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Neutrophil extracellular traps (NETs), a web-like structure of cytosolic and granule proteins assembled on decondensed chromatin, kill pathogens and cause tissue damage in diseases. Whether NETs can kill cancer cells is unexplored. Here, we report that a combination of glutaminase inhibitor CB-839 and 5-FU inhibited the growth of PIK3CA-mutant colorectal cancers (CRCs) in xenograft, syngeneic, and genetically engineered mouse models in part through NETs. Disruption of NETs by either DNase I treatment or depletion of neutrophils in CRCs attenuated the efficacy of the drug combination. Moreover, NETs were present in tumor biopsies from patients treated with the drug combination in a phase II clinical trial. Increased NET levels in tumors were associated with longer progression-free survival. Mechanistically, the drug combination induced the expression of IL-8 preferentially in PIK3CA-mutant CRCs to attract neutrophils into the tumors. Further, the drug combination increased the levels of ROS in neutrophils, thereby inducing NETs. Cathepsin G (CTSG), a serine protease localized in NETs, entered CRC cells through the RAGE cell surface protein. The internalized CTSG cleaved 14-3-3 proteins, released BAX, and triggered apoptosis in CRC cells. Thus, our studies illuminate a previously unrecognized mechanism by which chemotherapy-induced NETs kill cancer cells.

Purpose: Disparities in cancer care delivery remain a pressing health-care crisis within the United States (US). The use of immune checkpoint inhibitors (ICIs) and their management may be a disparity generator that impacts survival. This retrospective study assessed disparities in a cohort of patients with a variety of solid tumors treated with ICIs within a single health-care organization focusing on the impact of race, socioeconomic status (SES) and site of care delivery on survival and the development of severe immune-related adverse events (irAEs). Patients and Methods: Manual chart review was performed on all patients with solid tumors treated with ICIs within a health-care organization from 2012 to 2018. Care delivery was dichotomized as DOP (disease-oriented provider at academic center) and COP (community oncology provider). Primary and secondary outcomes were overall survival (OS) and rates of grade 3-4 irAEs, respectively. Relationships with covariates of interest, including race, socioeconomic status and type of care delivery, were assessed among both outcomes. Results: A total of 1070 eligible patients were identified. Of those, 11.4% were of Black race, 59.7% had either non-small cell lung cancer (NSCLC) or melanoma and 82.8% had stage IV disease. Patients of Black race and lower SES were more likely to be treated by DOPs (p<0.0001). A superior OS was associated with care delivered by DOPs when compared to COPs (HR 0.68; 95% CI 0.56-0.84; p=0.0002), which was durable after accounting for race, SES, histopathologic diagnosis and disease stage. Melanoma patients experienced higher rates of severe irAEs (HR 2.37; 95% CI 1.42-3.97; p=0.001). Race, SES and site of care delivery were not related to rates of severe irAEs. Conclusion: In a large health-care organization, patients treated with checkpoint inhibitors by DOPs benefited from a significant OS advantage that was durable after controlling for racial and socioeconomic factors, providing evidence that disease-oriented care has the potential to mitigate racial and socioeconomic disparities. Keywords: disparities, healthcare delivery, immunotherapy outcomes

Background Standard clinical practice and national guidelines dictate somatic testing of metastatic colorectal cancer (mCRC) tumors to guide appropriate therapy; however, previous studies suggest that not all patients are tested. The objective of this study was to investigate potential differences in testing for mCRC by demographic and clinical factors. Methods We performed a retrospective review of de‐identified patient data derived from electronic health records (EHRs) of 25,469 patients diagnosed with mCRC between the years 2013 and 2020. Our outcome was a receipt of the following tests: (a) biomarker testing (BRAF, KRAS, NRAS, MMR/MSI) and (b) next‐generation sequencing (NGS). We interrogated our data using the machine‐learning algorithm Classification and Regression Tree (CART), a unique approach to identifying combinations of, rather than individual demographic and clinical characteristics associated with receipt of testing. Results A total of 25,469 patients were identified with mCRC. Of these, 21,133 (83%) received either biomarker testing only (n = 12,485) or any testing (biomarker + NGS) (n = 8648). The proportion of patients who received any testing increased over calendar time for all age, race, and sex categories. Receipt of any testing was highest (90%) among younger and patients with better performance status, and there was no difference in receipt of any testing by race. The highest percentage of NGS testing was among those with better performance status, <70 years old, commercial or other governmental program payers, and low comorbidity burden; however, those who were Black or Hispanic had a lower prevalence of NGS testing than those who were White. Conclusions and Relevance Considerable variations exist in somatic biomarker testing across subgroups of the population. Identification of genomic alterations can aid in determining targeted treatment and improving clinical outcomes; therefore, equitable use of these testing strategies, particularly NGS, is necessary. The objective of this study was to investigate potential differences in biomarker testing for mCRC by demographic and clinical factors. Identification of genomic alterations can aid in determining targeted treatment and improve clinical outcomes; therefore, equitable use of these testing strategies, particularly NGS, is necessary.

Background Multimodality therapy incorporating a combination of cytoreductive surgery (CRS), intraperitoneal (IP) and systemic therapy continues to evolve for peritoneal carcinomatosis (PC) However, treatment and outcomes vary depending on tumor of origin. Aims To develop Appropriate Use Criteria (AUC) guidelines to facilitate treatment decision‐making for patients with PC based on available evidence. Materials and Methods The American Radium Society (ARS) multidisciplinary expert panel performed a comprehensive systematic review. Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) methodology was used. These studies were used to inform the expert panel, which then rated the appropriateness of various treatments in seven representative clinical scenarios through a well‐established modified Delphi consensus methodology. Results Treatment of PC is often treated with a combination of CRS and IP ± systemic chemotherapy but specific recommendations exist for different tumor types and outcomes vary. Discussion Treatment of PC is complex and varies depending on origin of primary tumor and extent of disease. These AUC assist in patient and treatment selection for different clinical scenarios. Conclusion A summary of recommendations is outlined to guide practitioners on the management of PC from different tumor origins.

BackgroundImmuno-STATs are modular fusion proteins designed for the selective activation of tumor antigen specific CD8+ T cells. CUE-102, the second Immuno-STAT in clinical trials, is composed of a human leukocyte antigen (HLA) complex, HLA-A*0201, a peptide epitope derived from the Wilms Tumor 1 (WT1) protein, and 4 molecules of reduced affinity human interleukin-2 (IL-2), and is designed to bind, expand, and activate WT1-specific CD8+ T cells for the treatment of WT1+ cancers. In pre-clinical studies, CUE-102 elicits selective expansion of WT1-specific cytotoxic CD8+ T cells in vitro and in vivo.MethodsCUE-102–01 is a phase 1, 2-part study evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary antitumor activity of CUE-102 monotherapy administered every three weeks in HLA-A*02:01 positive patients with WT1+ recurrent/metastatic colorectal, gastric/gastroesophageal Junction (GEJ), pancreatic or ovarian cancer that has progressed on conventional therapies. Trial eligibility includes HLA-A*02:01 genotype and tumor WT1 protein expression by immunohistochemistry. Part A is a dose escalation phase following 3+3 design rules with a Bayesian Logistic Regression Model (BLRM) overlay. Dose levels that exhibit an immune or tumor response may be expanded to further characterize activity and toxicity as allowed by safety rules. Part B is a dose expansion/confirmation phase in patients with colorectal cancer. Objectives include characterization of safety, PK,PD, recommended phase 2 dose (RP2D), and preliminary anti-tumor activity.Results12 patients have received CUE-102 monotherapy as of June 27, 2023. Doses ranging from 1 mg/kg to 4 mg/kg were determined to be safe and well-tolerated, enabling dose escalation to 8 mg/kg. Preliminary PK data support that anticipated drug exposures are observed in patients. Characterization of post-treatment expansion of WT1-reactive T cells in peripheral blood is ongoing. Stable disease of ≥ 12 weeks, as determined by RECIST 1.1, has been observed in 2 patients (1 with colorectal; 1 with gastric cancer) in the early dose cohorts, allowing for dose expansion of the 2 mg/kg cohort. Data on safety, PK, PD and preliminary anti-tumor activity from additional patients will be presented.ConclusionsCUE-102 is a novel T cell activating agent that to date demonstrates acceptable tolerability, favorable PK, and supportive preliminary PD readouts. No DLTs or drug-related SAEs have been observed in doses up to 4 mg/kg as of the data cut-off. Adverse events have been manageable and consistent with the CUE-102 mechanism of action and underlying disease. Early signs of anti-tumor activity are encouraging.AcknowledgementsThe authors would like to thank all the patients who are participating in this study. The study is sponsored by Cue Biopharma, with support from LG Chem, Ltd., Seoul, South Korea.Trial RegistrationClinicaltrials.gov NCT05360680Ethics ApprovalThis study was approved by Ethics and Institutional Review Boards (IRBs) at all study sites. IRB names/reference numbers: UH IRB STUDY20221273, BRANY 22–06-326–01, WCG IRB1340057, Advarra MCC# 22112, JHU IRB00349569, MDACC 2022–0761. All participants gave informed consent before taking part.

Appendiceal neuroendocrine neoplasms (ANENs) usually present as incidental findings at the time of appendectomy for acute appendicitis. They are rare, accounting for only 0.5–1% of intestinal neoplasms; they are found in 0.3–0.9% of all appendectomy specimens. They are usually sporadic tumors. There are several histological types including well-differentiated neuroendocrine tumors (NETs), poorly differentiated neuroendocrine carcinomas (NECs), and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). Histologic differentiation and the grade of well-differentiated NETs correlate with clinical behavior and prognosis. Management varies based on differentiation, aggressiveness, and metastatic potential. There is debate about the optimal surgical management for localized appendiceal NETs that are impacted by many factors including the tumor size, the extent of mesoappendiceal spread, lymphovascular invasion and perineural involvement. In addition, the data to guide therapy in metastatic disease are limited due to the paucity of these tumors. Here, we review the current advances in the management of ANENs within the context of a multidisciplinary approach to these tumors.

Background The benefits of chemotherapy in stage II colon cancer remain unclear, but it is recommended for high-risk stage II disease. Which patients receive chemotherapy and its impact on survival remains undetermined. Methods The National Cancer Database was surveyed between 2004 and 2016 for stage II colon cancer patients. Patients were categorized as high- or average-risk as defined by the National Comprehensive Cancer Network. The demographic characteristics of high- and average-risk patients who did and did not receive chemotherapy were compared using univariate and multivariable analyses. The survival of high- and average-risk patients was compared based on receipt of chemotherapy with Cox hazard ratios and Kaplan–Meier curves. Results Overall, 84,424 patients met the inclusion criteria. A total of 34,868 patients were high-risk and 49,556 were average-risk. In high-risk patients, the risk factors for not receiving chemotherapy included increasing age, distance from the treatment facility, Charlson–Deyo score, and lack of insurance. In average-risk patients, factors associated with receipt of chemotherapy were decreasing age, distance from the treatment facility, Charlson–Deyo score, and non-academic association of the treatment facility. In both, chemotherapy was significantly associated with increased survival on the Kaplan–Meier curve. In the Cox hazard ratio, only high-risk patients benefited from chemotherapy (hazard ratio 1.183, confidence interval 1.116–1.254). Conclusions Factors associated with not receiving chemotherapy in high-risk stage II colon cancers included increasing age, medical comorbidities, increasing distance from the treatment facility, and lack of insurance. Chemotherapy is associated with improved overall survival in high-risk patients.

Background Racial/ethnic disparities in metastatic colorectal cancer (mCRC) survival are well documented as is the impact that tumor mutation of KRAS and BRAF has on prognosis. It has been suggested that frequency differences of KRAS- and BRAF- mutated tumors may partially explain this disparity. Demographic differences in mutation frequency are not well established nor whether mutation and microsatellite instability (MSI) differentially impact survival among groups. Methods Using data for 11,117 patients diagnosed with de-novo mCRC from an electronic health record-derived database we estimated adjusted odds ratios (aOR) to characterize the association between demographics and MSI and KRAS/NRAS/BRAF -mutation status. Stratified Cox models were used to identify differences in overall survival (OS), adjusting for treatment and demographics. Results Being female, compared to male, (aOR KRAS :1.33 (1.23–1.44); aOR BRAF :1.84 (1.56–2.16)), and non-Hispanic Black race (NHB), compared to non-Hispanic White (NHW) (aOR KRAS :1.62 (1.42–1.85); aOR BRAF : 0.55 (0.38–0.77)) were associated with KRAS- or BRAF- mutant tumors. MSI prevalence was similar across race/ethnicity but higher in women. BRAF- mutant tumors were associated with poorer prognosis overall, especially among non-white patients. Among patients who had KRAS/NRAS/BRAF- WT tumors we observed no difference in OS by race or MSI. Among patients with KRAS -mutant tumors, Hispanic patients had more favorable prognosis adjusted hazards ratio (aHR) = 0.76 (0.65–0.89)) than their NHW counterparts. Among those with BRAF- mutant tumors, NHB patients had poorer prognosis than NHW patients (aHR:1.78 (1.08–2.93)). Conclusion MSI and frequency of KRAS and BRAF mutations differed by demographics. Racial/ethnic disparities in OS differed by mutation. Future studies should explore biological and/or social determinants underlying these differences.