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Nanoplasmonic structures designed for trace analyte detection using surface-enhanced Raman spectroscopy typically require sophisticated nanofabrication techniques. An alternative to fabricating such substrates is to rely on self-assembly of nanoparticles into close-packed arrays at liquid/liquid or liquid/air interfaces. The density of the arrays can be controlled by modifying the nanoparticle functionality, pH of the solution and salt concentration. Importantly, these arrays are robust, self-healing, reproducible and extremely easy to handle. Here, we report on the use of such platforms formed by Au nanoparticles for the detection of multi-analytes from the aqueous, organic or air phases. The interfacial area of the Au array in our system is ≈25 mm 2 and can be made smaller, making this platform ideal for small-volume samples, low concentrations and trace analytes. Importantly, the ease of assembly and rapid detection make this platform ideal for in-the-field sample testing of toxins, explosives, narcotics or other hazardous chemicals. Nanoplasmonic structures that can detect trace analytes via surface-enhanced Raman spectroscopy typically require sophisticated nanofabrication techniques. Self-assembly of gold nanoparticles into close-packed arrays at liquid/liquid and liquid/air interfaces is now used for the detection of multi-analytes from aqueous, organic or air phases.

To investigate incidence, treatment patterns and outcomes of gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) in the United States. The 2019 National Cancer Database was searched for adult GEP-NEN patients. Main outcomes included overall and site-specific incidence, treatment patterns, and overall survival (OS). Overall survival was evaluated using averaged Cox regression. 86,324 GEP-NEN patients were included (6.33% of all GEP malignancies). From 2004 to 2016, annual GEP-NEN cases increased ( n  = 4,010 to n  = 9,379), largely driven by low-stage, low-grade disease. Most patients received surgery, either alone (72.9%) or in combination with systemic therapy (4.9%). Longest overall survival (OS) was evident in patients with low stage and low grade GEP-NEN of the small intestine and rectum ( p  < 0.001). Patients undergoing surgical resection demonstrated longest OS. The addition of systemic therapy was most effective in high stage G3 NEN. Having higher income ( ≥ $63,333) and private insurance or Medicare, but not Medicaid, was associated with improved survival. GEP-NEN incidence increases, likely due to improved detection and diagnosis. Treatment patterns have evolved to follow the latest international guidelines and site-specific improvement in survival is noted. In addition to disease specific factors, insurance access and socioeconomic factors emerged as potential targets for improving outcomes.

Background TAS-102 (trifluridine and tipiracil hydrochloride; a novel combination oral nucleoside anti-tumor agent) has recently received regulatory approval for patients with refractory metastatic colorectal cancer (mCRC). Internal review of data at a single-institution showed a trend towards better overall survival (OS) for patients who experienced chemotherapy-induced neutropenia at 1-month (CIN-1-month). To explore this finding further, a cohort study was designed based on outcome data from three centers in United States and one from Japan. Methods CIN-1-month after starting TAS-102 was defined by the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 as a neutrophil count decrease of ≥ grade 2 (absolute neutrophil count < 1500/mm 3 ). Patients had confirmed mCRC that was refractory to standard therapies. Patient demographics and clinical characteristics were compared between patients with CIN-1-month ( CIN-1-month positive ) versus those who did not have CIN-1-month ( CIN-1-month negative ); with the median progression-free survival (PFS) and OS were calculated using the Kaplan-Meier method, and differences evaluated using the Log-rank test. Results Our cohort study had a total of 149 patients with data regarding their neutrophil assessment at 1-month mark. Patients who developed ≥ grade 2 CIN-1-month had a both longer PFS (median 3.0 months versus 2.4 months; Log-rank P -value = 0.01), as well as OS (14.0 versus 5.6 months; Log-rank P -value < 0.0001). Only CIN-1-month (adjusted HR: 0.21 (95 % CI: 0.11–0.38) and higher baseline CEA levels (adjusted HR: 2.00 (95 % CI: 1.22–3.35) were noted to be independent predictors of OS. Furthermore, the CIN-1-month was noted to be a statistically significantly predictor of OS over a wide range of cutoffs. Conclusions Our observations are novel and hypothesis generating. Neutropenia after starting TAS-102 was associated with better prognosis in patients with refractory mCRC. It can be postulated that the dosage of TAS-102 potentially may need to be increased to achieve better outcomes in patients not experiencing any neutropenia. Further pharmacologic investigations should help elucidate these issues.

Expert consensus on the potential benefits of early cancer detection does not exist for most cancer types. We convened 10 practicing oncologists using a RAND/UCLA modified Delphi panel to evaluate which of 20 solid tumors, representing >40 American Joint Committee on Cancer (AJCC)-identified cancer types and 80% of total cancer incidence, would receive potential clinical benefits from early detection. Pre-meeting, experts estimated how long cancers take to progress and rated the current curability and benefit (improvement in curability) of an annual hypothetical multi-cancer screening blood test. Post-meeting, experts rerated all questions. Cancers had varying estimates of the potential benefit of early cancer detection depending on estimates of their curability and progression by stage. Cancers rated as progressing quickly and being curable in earlier stages (stomach, esophagus, lung, urothelial tract, melanoma, ovary, sarcoma, bladder, cervix, breast, colon/rectum, kidney, uterus, anus, head and neck) were estimated to be most likely to benefit from a hypothetical screening blood test. Cancer types rated as progressing quickly but having comparatively lower cure rates in earlier stages (liver/intrahepatic bile duct, gallbladder, pancreas) were estimated to have medium likelihood of benefit from a hypothetical screening blood test. Cancer types rated as progressing more slowly and having higher curability regardless of stage (prostate, thyroid) were estimated to have limited likelihood of benefit from a hypothetical screening blood test. The panel concluded most solid tumors have a likelihood of benefit from early detection. Even among difficult-to-treat cancers (e.g., pancreas, liver/intrahepatic bile duct, gallbladder), early-stage detection was believed to be beneficial. Based on the panel consensus, broad coverage of cancers by screening blood tests would deliver the greatest potential benefits to patients.

Checkpoint inhibitors represent an effective treatment approach for a variety of cancers through their inhibition of immune regulatory pathways within the tumor microenvironment (TME). Unfortunately only a minority of patients with cancer achieve clinical benefit from immunotherapy, with the TME emerging as an important predictor of outcomes and sensitivity to therapy. The extent and pattern of T-cell infiltration can vary prominently within/across tumors and represents a biological continuum. Three immune profiles have been identified along this continuum: ‘immune-desert’ or ‘T-cell cold’ phenotype, ‘immune-active’, ‘inflamed’, or ‘T-cell hot’ phenotype, and ‘immune excluded’ phenotype. Of the three profiles, immune excluded remains the most ill-defined with no clear, universally accepted definition even though it is commonly associated with lack of response to immune checkpoint inhibitors and poor clinical outcomes. To address this, 16 multidisciplinary cancer experts from around the world were invited to participate in a symposium using a three-round modified Delphi approach. The first round was an open-ended questionnaire distributed via email and the second was an in-person discussion of the first round results that allowed for statements to be revised as necessary to achieve a maximum consensus (75% agreement) among the rating committee (RC). The final round questionnaire was distributed to the RC via email and had a 100% completion rate. The Delphi process resulted in moving us closer to a consensus definition for immune exclusion that is practical, clinically pertinent, and applicable across a wide range of cancer histologies. A general consensus of the role of immune exclusion in resistance to checkpoint therapy and five research priorities emerged from this process. Together, these tools could help efforts designed to address the underlying mechanisms of immune exclusion that span cancer types and, ultimately, aid in the development of treatments to target these mechanisms to improve patient outcomes.

IntroductionThe epigenetic silencing of O6-methylguanine DNA methyltransferase (MGMT) is associated with reduced DNA repair capacity, carcinogenesis and increased sensitivity to alkylating chemotherapy. However, the biological role and clinical significance of MGMT overexpression in cancer remains poorly understood.MethodsUsing multiplexed quantitative immunofluorescence we measured the localized levels of MGMT protein, γH2AX and CD8+ T cells in multiple retrospective colorectal cancer (CRC) cohorts. Genomic and transcriptomic features of selected cases were also studied with whole exome DNA sequencing and genome-wide methylation analysis. MGMT-methylated human CRC cells SW620 were transfected with an MGMT-containing plasmid and co-cultured with allogeneic peripheral blood mononuclear cells.ResultsA subset of CRCs showed MGMT protein upregulation associated with lower γH2AX, reduced CD8+ tumor infiltrating lymphocytes (TILs), mismatch repair proficient (pMMR) status and shorter survival. CD8+ TILs were more distant from MGMT-expressing cells than MGMT-negative cells and the MGMT promoter methylation status did not highly correlate with MGMT protein levels in CRC. In genomic/transcriptomic analysis, high MGMT expression was associated with a lower nonsynonymous somatic mutational burden, higher transition-to-transversion mutation ratio, increased deleterious TP53 variants and distinct transcriptomic profiles. The exogenous expression of MGMT in SW620 CRC cells reduced the number of spontaneous nonsynonymous mutations, reproduced mutational features of MGMT-high CRC and limited the in vitro T-cell-mediated killing of malignant cells induced by proinflammatory cytokines in tumor/immune cell co-cultures.ConclusionsMGMT overexpression identifies a previously undescribed subset of CRCs with distinct biological and clinical properties including reduced mutagenesis, adaptive immune evasion, predominantly pMMR phenotype and aggressive clinical course. Direct, quantitative assessment of MGMT protein expression using spatially resolved analysis is more reliable than inference of MGMT expression by promoter methylation status in CRC.

Background Treatment for metastatic colorectal cancer patients beyond the second line remains challenging, highlighting the need for early phase trials of combination therapies for patients who had disease progression during or following two prior lines of therapy. Leveraging hybrid control design in these trials may preserve the benefits of randomization while strengthening evidence by integrating historical trial data. Few examples have been established to assess the applicability of such design in supporting early phase metastatic colorectal cancer trials. Methods MORPHEUS-CRC is an umbrella, multicenter, open-label, phase Ib/II, randomized, controlled trial (NCT03555149), with active experimental arms ongoing. Patients enrolled were assigned to a control arm (regorafenib, 15 patients randomized and 13 analysed) or multiple experimental arms for immunotherapy-based treatment combinations. One experimental arm (atezolizumab + isatuximab, 15 patients randomized and analysed) was completed and included in the hybrid-control study, where the hybrid-control arm was constructed by integrating data from the IMblaze370 phase 3 trial (NCT02788279). To estimate treatment efficacy, Cox and logistic regression models were used in a frequentist framework with standardized mortality ratio weighting or in a Bayesian framework with commensurate priors. The primary endpoint is objective response rate, while disease control rate, progression-free survival, and overall survival were the outcomes assessed in the hybrid-control study. Results The experimental arm showed no efficacy signal, yet a well-tolerated safety profile in the MORPHEUS-CRC trial. Treatment effects estimated in hybrid control design were comparable to those in the MORPHEUS-CRC trial using either frequentist or Bayesian models. Conclusions Hybrid control provides comparable treatment-effect estimates with generally improved precision, and thus can be of value to inform early-phase clinical development in metastatic colorectal cancer. Plain language summary Treatment of patients with metastatic colorectal cancer – meaning that it has spread to other parts of the body – is difficult, and new therapies are needed for patients when standard therapies stop working. We compare a combination of drugs with a standard treatment for patients with metastatic colorectal cancer in a clinical trial, in which patients are randomly allocated to either the combination or the control (standard) treatment. We find that while the combination is safe, it isn’t effective. We also show, however, that we can combine data from our control group and the control group of a previous trial to more precisely estimate treatment effects. Statistical approaches such as this to combine data from trials may mean that fewer patients have to be recruited to control groups in future trials, to improve access to potentially effective new treatments. Li et al. report outcomes from the atezolizumab/isatuximab arm of the phase Ib/II MORPHEUS-CRC trial in patients with metastatic colorectal cancer. In addition, the authors leverage historical control data from the phase III IMblaze370 study to provide more precise treatment effect estimates.

Homologous recombination (HR) and nucleotide excision repair (NER) are the two most frequently disabled DNA repair pathways in cancer. HR-deficient breast, ovarian, pancreatic and prostate cancers respond well to platinum chemotherapy and PARP inhibitors. However, the frequency of HR deficiency in gastric and esophageal adenocarcinoma (GEA) still lacks diagnostic and functional validation. Using whole exome and genome sequencing data, we found that a significant subset of GEA, but very few colorectal adenocarcinomas, show evidence of HR deficiency by mutational signature analysis (HRD score). High HRD gastric cancer cell lines demonstrated functional HR deficiency by RAD51 foci assay and increased sensitivity to platinum chemotherapy and PARP inhibitors. Of clinical relevance, analysis of three different GEA patient cohorts demonstrated that platinum treated HR deficient cancers had better outcomes. A gastric cancer cell line with strong sensitivity to cisplatin showed HR proficiency but exhibited NER deficiency by two photoproduct repair assays. Single-cell RNA-sequencing revealed that, in addition to inducing apoptosis, cisplatin treatment triggered ferroptosis in a NER-deficient gastric cancer, validated by intracellular GSH assay. Overall, our study provides preclinical evidence that a subset of GEAs harbor genomic features of HR and NER deficiency and may therefore benefit from platinum chemotherapy and PARP inhibitors.

BackgroundThe release of ATP from dying cancer cells in response to platinum-based chemotherapy increases extracellular adenosine, which binds to and activates A2aR and A2bR receptors to generate an immunosuppressive microenvironment. This is mediated by the activation of A2aR on intra-tumoral T and NK cells, A2aR and A2bR on tumor-infiltrating myeloid cells, and A2bR on cancer cells.1 Importantly, expression of A2bR and CD73, an adenosine-producing enzyme, on cancer cells is upregulated by oncogenic drivers such as KRAS.2 Consistent with this, tumors from CRC subjects express high levels of A2bR. Adenosine receptor blockade may therefore enhance the therapeutic efficacy of certain chemotherapeutic agents. AB928 is the first clinical-stage small-molecule dual adenosine receptor antagonist, targeting both A2aR and A2bR. The preliminary safety and clinical efficacy of AB928 + mFOLFOX-6 in metastatic colorectal cancer (ARC-3; NCT03720678) were recently described.3 This presentation describes the preliminary identification of molecular markers that correlate with the extent of clinical benefit in this trial.MethodsA total of 35 subjects enrolled in this study: 12 (1L); 4 (2L); and 19 (3L+). Baseline and on-treatment biopsy samples were subjected to immunofluorescent staining as well as WES and RNAseq analysis.ResultsAnalysis of the primary CRC dataset in TCGA highlights this tumor type as having high levels of CD73, coupled with a paucity of Tissue Nonspecific Alkaline Phosphatase (TNAP), another enzyme that can produce adenosine. In our mCRC study samples, TNAP was often present, being expressed on either stroma or tumor and in a non-overlapping manner with CD73. Analysis of the expression levels of these enzymes and other proteins involved in the adenosine axis (e.g., A2bR) revealed trends that could have predictive value, particularly in late-line subjects. Correlative trends were also observed between the infiltration of lymphocytes within baseline tumor samples and the extent of clinical benefit. Based on a preliminary and ongoing analysis of baseline biopsies, a number of molecular markers may correlate with better clinical outcomes, most relevantly in late-line mCRC subjects treated with AB928 + mFOLFOX-6. These data suggest the possibility that adenosine-related markers may be helpful in future studies for selection of patients to be treated with AB928 + mFOLFOX-6 therapy.ConclusionsN/AAcknowledgementsN/ATrial RegistrationNCT03720678Ethics ApprovalThe study was approved by all the study site Institution’s Ethics Boards, with Advarra IRB being the first, approval number SSU00070639 in USA.ConsentN/AReferencesVijayan D, et al. Nat Rev Cancer. 2017;17(12):765Udyavar A, et.al AACR Annual Meeting 2019.Cecchini M, et.al. AACR Annual Meeting 2020.