment strategy for advanced melanoma. Targeting MDSCs remains an attractive mechanism to enhance the efficacy of immunotherapies, and this combination merits further investigation. See related commentary by Olson and Luke, p. 1167.

Adoption of Optimal Small (6-9 mm) Colorectal Polyp Resection Technique Over Time.

BACKGROUND: Cold snare polypectomy (CSP) is the preferred resection technique for small (6-9 mm) polyps due to lower rate of incomplete resection compared to cold forceps polypectomy (CFP) and improved safety profile over hot snare polypectomy (HSP). AIMS: To describe resection techniques for small (6-9 mm) polyps and determine factors associated with sub-optimal technique. METHODS: This was retrospective cohort study of colonoscopies performed by gastroenterological and surgical endoscopists from 2012 to 2019 where at least one 6-9 mm polyp was removed. Patient, provider, and procedure characteristics were collected. Univariate and multivariate regression analyses were performed to determine factors associated with sub-optimal technique. RESULTS: In total, 773 colonoscopies where 1,360 6-9 mm polyps removed by 21 endoscopists were included. CSP was used for 1,122 (82.5%), CFP for 61 (4.5%), and HSP for 177 (13.0%). Surgeon specialty was associated with CFP use (aOR 7.81; 95% CI 3.02-20.16). Polyp location in left colon (aOR 1.65; 95% CI 1.17-2.33) and pedunculated morphology (aOR 12.76; 95% CI 7.24-22.50) were associated with HSP. There was a significant increase in overall CSP use from 30.4% in 2012 to 96.8% in 2019. CONCLUSIONS: 82.5% of all 6-9 mm polyps removed from 2012 to 2019 were removed using a cold snare with significant increase in CSP from 2012 to 2019. Differences in how optimal technique was adopted over time based on specialty highlight the need for standardized practice guidelines and quality monitoring.

From Biomass to Functional Crystalline Diamond Nanothread: Pressure-Induced Polymerization of 2,5-Furandicarboxylic Acid.

2,5-Furandicarboxylic acid (FDCA) is one of the top-12 value-added chemicals from sugar. Besides the wide application in chemical industry, here we found that solid FDCA polymerized to form an atomic-scale ordered sp3-carbon nanothread (CNTh) upon compression. With the help of perfectly aligned π-π stacked molecules and strong intermolecular hydrogen bonds, crystalline poly-FDCA CNTh with uniform syn-configuration was obtained above 11 GPa, with the crystal structure determined by Rietveld refinement of the X-ray diffraction (XRD). The in situ XRD and theoretical simulation results show that the FDCA experienced continuous [4 + 2] Diels-Alder reactions along the stacking direction at the threshold C···C distance of ∼2.8 Å. Benefiting from the abundant carbonyl groups, the poly-FDCA shows a high specific capacity of 375 mAh g-1 as an anode material of a lithium battery with excellent Coulombic efficiency and rate performance. This is the first time a three-dimensional crystalline CNTh is obtained, and we demonstrated it is the hydrogen bonds that lead to the formation of the crystalline material with a unique configuration. It also provides a new method to move biomass compounds toward advanced functional carbon materials.

The Effect of Intrathoracic Lesion Location on Initial Tyrosine Kinase Inhibitor Response in Advanced Oncogene-Addicted Non-Small Cell Lung Cancer: A Comparison Between RECIST 1.1 and a Novel Method of Response Assessment (MAX).

INTRODUCTION: Different subtypes of non-small cell lung cancer (NSCLC) are associated with different patterns of metastatic spread. Anatomic location of lesions in the chest may influence patterns of cancer growth and the shrinkage to therapy. Consequently, lesion location could affect apparent response rates per RECIST. We sought to explore this and develop, as needed, treatment response assessments less affected by the location. METHODS: Cases of advanced oncogene-addicted NSCLC (EGFR, ALK, and ROS1) with pre- and on-therapy imaging during initial targeted therapy were identified. Lesions located in the lung parenchyma, pleural space or intra-thoracic lymph nodes were identified and analyzed separately from each other by RECIST 1.1 (unidimensional measurements) and by a novel MAX methodology (bidimensional measurements) which takes the axis with the greatest absolute percentage change on therapy in each location as the representative measurement. RESULTS: Three hundred three patients with 446 unidimensional measured lesions were included for RECIST analysis. Two hundred forty nine patients with 386 bidimensional measured lesions were included for MAX analysis, as well as the analysis comparing RECIST and MAX. Intrathoracic location significantly impacted percentage shrinkage and the response rate per RECIST. The response rates for pleural, intra-parenchymal and nodal lesions were 34.1%, 49.6%, and 68.3%, respectively (P = .0002). The MAX methodology both increased the apparent treatment effect and made it consistent between intrathoracic locations. For pleural, parenchymal and nodal lesions, the MAX calculated response rate were 83.7%, 72.2%, and 75.4%, respectively (P-value = .24). CONCLUSION: Intrathoracic lesion location affects RECIST-based treatment effectiveness estimations. The MAX methodology neutralizes location effect when examining impact of treatment and should be explored further.

Oncogene Overlap Analysis of Circulating Cell-free Tumor DNA to Explore the Appropriate Criteria for Defining MET Copy Number-Driven Lung Cancer.

INTRODUCTION: Defining clinically relevant MET amplification levels in non-small cell lung cancer (NSCLC) remains challenging. We hypothesize that oncogene overlap and MET amplicon size decline with increase in MET plasma copy number (pCN), thus enriching for MET-dependent states. PATIENTS AND METHODS: We interrogated cell-free DNA NGS results of 16,782 patients with newly diagnosed advanced NSCLC to identify those with MET amplification as reported using Guardant360. Co-occurring genomic mutations and copy number alterations within each sample were evaluated. An exploratory method of adjusting for tumor fraction was also performed and amplicon size for MET was analyzed when available. RESULTS: MET amplification was detected in 207 (1.2%) of samples. pCN ranged from 2.1 to 52.9. Of these, 43 (20.8%) had an overlapping oncogenic driver, including 23 (11.1%) METex14 skipping or other MET mutations. The degree of (non-MET) oncogene overlap decreased with increases in pCN. Patients with MET pCN ≥ 2.7 had lower rates of overlapping drivers compared to those with MET pCN < 2.7 (6.1% vs. 16.3%, P = .033). None of the 7 patients with pCN > 6.7 had an overlapping driver. After adjusting for tumor fraction, adjusted pCN (ApCN) was also lower for those with overlapping drivers than those without (median ApCN 4.9 vs. 7.3, P =.024). There was an inverse relationship between amplicon size and pCN. CONCLUSIONS: We propose that a high MET pCN and/or ApCN, together with the absence of overlapping oncogenic drivers and small MET amplicon size, will enrich for patients most likely to derive benefit from MET targeted therapy.