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Background: Inflammatory breast cancer (IBC) is a rare but aggressive tumor type accounting for up to 10% of breast cancer deaths. One-third of IBCs express high PD-L1 that can be targeted by atezolizumab (Az). MEK inhibitor cobimetinib (Co) not only inhibits the RAS-MAPK pathway but can further enhance immune-mediated killing. Thus, we hypothesize that Az+Co may enhance the efficacy of chemotherapy in metastatic IBC (mIBC). We opened a trial to test this hypothesis with a comprehensive multi-omics biomarker assessment. Patients and Methods: In a single-center, open-label phase II study, cohort 1 received one cycle of Az+ Co, followed by four cycles of Az+Co+eribulin (E) to induce a maximum clinical response, followed by Az+Co maintenance. Pre and Post one cycle of Az+Co tumors were collected for immunohistochemistry (IHC), multiplex immunofluorescence (mIF), whole-exome sequencing (WES), and RNA sequencing (RNAseq). Blood was collected for circulating tumor DNA (ctDNA). Results: Seventeen patients were enrolled in cohort 1. Seven had PR, and three had SD as the best responses. Fourteen had pre, and six had pre/post tumors. The levels of PD-L1 expression at pre/post were not associated with responses. WES revealed the median tumor mutation burden at pre- was 9mt/Mb. More than 50% had TP53 and PI3K pathway mutations at pre. RTK-RAS and Notch pathways were altered in 4/9 cases. PRDM9 and DPY19L2 single-gene mutations were commonly noted in pre. No cancer-associated gene aberration, including potential biomarkers of anti-PDL1 agent response was associated with clinical outcomes. Transcriptomic gene set enrichment analysis demonstrated a greater degree of TNFa and TGFb signaling, Oxphos, angiogenesis, and epithelial-to-mesenchymal transition (EMT) processes in tumors from patients with poor response. Immune profiling by RNAseq revealed two responders to have elevated effector memory T cells, NK T cells, myeloid dendritic cells, and M1 macrophage signatures in pre-samples, but post-samples were not available. mIF confirmed a higher frequency of NK-T cells. The ctDNA analysis from serially collected blood samples is ongoing. Discussion: In this comprehensive multi-omics analysis of pre-and-post-Az+Co, we observed several novel findings, while conventional biomarkers for Az and Co did not correlate with clinical responses. EMT, Oxphos, Notch, and chronic inflammation pathways, which are not previously well reported, were observed in this IBC cohort. These markers warrant further validation to see if they carry significance as therapeutic targets in IBC. Citation Format: Bora Lim, Angela Alexander, Jie S. Willey, Huiming Sun, Suyu Liu, Anisha B. Patel, Edwin Roger Parra, Cara Haymaker, Luisa Solis Soto, Alejandra Serrano, Baohua Sun, Cibelle Freitas Pinto Lima, Auriole Tamegnon, Renganayaki K. Pandurengan, Dzifa Douse, Jessica Lan, Luthra Raja, Randy Chu, Mark Knafl, Scott E. Woodman, Haifeng Zhu, Katja Shulze, Katherine Fedenko, Walter Darbonne, Naoto T. Ueno, Vicente Valero. Biomarker analysis: Multi-omics elucidation of Cohort 1 from a phase II study of a triple combination of Atezolizumab + cobimetinib + eribulin in patients with metastatic inflammatory breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-19.

New antimicrobial peptides (AMPs) were developed with selective antifungal activity and high efficiency in wound healing.

The benefit of local consolidative therapy (LCT) for oligometastasis across histologies remains uncertain. EXTernal beam radiation to Eliminate Nominal metastatic Disease (EXTEND; NCT03599765) is a randomized phase 2 basket trial evaluating the effectiveness of LCT for oligometastatic solid tumors. We report here the prospective results of the single-arm "lead-in" phase intended to identify histologies most likely to accrue to histology-specific endpoints in the randomized phase.Eligible histologies included colorectal, sarcoma, lung, head and neck, ovarian, renal, melanoma, pancreatic, prostate, cervix/uterine, breast, and hepatobiliary. Patients received LCT to all sites of active metastatic disease and primary/regional disease (as applicable) plus standard-of-care systemic therapy or observation. The primary endpoint in EXTEND was progression-free survival (PFS), and the primary endpoint of the lead-phase was histology-specific accrual feasibility. Adverse events were graded by Common Terminology Criteria for Adverse Events version 4.0.From August 2018 through January 2019, 50 patients were enrolled and 49 received definitive LCT. Prostate, breast, and kidney were the highest enrolling histologies and identified for independent accrual in the randomization phase. Most patients (73%) had 1 or 2 metastases, most often in lung or bone (79%), and received ablative radiation (62%). Median follow-up for censored patients was 38 months (range, 16-42 months). Median PFS was 13 months (95% confidence interval, 9-24), 3-year overall survival rate was 73% (95% confidence interval, 57%-83%), and local control rate was 98% (93 of 95 tumors). Two patients (4%) had Common Terminology Criteria for Adverse Events grade 3 toxic effects related to LCT; no patient had grade 4 or 5 toxic effects.The prospective lead-in phase of the EXTEND basket trial demonstrated feasible accrual, encouraging PFS, and low rates of severe toxic effects at mature follow-up. The randomized phase is ongoing with histology-based baskets that will provide histology-specific evidence for LCT in oligometastatic disease.

Nonalcoholic steatohepatitis (NASH) is the fastest growing cause of hepatocellular carcinoma (HCC) in the United States. Changes in

ImportanceDespite evidence demonstrating an overall survival benefit with up-front hormone therapy in addition to established synergy between hormone therapy and radiation, the addition of metastasis-directed therapy (MDT) to hormone therapy for oligometastatic prostate cancer, to date, has not been evaluated in a randomized clinical trial.ObjectiveTo determine in men with oligometastatic prostate cancer whether the addition of MDT to intermittent hormone therapy improves oncologic outcomes and preserves time with eugonadal testosterone compared with intermittent hormone therapy alone.Design, Setting, ParticipantsThe External Beam Radiation to Eliminate Nominal Metastatic Disease (EXTEND) trial is a phase 2, basket randomized clinical trial for multiple solid tumors testing the addition of MDT to standard-of-care systemic therapy. Men aged 18 years or older with oligometastatic prostate cancer who had 5 or fewer metastases and were treated with hormone therapy for 2 or more months were enrolled to the prostate intermittent hormone therapy basket at multicenter tertiary cancer centers from September 2018 to November 2020. The cutoff date for the primary analysis was January 7, 2022.InterventionsPatients were randomized 1:1 to MDT, consisting of definitive radiation therapy to all sites of disease and intermittent hormone therapy (combined therapy arm; n = 43) or to hormone therapy only (n = 44). A planned break in hormone therapy occurred 6 months after enrollment, after which hormone therapy was withheld until progression.Main Outcomes and MeasuresThe primary end point was disease progression, defined as death or radiographic, clinical, or biochemical progression. A key predefined secondary end point was eugonadal progression-free survival (PFS), defined as the time from achieving a eugonadal testosterone level (≥150 ng/dL; to convert to nanomoles per liter, multiply by 0.0347) until progression. Exploratory measures included quality of life and systemic immune evaluation using flow cytometry and T-cell receptor sequencing.ResultsThe study included 87 men (median age, 67 years [IQR, 63-72 years]). Median follow-up was 22.0 months (range, 11.6-39.2 months). Progression-free survival was improved in the combined therapy arm (median not reached) compared with the hormone therapy only arm (median, 15.8 months; 95% CI, 13.6-21.2 months) (hazard ratio, 0.25; 95% CI, 0.12-0.55; P P = .03). Flow cytometry and T-cell receptor sequencing demonstrated increased markers of T-cell activation, proliferation, and clonal expansion limited to the combined therapy arm.Conclusions and RelevanceIn this randomized clinical trial, PFS and eugonadal PFS were significantly improved with combination treatment compared with hormone treatment only in men with oligometastatic prostate cancer. Combination of MDT with intermittent hormone therapy may allow for excellent disease control while facilitating prolonged eugonadal testosterone intervals.Trial RegistrationClinicalTrials.gov Identifier: NCT03599765

Supplementary Table #1

Significant morbidity and expense result from frequent recurrences of nonmuscle-invasive bladder cancer (NMIBC) after standard treatment, and carcinoma in situ (Tis) is a poor prognostic factor. Predicated on observational and preclinical data strongly supporting cyclooxygenase-2 (COX-2) in the pathogenesis, and the activity of COX-2 inhibitors, in bladder cancer, we conducted a randomized, double-blind, placebo-controlled trial to determine whether celecoxib could reduce the time-to-recurrence (TTR) in NMIBC patients at high risk for recurrence. A total of 146 patients were randomized to celecoxib (200 mg) or placebo orally twice daily for at least 12 months. The average treatment duration was 1.25 years. Primary intent-to-treat analysis revealed celecoxib did not statistically significantly prolong TTR compared with placebo (P = 0.17, log rank) with a median follow-up of 2.49 years. The recurrence-free rate at 12 months with celecoxib was 88% (95% CI: 0.81–0.96) versus 78% (95% CI: 0.69–0.89) with placebo. After controlling for covariates with Cox regression analysis, recurrence rates did not differ between the two study arms (HR = 0.69; 95% CI: 0.37–1.29). However, celecoxib had a marginally significant effect on reducing metachronous recurrences (vs. placebo) with HR of 0.56 (95% CI: 0.3–1.06; P = 0.075). Celecoxib was well tolerated, with similar adverse events and quality-of-life in both arms. Our clinical trial results do not show a clinical benefit for celecoxib in preventing NMIBC recurrence but further investigation of COX-2 inhibitors in this setting is warranted. Cancer Prev Res; 4(10); 1580–9. ©2011 AACR.

Perspective on This Article from A Randomized Controlled Trial of Celecoxib to Prevent Recurrence of Nonmuscle-Invasive Bladder Cancer

Malignant peritoneal mesothelioma (MPeM) is a rare but aggressive malignancy with limited treatment options. VEGF inhibition enhances efficacy of immune-checkpoint inhibitors by reworking the immunosuppressive tumor milieu. Efficacy and safety of combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade (AtezoBev) was assessed in 20 patients with advanced and unresectable MPeM with progression or intolerance to prior platinum–pemetrexed chemotherapy. The primary endpoint of confirmed objective response rate per RECISTv1.1 by independent radiology review was 40% [8/20; 95% confidence interval (CI), 19.1–64.0] with median response duration of 12.8 months. Six (75%) responses lasted for >10 months. Progression-free and overall survival at one year were 61% (95% CI, 35–80) and 85% (95% CI, 60–95), respectively. Responses occurred notwithstanding low tumor mutation burden and PD-L1 expression status. Baseline epithelial–mesenchymal transition gene expression correlated with therapeutic resistance/response (r = 0.80; P = 0.0010). AtezoBev showed promising and durable efficacy in patients with advanced MPeM with an acceptable safety profile, and these results address a grave unmet need for this orphan disease.Significance:Efficacy of atezolizumab and bevacizumab vis-à-vis response rates and survival in advanced peritoneal mesothelioma previously treated with chemotherapy surpassed outcomes expected with conventional therapies. Biomarker analyses uncovered epithelial–mesenchymal transition phenotype as an important resistance mechanism and showcase the value and feasibility of performing translationally driven clinical trials in rare tumors.See related commentary by Aldea et al., p. 2674.This article is highlighted in the In This Issue feature, p. 2659

Early detection of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcomes; however, PDAC is usually diagnosed late. Therefore, blood-based minimally invasive biomarker assays for limited volume clinical samples are urgently needed. A novel miRNA profiling platform (Abcam Fireplex-Oncology Panel) was used to investigate the feasibility of developing early detection miRNA biomarkers with 20 μL plasma from a training set (58 stage II PDAC cases and 30 controls) and two validation sets (34 stage II PDAC cases and 25 controls; 44 stage II PDAC cases and 18 controls). miR-34a-5p [AUC = 0.77; 95% confidence interval (CI), 0.66–0.87], miR-130a-3p (AUC = 0.74; 95% CI, 0.63–0.84), and miR-222-3p (AUC = 0.70; 95% CI, 0.58–0.81) were identified as significantly differentially abundant in plasma from stage II PDAC versus controls. Although none of the miRNAs individually outperformed the currently used serologic biomarker for PDAC, carbohydrate antigen 19-9 (CA19-9), combining the miRNAs with CA 19-9 improved AUCs from 0.89 (95% CI, 0.81–0.95) for CA 19-9 alone to 0.92 (95% CI, 0.86–0.97), 0.94 (95% CI, 0.89–0.98), and 0.92 (95% CI, 0.87–0.97), respectively. Gene set enrichment analyses of transcripts correlated with high and low expression of the three miRNAs in The Cancer Genome Atlas PDAC sample set. These miRNA biomarkers, assayed in limited volume plasma together with CA19-9, discriminate stage II PDAC from controls with good sensitivity and specificity. Unbiased profiling of larger cohorts should help develop an informative early detection biomarker assay for diagnostic settings.Prevention Relevance:Development of minimally invasive biomarker assays for detection of premalignant disease and early-stage pancreatic cancer is key to improving patient survival. This study describes a limited volume plasma miRNA biomarker assay that can detect early-stage resectable pancreatic cancer in clinical samples necessary for effective prevention and clinical intervention.

Supplementary Tables 1-3 and Table A-1, Figure 1, Appendix and Information from The BATTLE Trial: Personalizing Therapy for Lung Cancer

Supplemental Figure #1

Supplementary Data from Immunohistochemical Expression of Estrogen and Progesterone Receptors Identifies a Subset of NSCLCs and Correlates with EGFR Mutation

Supplementary Figure 1: Heatmap of the 68 non-small cell lung cancer cell lines with EGFR wild-type used to train the Sorafenib Sensitivity Signature; Supplementary Figure 2: Heatmap of the 37 patients with EGFR mutant tumors using the Sorafenib Sensitivity signature; yes: disease control at 8 weeks; no: no disease control at 8 weeks.

Purpose: To report the clinical efficacy of sorafenib and to evaluate biomarkers associated with sorafenib clinical benefit in the BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) program.Patients and Methods: Patients with previously treated non–small cell lung cancer (NSCLC) received sorafenib until progression or unacceptable toxicity. Eight-week disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were assessed. Prespecified biomarkers included K-RAS, EGFR, and B-RAF mutations, and EGFR gene copy number. Gene expression profiles from NSCLC cell lines and patient tumor biopsies with wild-type EGFR were used to develop a sorafenib sensitivity signature (SSS).Results: A total of 105 patients were eligible and randomized to receive sorafenib. Among 98 patients evaluable for eight-week DCR, the observed DCR was 58.2%. The median PFS and OS were 2.83 [95% confidence interval (CI), 2.04–3.58] and 8.48 months (95% CI, 5.78–10.97), respectively. Eight-week DCR was higher in patients with wild-type EGFR than patients with EGFR mutation (P = 0.012), and in patients with EGFR gene copy number gain (FISH-positive) versus patients FISH-negative (P = 0.048). In wild-type EGFR tumors, the SSS was associated with improved PFS (median PFS 3.61 months in high SSS vs. 1.84 months in low SSS; P = 0.026) but not with eight-week DCR. Increased expression of fibroblast growth factor-1, NF-κB, and hypoxia pathways were identified potential drivers of sorafenib resistance.Conclusion: Sorafenib demonstrates clinical activity in NSCLC, especially with wild-type EGFR. SSS was associated with improved PFS. These data identify subgroups that may derive clinical benefit from sorafenib and merit investigation in future trials. Clin Cancer Res; 19(24); 6967–75. ©2013 AACR.

From the angle of Sustainable Development Goals (SDGs), this research note explores renewable energy in food supply chain and sustainable marine fishery. With an initial theoretical analysis, it is observed that the share of renewable energy, as reflected by SDG Indicator 7.2.1, can contribute to the measurement of and data computation for SDG Indicators 12.3.1 and 14.7.1. This is because renewable energy becomes a significant component of on board cost for harvesting, processing, and preserving fishes by marine vessels/fleets. Also renewable energy can be used to estimate food waste because it functions as an estimation for municipal solid waste if data is not directly available. A number of scientific and practical implications are generated. For example, more interdisciplinary studies on the interactions across SDGs should be encouraged, and more in-depth empirical research are also expected in future. The connections between renewable energy, food supply chain, and sustainable marine fishery also call for more holistic policies for sustainable development, with adequate consideration of disparities in country contexts. Effective actions should be taken to further enhance the statistical capacities of countries and international organizations, which will be a foundation for applying more sophisticated techniques into the analysis of data in this field. The main objectives of this short research note are to provoke more scientific thoughts and provide policy-oriented recommendations. It leaves spaces for more empirical evidence-based future research including another study under the author’s plan.

This article explores the relationship between social protection and gender gaps in using enabling technology with the perspective of Sustainable Development Goals (SDGs), as both are SDG Indicators. A cross-country comparative examination of 38 countries shows that gender disparity in mobile phone ownership is significantly and negatively correlated with the overall mobile phone owning rate and the proportion of females owning a mobile phone in a country. The coverage of social insurance programmes in a country has very weak and negative association with gender disparity in mobile phone ownership, and the correlation is statistically insignificant. The cross-country variations in mobile phone ownership are significant if gender is not considered. The results suggest that the social protection systems in these countries may not be gender-sensitive enough. A number of practical implications are provided based on the empirical evidence, and improvements in future studies are also suggested since this article is an initial output of a series of follow-up research in the author’s plan.

Characteristic towns are the continuation and development of the construction of "small towns", and have become an important node of the development of "urban-rural integration". Characteristic tourism town is one of the important models of rural tourism development. It plays an important role in promoting the solution of "Three rural issues", increasing farmers' opportunities for entrepreneurship and employment, improving farmers' income, building a beautiful countryside and finally realizing rural revitalization. The restrictive factors and main problems of the development of characteristic tourism towns in Northern Anhui are: single business model and shallow cultural excavation level. The development foundation is relatively weak, and the industrial products are not closely related. The essence of cultural characteristics is not fully reflected, which needs to be deeply excavated. Through the analysis, the following development ideas and countermeasures of characteristic tourism towns in Northern Anhui are formed: first, give full play to the resources with the most comparative advantages and take the road of characteristic development. Second, make leisure tourism closely related to the characteristic industries and products of small towns. Third, deeply excavate and fully absorb traditional culture, and create a new idea of developing characteristic tourism towns in Northern Anhui with the combination of culture and tourism. Fourth, actively explore the new mode of "Internet plus tourism".

Immunotherapy is an innovative treatment approach that harnesses a patient’s immune system to treat cancer. It has provided an alternative and complementary treatment modality to conventional chemotherapy. Combining immunotherapy with cytotoxic chemotherapy agent has become the leading trend and the most active research field in oncology. To accommodate this growing trend, we propose a Bayesian phase I/II dose-finding design to identify the optimal biological dose combination (OBDC), defined as the dose combination with the highest desirability in the risk-benefit trade-off. We propose new statistical models to describe the relationship between the doses and treatment outcomes, including immune response, toxicity and progression-free survival (PFS). During the trial, based on accrued data, we continuously update model estimates and adaptively assign patients to dose combinations with high desirability. The simulation study shows that our design has desirable operating characteristics.

In recent years, China’s higher education sector has started to establish special programs to train and support talents to seek career opportunities in the United Nations (UN). To explore these special programs and understand their relationship with China’s internationalization strategies and its higher education, we used the center-periphery model as the theoretical framework. We analyzed 53 institutional documents and conducted semi-structured interviews among 5 university staff members and 21 students/recent graduates who were involved in these special programs. The analysis on the special programs implied Chinese higher education’s peripheral position in supporting talents to work in the UN. This was reflected by the conforming practice, including accepting current UN recruitment regulations and English’s dominance in the UN recruitment practice. However, we also identified alternative dynamics that China and its higher education do not simply obey the center-periphery model and accept their peripheral status. Instead, special programs were established to achieve China’s global strategy of moving to the center of international arena via multilateralism and international organizations such as the UN. This study sheds light on further explorations of the state-university relationship in China in the globalization era, especially from the perspective of cultural diplomacy and soft power.