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Triple-negative inflammatory breast cancer (TN-IBC) is the most aggressive type of breast cancer, yet its defining genomic, molecular, and immunological features remain largely unknown. In this study, we performed the largest and most comprehensive genomic and transcriptomic analyses of prospectively collected TN-IBC patient samples from a phase II clinical trial (ClinicalTrials.gov, NCT02876107, registered on August 22, 2016) and compared them to similarly analyzed stage III TN-non-IBC patient samples (ClinicalTrials.gov, NCT02276443, registered on October 21, 2014). We found that TN-IBC tumors have distinctive genomic, molecular, and immunological characteristics, including a lower tumor mutation load than TN-non-IBC, and an association of immunosuppressive tumor-infiltrating immune components with an unfavorable response to neoadjuvant chemotherapy. To our knowledge, this is the only study in which TN-IBC and TN-non-IBC samples were collected prospectively. Our analysis improves the understanding of the molecular landscape of the most aggressive subtype of breast cancer. Further studies are needed to discover novel prognostic biomarkers and druggable targets for TN-IBC., Competing Interests: Competing interests C.Y. has received research support (to the institution) from Amgen, Merck, Genentech, and GSK. N.T.U. holds consulting roles with the following companies: AstraZeneca Pharmaceuticals LP (USA and UK), Bayer AG, Bristol Myers Squibb Company, Carna Biosciences, Inc., CytoDyn Inc., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly and Company, Genentech, Inc., Genomic Health, Inc., Gilead Sciences, Inc., Lavender Health, OncoCyte Corporation, Pear Bio, Peptilogics, Inc., Pfizer Inc., Phoenix Molecular Designs, Preferred Medicine, Carisma Therapeutics, Inc., Sysmex Corporation, Takeda Pharmaceutical Company Limited (Japan), and Unitech Medical, Inc. N.T.U. holds consulting roles with the following companies: AstraZeneca Pharmaceuticals LP (USA and UK), Bayer AG, Bristol Myers Squibb Company, Carna Biosciences, Inc., CytoDyn Inc., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly and Company, Genentech, Inc., Genomic Health, Inc., Gilead Sciences, Inc., Lavender Health, OncoCyte Corporation, Pear Bio, Peptilogics, Inc., Pfizer Inc., Phoenix Molecular Designs, Preferred Medicine, Carisma Therapeutics, Inc., Sysmex Corporation, Takeda Pharmaceutical Company Limited (Japan), and Unitech Medical, Inc. N.T.U. has ownership of stock: Pear Bio and Phoenix Molecular Designs. N.T.U. holds speaker or preceptorship roles with the following companies: Daiichi Sankyo Co., Ltd., Kyowa Kirin Co., Ltd., Pfizer Inc., AstraZeneca Pharmaceuticals LP, Total Health Conferencing, and Eli Lilly and Company. N.T.U. has research agreements in place with the following companies: AnHeart Therapeutics Inc., Eisai Co., Ltd., Gilead Sciences, Inc., Phoenix Molecular Designs, Daiichi Sankyo, Inc., Puma Biotechnology, Inc., Merck Co., Oncolys BioPharma Inc., OBI Pharma Inc., ChemDiv, Inc., Tolero Pharmaceuticals, Inc., and VITRAC Therapeutics, LLC. All other authors have no relevant conflict of interest disclosures., (© 2024. The Author(s).)

Importance: Disparity in overall survival (OS) and differences in the frequency of driver gene variants by race and ethnicity have been separately observed in patients with colorectal cancer; however, how these differences contribute to survival disparity is unknown., Objective: To quantify the association of molecular, socioeconomic, and clinical covariates with racial and ethnic disparities in overall survival among patients with colorectal cancer., Design, Setting, and Participants: This single-center cohort study was conducted at a tertiary-level cancer center using relevant data on all patients diagnosed with colorectal cancer from January 1, 1973, to March 1, 2023. The relative contribution of variables to the disparity was determined using mediation analysis with sequential multivariate Cox regression models., Main Outcome: OS, from diagnosis date and from start of first-line chemotherapy., Results: The study population of 47 178 patients (median [IQR] age, 57.0 [49-66] years; 20 465 [43.4%] females and 26 713 [56.6%] males; 3.0% Asian, 8.7% Black, 8.8% Hispanic, and 79.4% White individuals) had a median (IQR) follow-up from initial diagnosis of 124 (174) months and OS of 55 (145) months. Compared with White patients, Black patients had worse OS (hazard ratio [HR], 1.16; 95% CI, 1.09-1.24; P <.001), whereas Asian and Hispanic patients had better OS (HR, 0.66; 95% CI, 0.59-0.74; P <.001; and 0.86; 95% CI, 0.81-0.92; P <.001, respectively). When restricted to patients with metastatic disease, the greatest disparity was between Black patients compared with White patients (HR, 1.2; 95% CI, 1.06-1.37; P <.001). Evaluating changes in OS disparity over 20 years showed disparity decreasing among Asian, Hispanic, and White patients, but increasing between Black patients and White patients (HRs, 1.18; 95% CI, 1.07-1.31 for 2008-2012; 1.24, 95% CI, 1.08-1.42 for 2013-2017; and 1.50; 95% CI, 1.20-1.87 for 2018-2023). Survival outcomes for first-line chemotherapy were worse for Black patients compared with White patients (median OS, 18 vs 26 months; HR, 1.30; 95% CI, 1.01-1.70). Among 7628 patients who had clinical molecular testing, APC, KRAS, and PIK3CA showed higher variant frequency in Black patients (false discovery rate [FDR], 0.01; < 0.001; and 0.01, respectively), whereas BRAF and KIT were higher among White patients (FDR, 0.001 and 0.01). Mediation analysis identified neighborhood socioeconomic status as the greatest contributor to OS disparity (29%), followed by molecular characteristics (microsatellite instability status, KRAS variation and BRAF variation, 10%), and tumor sidedness (9%)., Conclusions: This single-center cohort study identified substantial OS disparity and differing frequencies of driver gene variations by race and ethnicity. Socioeconomic status had the largest contribution but accounted for less than one-third of the disparity, with substantial contribution from tumor molecular features. Further study of the associations of genetic ancestry and the molecular pathogenesis of colorectal cancer with chemotherapy response is needed.

Purpose: Appendiceal adenocarcinoma (AA) remains an orphan disease with limited treatment options for patients unable to undergo surgical resection. Evidence supporting the efficacy of combined VEGF and PD-1 inhibition in other tumor types provided a compelling rationale for investigating this combination in AA, where immune checkpoint inhibitors have not been explored previously., Experimental Design: We conducted a prospective, single-arm phase II study evaluating efficacy and safety of atezolizumab in conjunction with bevacizumab (Atezo+Bev) in advanced, unresectable AA., Results: Patients treated with the Atezo+Bev combination had 100% disease control rate (1 partial response, 15 stable disease) with progression-free survival (PFS) of 18.3 months and overall survival not-yet-reached with median duration of follow-up of 40 months. These survival intervals were significantly longer relative to a clinically and molecularly matched synthetic control cohort treated with cytotoxic chemotherapy designed for colorectal cancer (PFS of 4.4 months, P = 0.041)., Conclusions: In light of recent data demonstrating a lack of efficacy of 5-fluorouracil-based chemotherapy, Atezo+Bev is a promising treatment option for patients with low-grade unresectable AA; further study is warranted., Significance: AA remains an orphan disease with limited systemic therapy options for patients who are not candidates for surgical resection. These data suggest activity from combined VEGF and PD-L1 inhibition that warrants further study., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: Dynamic operations platforms allow for cross-platform data extraction, integration, and analysis, although application of these platforms to large-scale oncology enterprises has not been described. This study presents a pipeline for automated, high-fidelity extraction, integration, and validation of cross-platform oncology data in patients undergoing treatment for rectal cancer at a single, high-volume institution., Methods: A dynamic operations platform was used to identify patients with rectal cancer treated at MD Anderson Cancer Center between 2016 and 2022 who had magnetic resonance imaging (MRI) imaging and preoperative treatment details available in the electronic health record (EHR). Demographic, clinicopathologic, tumor mutation, radiographic, and treatment data were extracted from the EHR using a methodology adaptable to any disease site. Data accuracy was assessed by manual review. Accuracy before and after implementation of synoptic reporting was determined for MRI data., Results: A total of 516 patients with localized rectal cancer were included. In the era after institutional adoption of synoptic reports, the dynamic operations platform extracted T (tumor) category data from the EHR with 95% accuracy compared with 87% before the use of synoptic reports, and N (lymph node) category with 88% compared with 58%. Correct extraction of pelvic sidewall adenopathy was 94% compared with 78%, and extramural vascular invasion accuracy was 99% compared with 89%. Neoadjuvant chemotherapy and radiation data were 99% accurate for patients who had synoptic data sources., Conclusion: Using dynamic operations platforms enables automated cross-platform integration of multiparameter oncology data with high fidelity in patients undergoing multimodality treatment for rectal cancer. These pipelines can be adapted to other solid tumors and, together with standardized reporting, can increase efficiency in clinical research and the translation of actionable findings toward optimizing patient outcomes.

Importance: Serum tumor markers carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 125 (CA125) have been useful in the management of gastrointestinal and gynecological cancers; however, there is limited information regarding their utility in patients with appendiceal adenocarcinoma., Objective: To assess the association of serum tumor markers (CEA, CA19-9, and CA125) with clinical outcomes and pathologic and molecular features in patients with appendiceal adenocarcinoma., Design, Setting, and Participants: This is a retrospective cohort study at a single tertiary care comprehensive cancer center. The median (IQR) follow-up time was 52 (21-101) months. Software was used to query the MD Anderson internal patient database to identify patients with a diagnosis of appendiceal adenocarcinoma and at least 1 tumor marker measured at MD Anderson between March 2016 and May 2023. Data were analyzed from January to December 2023., Main Outcomes and Measures: Association of serum tumor markers with survival in patients with appendiceal adenocarcinoma. Cox proportional hazards regression analyses were also performed to assess associations between clinical factors (serum tumor marker levels, demographics, and patient and disease characteristics) and patient outcomes (overall survival)., Results: A total of 1338 patients with appendiceal adenocarcinoma were included, with a median (range) age at diagnosis of 56.5 (22.3-89.6) years. The majority of the patients had metastatic disease (1080 patients [80.7%]). CEA was elevated in 742 of the patients tested (56%), while CA19-9 and CA125 were elevated in 381 patients (34%) and 312 patients (27%), respectively. Individually, elevation of CEA, CA19-9, or CA125 were associated with worse 5-year survival; elevated vs normal was 81% vs 95% for CEA (hazard ratio [HR], 4.0; 95% CI, 2.9-5.6), 84% vs 92% for CA19-9 (HR, 2.2; 95% CI, 1.4-3.4), and 69% vs 93% for CA125 (HR, 4.6; 95% CI, 2.7-7.8) (P < .001 for all). Quantitative evaluation of tumor markers was associated with outcomes. Patients with highly elevated (top 10th percentile) CEA, CA19-9, or CA125 had markedly worse survival, with 5-year survival rates of 59% for CEA (HR, 9.8; 95% CI, 5.3-18.0), 64% for CA19-9 (HR, 6.0; 95% CI, 3.0-11.7), and 57% for CA125 (HR, 7.6; 95% CI, 3.5-16.5) (P < .001 for all). Although metastatic tumors had higher levels of all tumor markers, when restricting survival analysis to 1080 patients with metastatic disease, elevated CEA, CA19-9, or CA125 were all still associated worse survival (HR for CEA, 3.4; 95% CI, 2.5-4.8; P < .001; HR for CA19-9, 1.8; 95% CI, 1.2-2.7; P = .002; and HR for CA125, 3.9; 95% CI, 2.4-6.4; P < .001). Interestingly, tumor grade was not associated with CEA or CA19-9 level, while CA-125 was slightly higher in high-grade tumors relative to low-grade tumors (mean value, 18.3 vs 15.0; difference, 3.3; 95% CI, 0.9-3.7; P < .001). Multivariable analysis identified an incremental increase in the risk of death with an increase in the number of elevated tumor markers, with an 11-fold increased risk of death in patients with all 3 tumor markers elevated relative to those with none elevated. Somatic mutations in KRAS and GNAS were associated with significantly higher levels of CEA and CA19-9., Conclusions and Relevance: In this retrospective study of serum tumor markers in patients with appendiceal adenocarcinoma, CEA, CA19-9, and CA125 were associated with overall survival in appendiceal adenocarcinoma. Given their value, all 3 biomarkers should be included in the initial workup of patients with a diagnosis of appendiceal adenocarcinoma.

The relevance of KRAS mutation alleles to clinical outcome remains inconclusive in pancreatic adenocarcinoma (PDAC). We conducted a retrospective study of 803 patients with PDAC (42% with metastatic disease) at MD Anderson Cancer Center. Overall survival (OS) analysis demonstrated that KRAS mutation status and subtypes were prognostic (p < 0.001). Relative to patients with KRAS wildtype tumors (median OS 38 months), patients with KRAS G12R had a similar OS (median 34 months), while patients with KRAS Q61 and KRAS G12D mutated tumors had shorter OS (median 20 months [HR: 1.9, 95% CI 1.2-3.0, p = 0.006] and 22 months [HR: 1.7, 95% CI 1.3-2.3, p < 0.001], respectively). There was enrichment of KRAS G12D mutation in metastatic tumors (34% vs 24%, OR: 1.7, 95% CI 1.2-2.4, p = 0.001) and enrichment of KRAS G12R in well and moderately differentiated tumors (14% vs 9%, OR: 1.7, 95% CI 1.05-2.99, p = 0.04). Similar findings were observed in the external validation cohort (PanCAN's Know Your Tumor® dataset, n = 408)., (© 2024. The Author(s).)

Importance: Serum tumor markers CEA, CA19-9, & CA125 have been useful in the management of gastrointestinal and gynecological cancers, however there is limited information regarding their utility in patients with appendiceal adenocarcinoma., Objective: Assessing the association of serum tumor markers (CEA, CA19-9, and CA125) with clinical outcomes, pathologic, and molecular features in patients with appendiceal adenocarcinoma., Design: This is a retrospective study with results reported in 2023. The median follow-up time was 43 months., Setting: Single tertiary care comprehensive cancer center., Participants: Under an approved Institutional Review Board protocol, the Palantir Foundry software system was used to query the MD Anderson internal patient database to identify patients with a diagnosis of appendiceal adenocarcinoma and at least one tumor marker measured at MD Anderson between 2016 and 2023., Results: A total of 1,338 patients with appendiceal adenocarcinoma were included, with a median age of 56.5 years. The majority of the patients had metastatic disease (80.7%). CEA was elevated in more than half of the patients tested (56%), while CA19-9 and CA125 were elevated in 34% and 27%, respectively. Individually, elevation of CEA, CA19-9, or CA125 were associated with worse 5-year survival; 82% vs 95%, 84% vs 92%, and 69% vs 93% elevated vs normal for CEA, CA19-9, and CA125 respectively (all p<0.0001). Quantitative evaluation of tumor markers increased prognostic ability. Patients with highly elevated (top 10 th percentile) CEA, CA19-9 or CA125 had markedly worse survival with 5-year survival rates of 59%, 64%, and 57%, respectively (HR vs. normal : 9.8, 6.0, 7.6, all p<0.0001). Although metastatic tumors had higher levels of all tumor markers, when restricting survival analysis to 1080 patients with metastatic disease elevated CEA, CA19-9 or CA125 were all still associated worse survival (HR vs. normal : 3.4, 1.8, 3.9, p<0.0001 for CEA and CA125, p=0.0019 for CA19-9). Interestingly tumor grade was not associated with CEA or CA19-9 level, while CA-125 was slightly higher in high relative to low-grade tumors (18.3 vs. 15.0, p=0.0009). Multivariable analysis identified an incremental increase in the risk of death with an increase in the number of elevated tumor markers, with a 11-fold increased risk of death in patients with all three tumor markers elevated relative to those with none elevated. Mutation in KRAS and GNAS were associated with significantly higher levels of CEA and CA19-9., Conclusions: These findings demonstrate the utility of measuring CEA, CA19-9, and CA125 in the management of appendiceal adenocarcinoma. Given their prognostic value, all three biomarkers should be included in the initial workup of patients diagnosed with appendiceal adenocarcinoma.

The relevance of KRAS mutation alleles to clinical outcome remains inconclusive in pancreatic adenocarcinoma (PDAC). We conducted a retrospective study of 803 PDAC patients (42% with metastatic disease) at MD Anderson Cancer Center. Overall survival (OS) analysis demonstrated that KRAS mutation status and subtypes were prognostic (p<0.001). Relative to patients with KRAS wildtype tumors (median OS 38 months), patients with KRAS G12R had a similar OS (median 34 months), while patients with KRAS Q61 and KRAS G12D mutated tumors had shorter OS (median 20 months [HR: 1.9, 95% CI 1.2-3.0, p=0.006] and 22 months [HR: 1.7, 95% CI 1.3-2.3, p<0.001], respectively). There was enrichment of KRAS G12D mutation in metastatic tumors (34% vs 24%, OR: 1.7, 95% CI 1.2-2.4, p=0.001) and enrichment of KRAS G12R in well and moderately differentiated tumors (14% vs 9%, OR: 1.7, 95% CI 1.05-2.99, p=0.04). Similar findings were observed in the external validation cohort (PanCAN's Know Your Tumor ® dataset, n=408)., Competing Interests: Additional Declarations: There is a conflict of interest Dan Zhao is an advisory board member for Affini-T and she has clinical trial contract with CARsgen and Mirati. Disclosures and Competing interests: This data has not been previously presented. COI disclosures pending from authors.

There is scant information on the clinical progression, end-of-life decisions, and cause of death of patients with cancer diagnosed with COVID-19. Therefore, we conducted a case series of patients admitted to a comprehensive cancer center who did not survive their hospitalization. To determine the cause of death, 3 board-certified intensivists reviewed the electronic medical records. Concordance regarding cause of death was calculated. Discrepancies were resolved through a joint case-by-case review and discussion among the 3 reviewers. During the study period, 551 patients with cancer and COVID-19 were admitted to a dedicated specialty unit; among them, 61 (11.6%) were nonsurvivors. Among nonsurvivors, 31 (51%) patients had hematologic cancers, and 29 (48%) had undergone cancer-directed chemotherapy within 3 months before admission. The median time to death was 15 days (95% confidence interval [CI], 11.8 to 18.2). There were no differences in time to death by cancer category or cancer treatment intent. The majority of decedents (84%) had full code status at admission; however, 53 (87%) had do-not-resuscitate orders at the time of death. Most deaths were deemed to be COVID-19 related (88.5%). The concordance between the reviewers for the cause of death was 78.7%. In contrast to the belief that COVID-19 decedents die because of their comorbidities, in our study only 1 of every 10 patients died of cancer-related causes. Full-scale interventions were offered to all patients irrespective of oncologic treatment intent. However, most decedents in this population preferred care with nonresuscitative measures rather than full support at the end of life., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: Clinical management of patients receiving immune checkpoint inhibitors (ICIs) could be informed using accurate predictive tools to identify patients at risk of short-term acute care utilization (ACU). We used routinely collected data to develop and assess machine learning (ML) algorithms to predict unplanned ACU within 90 days of ICI treatment initiation., Methods: We used aggregated electronic health record data from 7,960 patients receiving ICI treatments to train and assess eight ML algorithms. We developed the models using pre-SARS-COV-19 COVID-19 data generated between January 2016 and February 2020. We validated our algorithms using data collected between March 2020 and June 2022 (peri-COVID-19 sample). We assessed performance using area under the receiver operating characteristic curves (AUROC), sensitivity, specificity, and calibration plots. We derived intuitive explanations of predictions using variable importance and Shapley additive explanation analyses. We assessed the marginal performance of ML models compared with that of univariate and multivariate logistic regression (LR) models., Results: Most algorithms significantly outperformed the univariate and multivariate LR models. The extreme gradient boosting trees (XGBT) algorithm demonstrated the best overall performance (AUROC, 0.70; sensitivity, 0.53; specificity, 0.74) on the peri-COVID-19 sample. The algorithm performance was stable across both pre- and peri-COVID-19 samples, as well as ICI regimen and cancer groups. Type of ICI agents, oxygen saturation, diastolic blood pressure, albumin level, platelet count, immature granulocytes, absolute monocyte, chloride level, red cell distribution width, and alcohol intake were the top 10 key predictors used by the XGBT algorithm., Conclusion: Machine learning algorithms trained using routinely collected data outperformed traditional statistical models when predicting 90-day ACU. The XGBT algorithm has the potential to identify high-ACU risk patients and enable preventive interventions to avoid ACU.

Importance: Therapies for patients with advanced well-differentiated neuroendocrine tumors (NETs) have expanded but remain inadequate, with patients dying of disease despite recent advances in NET therapy. While patients with other cancers have seen long-term disease control and tumor regression with the application of immunotherapies, initial prospective studies of single-agent programmed cell death 1 inhibitors in NET have been disappointing., Objective: To evaluate the response rate following treatment with the combination of the vascular endothelial growth factor inhibitor bevacizumab with the programmed cell death 1 ligand 1 inhibitor atezolizumab in patients with advanced NETs., Design, Setting, and Participants: This single-arm, open-label nonrandomized clinical study in patients with rare cancers included 40 patients with advanced, progressive grade 1 to 2 NETs (20 with pancreatic NETs [pNETs] and 20 with extrapancreatic NETs [epNETs]) treated at a tertiary care referral cancer center between March 31, 2017, and February 19, 2019. Data were analyzed from June to September 2021., Interventions: Patients received intravenous bevacizumab and atezolizumab at standard doses every 3 weeks until progression, death, or withdrawal., Main Outcomes and Measures: The primary end point was objective radiographic response using Response Evaluation Criteria in Solid Tumors, version 1.1, with progression-free survival (PFS) as a key secondary end point., Results: Following treatment of the 40 study patients with bevacizumab and atezolizumab, objective response was observed in 4 patients with pNETs (20%; 95% CI, 5.7%-43.7%) and 3 patients with epNETs (15%; 95% CI, 3.2%-37.9%). The PFS was 14.9 (95% CI, 4.4-32.0) months and 14.2 (95% CI, 10.2-19.6) months in these cohorts, respectively., Conclusions and Relevance: In this nonrandomized clinical trial, findings suggest that clinical responses in patients with NET may follow treatment with the combination of bevacizumab and atezolizumab, with a PFS consistent with effective therapies., Trial Registration: ClinicalTrials.gov Identifier: NCT03074513.

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 ., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: The mutation of the KRAS (Kirsten rat sarcoma virus) gene is a prevalent genetic alteration in metastatic colorectal cancer (mCRC). According to previous research, this mutation significantly affects clinical outcomes and quality of life (QOL). This research investigated the association between KRAS mutant status and various aspects of QOL in mCRC patients. Methods: This case-control study involved 90 admitted patients with mCRC. The patients were either mCRC with positive KRAS mutants (case group) or those without the mutation (control group). The KRAS mutation status of each patient was determined using standard molecular testing. The QOL was evaluated through validated questionnaires from the European Organization for Research and Treatment of Cancer (EORTC), including QLQ-C30 and the QLQ-CR29 questionnaire for colorectal cancer patients. Differences in QOL between the groups and the association of QOL with the odds of KRAS mutation were analyzed using appropriate statistical tests. Results: Patients in the wild-type KRAS group had significantly higher scores on the global health status (GHS) of the QLQ-C30 scale compared to those with a KRAS mutation [(64.26 ± 4.63 vs. 49.63 ± 4, crude; p = 0.019, adjusted; p = 0.024). The mean score of the social functioning scale of the KRAS mutation group was significantly higher than the wild-type [(40 ± 5.84 vs. 24.81 ± 4.39, crude; p = 0.040, adjusted; p = 0.021)]. Based on the QLQ-CR29 questionnaire, average QOL scores were suboptimal for both groups but insignificant. Further, both crude and adjusted analyses showed that KRAS mutation odds were significantly linked to improved social functioning [(crude; OR = 1.013; P = 0.044), (adjusted; OR = 1.017; P = 0.019)] and negatively associated with GHS [(crude; OR = 0.983; P = 0.022), (adjusted; OR = 0.982; P = 0.022)]. Conclusion: The study revealed a low QOL in mCRC, a notable difference in social functioning, and the GHS among patients with and without mutations. Further research is needed to develop targeted interventions to enhance QOL in patients with KRAS mutation. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment modality, offering promising outcomes for various malignancies. However, the efficacy of ICIs varies among patients, highlighting the essential need of accurate predictive biomarkers. This review synthesizes the current understanding of biomarkers for ICI therapy, and discusses the clinical utility and limitations of these biomarkers in predicting treatment outcomes. It discusses three US Food and Drug Administration (FDA)-approved biomarkers, programmed cell death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), and microsatellite instability (MSI), and explores other potential biomarkers, including tumor immune microenvironment (TIME)-related signatures, human leukocyte antigen (HLA) diversity, non-invasive biomarkers such as circulating tumor DNA (ctDNA), and combination biomarker strategies. The review also addresses multivariable predictive models integrating multiple features of patients, tumors, and TIME, which could be a promising approach to enhance predictive accuracy. The existing challenges are also pointed out, such as the tumor heterogeneity, the inconstant nature of TIME, nonuniformed thresholds and standardization approaches. The review concludes by emphasizing the importance of biomarker research in realizing the potential of personalized immunotherapy, with the goal of improving patient selection, treatment strategies, and overall outcomes in cancer treatment. [ABSTRACT FROM AUTHOR]

Summary: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a poor 5‑year survival rate. The majority of PDAC cases harbor KRAS mutations, predominantly at codon 12, with G12D being the most common. While selective inhibitors like sotorasib have shown promise in KRASG12C-mutated PDAC, these mutations are rare, and resistance develops rapidly. Efforts to target more prevalent mutations like KRASG12D are ongoing, with compounds such as MRTX1133 showing preclinical efficacy. Resistance mechanisms include secondary mutations and pathway reactivation, prompting the development of pan-(K)RAS inhibitors (e.g., RMC-6236) and combination strategies targeting upstream effectors. Novel approaches, such as KRAS-targeted vaccines and T‑cell receptor (TCR) therapies, offer additional potential. Continued clinical trials are crucial to optimizing KRAS-targeted therapies in PDAC. [ABSTRACT FROM AUTHOR]

Background: The balance between antioxidants and pro-oxidants plays a significant role in the context of oxidative stress, influenced by both physiological and non-physiological factors. Objectives: In this study, 18 prescribed antibiotics (including doxycycline hydrochloride, tigecycline, rifampicin, tebipenem, cefuroxime, cefixime, potassium clavulanate, colistin, ampicillin, amoxicillin, amikacin, nalidixic acid, azithromycin, pipemidic acid trihydrate, pivmecillinam, aztreonam, fosfomycin sodium, and ciprofloxacin) were subjected to simultaneous determination of antioxidant and pro-oxidant potential to assess if pro-oxidant activity is a dominant co-mechanism of antibacterial activity or if any antibiotic exhibits a balanced effect. Methods: This study presents a recently developed approach for the simultaneous assessment of antioxidant and pro-oxidant potential on a single microplate in situ, applied to prescribed antibiotics. Results: Ten antibiotics from eighteen showed lower antioxidant or pro-oxidant potential, while five exhibited only mild potential with DPPH50 values over 0.5 mM. The pro-oxidant antioxidant balance index (PABI) was also calculated to determine whether antioxidant or pro-oxidant activity was dominant for each antibiotic. Surprisingly, three antibiotics—doxycycline hydrochloride, tigecycline, and rifampicin—showed significant measures of both antioxidant and pro-oxidant activities. Especially notable was tebipenem, a broad-spectrum, orally administered carbapenem, showed a positive PABI index ratio, indicating a dominant antioxidant over pro-oxidant effect. Conclusions: These findings could be significant for both therapy, where the antibacterial effect is enhanced by radical scavenging activity, and biotechnology, where substantial pro-oxidant activity might limit microbial viability in cultures and consequently affect yield. [ABSTRACT FROM AUTHOR]

Simple Summary: We present a case series of 16 patients with pancreatic acinar cell carcinoma treated at our institution for whom available molecular information was evaluated. Most of the patients had metastatic disease, and all patients tested for KRAS mutations were KRAS wild type. Five of 12 patients who underwent DNA damage repair gene testing had germline and/or somatic mutations. One patient was found to have RET fusion and responded favorably to selpercatinib for over 42 months. We also include two additional cases who underwent BostonGene testing, including genomic alterations, RNA expression, and tumor microenvironment (TME) features. One of the two cases was found to have NTRK1 fusion. These findings highlight the need for further investigation of acinar cell carcinoma using larger samples to refine treatment strategies for this rare pancreatic cancer. Objectives: Acinar cell carcinoma (ACC) accounts for about 1% of pancreatic cancers. The molecular and clinical features of ACC are less characterized than those of pancreatic ductal adenocarcinoma. Methods: We retrospectively evaluated the clinical and molecular features of ACC patients who underwent germline and/or somatic molecular testing at The University of Texas MD Anderson Cancer Center from 2008 to 2022 and two cases from 2023–2024 who underwent RNA and TME analysis by Boston Gene. Patient information was extracted from our institutional database with the approval of the Institutional Review Board. Results: We identified 16 patients with available molecular testing results. Fourteen patients had metastatic disease, one had borderline resectable disease, and one had localized resectable disease at diagnosis. Fifteen patients were wild type for KRAS (one patient had unknown KRAS status). Somatic/germline mutations of DNA damage repair genes (BRCA1/2, PALB2, and ATM) were present in 5 of 12 patients tested for these genes. One patient was found to have RET fusion and responded favorably to selpercatinib for over 42 months. The median overall survival (OS) was 24 months for patients with metastatic disease. One of the additional two cases who underwent BostonGene testing was found to have NTRK1 fusion. RNA and TME analysis by Boston Gene of the two cases reported immune desert features and relatively lower RNA levels of CEACAM5, CD47, CD74, and MMP1 and higher RNA levels of CDH6 compared with PDAC. [ABSTRACT FROM AUTHOR]

This paper investigates the application of a self-coder neural network in oilfield rod pump anomaly detection. Rod pumps are critical equipment in oilfield production engineering, and their stability and reliability are crucial to the production efficiency and economic benefits. However, rod pumps are often affected by anomalies such as wax deposition, leading to increased maintenance costs and production interruptions. Traditional wax deposition detection methods are inefficient and fail to provide early warning capabilities. This paper reviews the research progress in sucker rod pump anomaly detection and autoencoder neural networks, providing a detailed description of the construction and training process of the autoencoder neural network model. Utilizing data from the rod-pumped wells of the Tuha oilfield in China, this study achieves the automatic recognition of various anomalies through data preprocessing and the training of an autoencoder model. This study also includes a comparative analysis of the differences in the anomaly detection performance between the autoencoder and traditional methods and verifies the effectiveness and superiority of the proposed method. [ABSTRACT FROM AUTHOR]

Simple Summary: Plasmacytoid urothelial carcinoma (PUC) is a rare and aggressive histologic subtype of urothelial carcinoma of the bladder (BC) with high rates of upstaging and metastases. The aim of our study was to characterize treatment patterns and outcomes using a large national database and our institutional experiences, combating the challenge posed by the rarity of this variant. We demonstrated that, despite an improved pT0 rate associated with NAC, there remains an inconclusive overall survival increase. Additionally, PUC demonstrated a high predilection for peritoneal metastasis, further highlighting the need for investigation into more effective and subtype-tailored treatment options. Background: Plasmacytoid urothelial carcinoma (PUC) is a rare histologic subtype of urothelial carcinoma of the bladder (BC). Our objective was to characterize treatment patterns and outcomes of PUC in the NCDB and our recent institutional experience. Methods: The NCDB was queried for localized PUC cases between 2004 and 2020. Patients with PUC from a single institution (Yale School of Medicine) were also incorporated from 2021 onwards to not double-count patients. The primary outcomes were overall survival and treatment trends. Results: A total of 146 patients were included, 123 from NCDB and 23 from Yale. The median overall survival (mOS) was 28 [IQR 7.5, 50.3] months, 23 [IQR 8.4, 46.3] months for the NCDB patients, and 36 [IQR 4.3, 68.1] for the Yale patients. The mOS for patients receiving neoadjuvant chemotherapy (NAC) was 60.0 [28.0, 91.9] vs. 14.8 months [0, 34.3] for patients without NAC, p = 0.038, though the benefit was not preserved in a Cox proportional hazard analysis incorporating the clinical stage, receipt of NAC, and age. The peritoneum was the most common site of metastasis (78.3%), followed by the liver and bones. Conclusion: Our findings underscore the formidable challenge posed by PUC, emphasizing its limited response to current therapies. Despite higher pT0 rates with NAC, the OS benefit remains inconclusive, highlighting the need for more effective treatments. [ABSTRACT FROM AUTHOR]

Malignant peritoneal mesothelioma (MPM) is a rare tumor associated with a poor prognosis and a lack of consensus regarding treatment strategies. While the Checkmate 743 trial demonstrated the superiority of first-line nivolumab and ipilimumab over chemotherapy in malignant pleural mesothelioma (MPlM), few studies have assessed the effectiveness of immunotherapy against MPM, due to its rarity. Here, we report a major and sustained 12-month response in a 74-yearold female patient who received the anti-PD-1 nivolumab and the anti-CTLA4 ipilimumab as first-line therapy for diffuse MPM. PD-L1 was expressed and BAP1 expression was lost, as shown by immunohistochemistry, however the BAP1 gene was not mutated. Our findings suggest a role for ICI in non-resectable diffuse MPM exhibiting PD-L1 overexpression and loss of BAP1 expression, and instill new hope in their treatment. To our knowledge, this is the second reported case of dual immunotherapy used as first-line in MPM with a major clinical response. To investigate the clinical outcome, we conducted additional molecular analyses of the MPM tumor and we reviewed the literature on immunotherapy in MPM to discuss the role of PD-L1 and BAP1. [ABSTRACT FROM AUTHOR]

The KRAS mutation stands out as one of the most influential oncogenic mutations, which directly regulates the hallmark features of cancer and interacts with other cancer-causing driver mutations. However, there remains a lack of precise information on their cooccurrence with mutated variants of KRAS and any correlations between KRAS and other driver mutations. To enquire about this issue, we delved into cBioPortal, TCGA, UALCAN, and Uniport studies. We aimed to unravel the complexity of KRAS and its relationships with other driver mutations. We noticed that G12D and G12V are the prevalent mutated variants of KRAS and coexist with the TP53 mutation in PAAD and CRAD, while G12C and G12V coexist with LUAD. We also noticed similar observations in the case of PIK3CA and APC mutations in CRAD. At the transcript level, a positive correlation exists between KRAS and PIK3CA and between APC and KRAS in CRAD. The existence of the co-mutation of KRAS and other driver mutations could influence the signaling pathway in the neoplastic transformation. Moreover, it has immense prognostic and predictive implications, which could help in better therapeutic management to treat cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: The development of new treatments for patients with neuroendocrine neoplasms (NENs) is imperative. Immunotherapy has shown efficacy in various neoplasms, such as small cell lung cancer and Merkel cell carcinoma. Although immunotherapy's effectiveness is more limited in NENs, combining immune checkpoint inhibitors with other therapeutic strategies like chemotherapy or targeted therapies could improve outcomes. Additionally, identifying predictive immune biomarkers could enhance patient selection. Our objective was to review the current evidence of immunotherapy in NENs, covering efficacy results and potential predictive biomarkers. A raise in the incidence of NENs is expected. Therefore, the identification of new therapeutic strategies, such as immunotherapy, remains crucial. To date, immune checkpoint inhibitors as monotherapy have shown modest activity in unselected NENs. Although immunotherapy combos (plus another immune agents or chemotherapy, among others) are potentially more active than single agents, this has not been uniformly confirmed, even in high-grade NENs. Other immunotherapeutic strategies under development include bispecific antibodies, targeting specific tumor antigens like DLL3, and cell therapy. Currently, no predictive immune biomarkers are available to guide clinical decisions. A comprehensive tumor molecular profiling approach needs to be developed for the selection of patients with NEN who could potentially benefit from immunotherapy. Ideally, clinical trials should incorporate this tumor molecular profiling to identify predictive biomarkers and improve efficacy. Achieving this goal requires an international collaborative effort. [ABSTRACT FROM AUTHOR]

Background: Large cell neuroendocrine carcinoma (LCNEC) presents significant treatment challenges due to its rarity and limited therapeutic options. The LANCE study was designed to explore the survival benefits of incorporating atezolizumab in chemotherapy for metastatic LCNEC. Methods: In this non-randomized study, patients with metastatic LCNEC were prospectively enrolled and assigned to receive either standard chemotherapy plus atezolizumab followed by maintenance with atezolizumab or standard chemotherapy alone. The primary outcomes measured were 12- and 24-month survival rates, progression-free survival (PFS), and overall survival (OS) between the two groups. Results: Of the 22 patients screened, 17 met the inclusion criteria and received either atezolizumab plus platinum-based chemotherapy (n = 10) or chemotherapy alone (n = 7). After a median follow-up of 23.3 months, the 12-month survival rate was 57.1% (95% CI: 32.6–100%) and 14.3% (95% CI: 2.33–87.7%) for the atezolizumab and the chemotherapy-only groups, respectively. The survival benefit for the atezolizumab group was sustained at 24 months (45.7% vs. 14.3%). Overall survival was significantly higher for the atezolizumab group, and PFS was non-significantly associated with the addition of atezolizumab (log-rank p = 0.04 and 0.05, respectively). Conclusions: This pilot study suggests that the addition of atezolizumab to standard platinum-based chemotherapy may provide a substantial survival benefit compared with chemotherapy alone in the first-line treatment of metastatic LCNEC. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) represents a substantial risk to public health. Bevacizumab, the first US FDA-approved antiangiogenic drug (AAD) for human CRC treatment, faces resistance in patients. The role of lipid metabolism, particularly through OPA3-regulated lipid droplet production, in overcoming this resistance is under investigation. Methods: The protein expression pattern of OPA3 in CRC primary/normal tissues was evaluated by bioinformatics analysis. OPA3-overexpressed SW-480 and HCT-116 cell lines were established, and bevacizumab resistance and OPA3 effects on cell malignancy were examined. OPA3 protein/mRNA expression and lipid dropletrelated genes were measured with Western blot and qRT-PCR. OPA3 subcellular localization was detected using immunofluorescence. Proliferation and apoptosis were assessed via colony formation and flow cytometry. Tube formation assays were conducted to assess the angiogenic potential of human umbilical vein endothelial cells (HUVECs). Lipid analysis was used to measure the phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) levels in CRC cells. Results: Bioinformatics analysis revealed that OPA3 was downregulated in CRC. Overexpression of OPA3 inhibited CRC cell proliferation, stimulated apoptosis, and suppressed the angiogenic ability of HUVECs. OPA3 effectively reversed the resistance of CRC cells to bevacizumab and decreased lipid droplet production in CRC cells. Additionally, OPA3 reversed the bevacizumab-induced lipid droplet production in CRC cells, thereby increasing CRC cell sensitivity to bevacizumab treatment. Conclusion: This study suggests that OPA3 modulates lipid metabolism in CRC cells and reduces resistance to bevacizumab in CRC cells. Therefore, OPA3 may be a potential therapeutic target against the AAD resistance in CRC. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of human malignancies and carries an exceptionally poor prognosis. It is mostly driven by multiple oncogenic alterations, with the highest mutation frequency being observed in the KRAS gene, which is a key oncogenic driver of tumorogenesis and malignant progression in PDAC. However, KRAS remained undruggable for decades until the emergence of G12C mutation specific KRAS inhibitors. Despite this development, this therapeutic approach to target KRAS directly is not routinely used for PDAC patients, with the reasons being the rare presence of G12C mutation in PDAC with only 1–2% of occurring cases, modest therapeutic efficacy, activation of compensatory pathways leading to cell resistance, and absence of effective KRASG12D or pan-KRAS inhibitors. Additionally, indirect approaches to targeting KRAS through upstream and downstream regulators or effectors were also found to be either ineffective or known to cause major toxicities. For this reason, new and more effective treatment strategies that combine different therapeutic modalities aiming at achieving synergism and minimizing intrinsic or adaptive resistance mechanisms are required. In the current work presented here, pancreatic cancer cell lines with oncogenic KRAS G12C, G12D, or wild-type KRAS were treated with specific KRAS or SOS1/2 inhibitors, and therapeutic synergisms with concomitant MEK inhibition and irradiation were systematically evaluated by means of cell viability, 2D-clonogenic, 3D-anchorage independent soft agar, and bioluminescent ATP assays. Underlying pathophysiological mechanisms were examined by using Western blot analyses, apoptosis assay, and RAS activation assay. [ABSTRACT FROM AUTHOR]

Despite significant advancements in the treatment of other cancers, pancreatic ductal adenocarcinoma (PDAC) remains one of the world's deadliest cancers. More than 90% of PDAC patients harbor a Kirsten rat sarcoma (KRAS) gene mutation. Although the clinical potential of anti-KRAS therapies has long been realized, all initial efforts to target KRAS were unsuccessful. However, with the recent development of a new generation of KRAS-targeting drugs, multiple KRAS-targeted treatment options for patients with PDAC have entered clinical trials. In this review, we provide an overview of current standard of care treatment, describe RAS signaling and the relevance of KRAS mutations, and discuss RAS isoform- and mutation-specific differences. We also evaluate the clinical efficacy and safety of mutation-selective and multi-selective inhibitors, in the context of PDAC. We then provide a comparison of clinically relevant KRAS inhibitors to second-line PDAC treatment options. Finally, we discuss putative resistance mechanisms that may limit the clinical effectiveness of KRAS-targeted therapies and provide a brief overview of promising therapeutic approaches in development that are focused on mitigating these resistance mechanisms. [ABSTRACT FROM AUTHOR]

Single-point mutations in the Kirsten rat sarcoma (KRAS) viral proto-oncogene are the most common cause of human cancer. In humans, oncogenic KRAS mutations are responsible for about 30% of lung, pancreatic, and colon cancers. One of the predominant mutant KRAS G12D variants is responsible for pancreatic cancer and is an attractive drug target. At the time of writing, no Food and Drug Administration (FDA) approved drugs are available for the KRAS G12D mutant. So, there is a need to develop an effective drug for KRAS G12D. The process of finding new drugs is expensive and time-consuming. On the other hand, in silico drug designing methodologies are cost-effective and less time-consuming. Herein, we employed machine learning algorithms such as K-nearest neighbor (KNN), support vector machine (SVM), and random forest (RF) for the identification of new inhibitors against the KRAS G12D mutant. A total of 82 hits were predicted as active against the KRAS G12D mutant. The active hits were docked into the active site of the KRAS G12D mutant. Furthermore, to evaluate the stability of the compounds with a good docking score, the top two complexes and the standard complex (MRTX-1133) were subjected to 200 ns MD simulation. The top two hits revealed high stability as compared to the standard compound. The binding energy of the top two hits was good as compared to the standard compound. Our identified hits have the potential to inhibit the KRAS G12D mutation and can help combat cancer. To the best of our knowledge, this is the first study in which machine-learning-based virtual screening, molecular docking, and molecular dynamics simulation were carried out for the identification of new promising inhibitors for the KRAS G12D mutant. [ABSTRACT FROM AUTHOR]

Immunotherapy has revolutionised the treatment of oncological patients, but its application in various endocrine tumours is rather limited and is mainly used when conventional therapies have failed. Immune checkpoint inhibitors (ICIs) have been employed in progressive adrenocortical carcinoma, primarily utilizing the anti-PD-L1 agent pembrolizumab, obtaining overall response rates ranging between 14% and 23%. In contrast, the response rate in phaeochromocytoma/paraganglioma was substantially less at 9%, considering the small number of patients treated. Similarly, the response rate in advanced differentiated thyroid carcinomas treated with pembrolizumab was also low at 9%, although the combination of ICIs with tyrosine kinase inhibitors showed higher efficacy. Low response rates to ICIs have also been observed in progressive medullary thyroid cancer, except in tumours with a high mutation burden (TMB). Pembrolizumab or spartalizumab can be utilized in patients with high TMB anaplastic thyroid cancer, obtaining better response rates, particularly in patients with high PD-L1 expression. Immunotherapy has also been used in a few cases of parathyroid carcinoma, showing limited antitumour effect. Pituitary carcinomas may exhibit a more favourable response to ICIs compared to aggressive pituitary tumours, particularly corticotroph tumours. Patients with advanced neuroendocrine tumours achieve an overall response rate of 15%, which varies according to the primary tumour site of origin, degree of differentiation, and therapeutic regimen utilised. Future research is needed to evaluate the potential role of immunohistochemical biomarkers, such as programmed death 1/programmed death ligand 1 and TMB, as predictors for the response to immunotherapy. Furthermore, randomised prospective studies could provide more robust data on the efficacy and side effects of ICIs. [ABSTRACT FROM AUTHOR]

The KRAS proto-oncogene is a major driver of pancreatic tumorigenesis and is nearly ubiquitously mutated in pancreatic ductal adenocarcinoma (PDAC). KRAS point mutations are detected in over 90% of PDAC cases, and these mutations have been shown to be associated with worse therapy response and overall survival. Pathogenic KRAS mutations are mostly limited to codons 12, 13 and 61, with G12D, G12V, G12R, Q61H, and G13D accounting for approximately 95% of the mutant cases. Emerging data have shown the importance of specific mutant subtypes, as well as KRAS variant allele frequency on clinical prognosis. Furthermore, novel technologies and therapies are being developed to target specific mutant subtypes, with encouraging early results. In this paper, we aim to review the recent studies regarding the relative impact of specific mutant KRAS subtypes on oncologic outcomes, the application of variant allele frequency in next generation sequencing analyses, and the ongoing research into therapies targeting specific mutant KRAS subtypes. [ABSTRACT FROM AUTHOR]

Since the approval for the treatment of melanoma in 2014, immune checkpoint inhibitors (ICIs) have revolutionized the therapy pattern across various malignancies. Coinciding with their frequent usage, their adverse effects, including fever, cannot be neglected. In the context of cancer diseases and cancer treatments, fever of unknown origin (FUO), which has long posed a challenge for clinicians in terms of diagnosis and management, brings forth new connotation and significance. In this paper review, we present the concept of ICIs-associated FUO, consider activated immune system and elevated cytokines as common mechanisms by which ICIs induce fever and various immune-related adverse events (irAEs), summarize and compare the primary etiologies of ICI-associated FUO, and compare it with conventional types of FUO. [ABSTRACT FROM AUTHOR]

Simple Summary: This review examined the disparities between lung neuroendocrine tumors and gastroentero-pancreatic neuroendocrine tumors, two types of neuroendocrine tumors that originate from different parts of the body and have historically been treated similarly. This research delves into the differences in genetic makeup, behavior, and response to treatments such as chemotherapy, immunotherapy, and targeted therapies between these two types of tumors. This study aimed to explore these distinctions to develop more personalized and effective treatment strategies for patients with lung and gastroenteropancreatic neuroendocrine tumors. By recognizing and treating these two types of cancer as distinct entities rather than as a single disease, the medical community can significantly improve patient outcomes and highlight the importance of this research. Lung neuroendocrine tumors (LNETs) and gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are two distinct types of neuroendocrine tumors (NETs) that have traditionally been treated as a single entity despite originating from different sources. Although they share certain phenotypic characteristics and the expression of neuroendocrine markers, they exhibit differences in their microenvironment, molecular mutations, and responses to various therapeutic regimens. Recent research has explored the genetic alterations in these tumors, revealing dissimilarities in the frequently mutated genes, the role of EGFR in carcinogenesis, the presence of transcription factors, and the immunogenicity of the tumor and its microenvironment. Spread Through Air Spaces (STAS), a phenomenon unique to lung carcinomas, appears to play a crucial role in LNET prognosis. These distinctions are also evident in the cascade response of lung and GI tract neuroendocrine tumors to somatostatin analogs, Peptide Receptor Radionuclide Therapy (PRRT), chemotherapy, and immunotherapy. Identifying similarities and differences between the two groups may improve our understanding of the underlying mechanisms and facilitate the development of more effective treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Tumor-associated macrophages (TAMs) are an important subset of innate immune cells in the tumor microenvironment, and they are pivotal regulators of tumor-promoting inflammation and tumor progression. Evidence has proven that TAM numbers are substantially increased in cancers, and most of these TAMs are polarized toward the alternatively activated M2 phenotype; Thus, these TAMs strongly promote the progression of cancer diseases. Type 1 innate lymphocytes (ILC1s) are present in high numbers in intestinal tissues and are characterized by the expression of the transcription factor T-bet and the secretion of interferon (IFN)-γ, which can promote macrophages to polarize toward the classically activated antitumor M1 phenotype. However, the relationship between these two cell subsets in colon cancer remains unclear. Methods: Flow cytometry was used to determine the percentages of M1-like macrophages, M2-like macrophages and ILC1s in colon cancer tissues and paracancerous healthy colon tissues in the AOM/DSS-induced mouse model of colon cancer. Furthermore, ILC1s were isolated and bone marrow-derived macrophages were generated to analyze the crosstalk that occurred between these cells when cocultured in vitro. Moreover, ILC1s were adoptively transferred or inhibited in vivo to explore the effects of ILC1s on tumor-infiltrating macrophages and tumor growth. Results: We found that the percentages of M1-like macrophages and ILC1s were decreased in colon cancer tissues, and these populations were positively correlated. ILC1s promoted the polarization of macrophages toward the classically activated M1-like phenotype in vitro, and this effect could be blocked by an anti-IFN-γ antibody. The in vivo results showed that the administration of the Group 1 innate lymphocyte-blocking anti-NK1.1 antibody decreased the number of M1-like macrophages in the tumor tissues of MC38 tumor-bearing mice and promoted tumor growth, and adoptive transfer of ILC1s inhibited tumors and increased the percentage of M1-like macrophages in MC38 tumor-bearing mice. Conclusions: Our studies preliminarily prove for the first time that ILC1s promote the activation of M1-like macrophages by secreting IFN-γ and inhibit the progression of colon cancer, which may provide insight into immunotherapeutic approaches for colon cancer. [ABSTRACT FROM AUTHOR]

Background: Peritoneal mesothelioma (PM) is a rare disease with various histopathological subtypes. For malignant peritoneal mesothelioma and borderline subgroups locoregional therapy with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been implemented. The aim of our study was to retrospectively present the outcome after CRS and HIPEC for patients with different subtypes of peritoneal mesothelioma., Methods: In total 15 patients received CRS and HIPEC due to peritoneal mesothelioma at our tertiary referral hospital between 2013 and 2022. Surgical and oncologic outcomes of 14 of those patients were retrospectively evaluated as one patient was lost to follow-up., Results: The cohort consisted of 9 patients with diffuse malignant peritoneal mesothelioma (64.3%), 3 patients with multicystic peritoneal mesothelioma (21.4%) and 2 patients with well-differentiated peritoneal mesothelioma (14.3%). Complete cytoreduction was possible in 85.7% (n = 12). The major complication rate was 28.6% (n = 4) and the reoperation rate was 14.3% (n = 2). Median follow-up was 55 months (standard error, SE 15.0%, 95% confidence interval, CI 25.6-84.4 months). Over this time period 64.3% (n = 9) had no evidence of disease, 21.4% (n = 3) were alive with disease and 14.3% (n = 2) died of peritoneal mesothelioma. The median recurrence-free survival of patients was 13 months (SE 13.0%, 95% CI 0.0-32.2 months). None of the patients with multicystic peritoneal mesothelioma had evidence of disease at the time of last follow-up., Conclusion: Patients with peritoneal mesothelioma should receive locoregional treatment as good oncological results can be achieved with reasonable postoperative morbidity. Thus, awareness is necessary for this rare but potentially aggressive disease to offer the best medical care., (© 2024. The Author(s).)

Down syndrome (DS) is a chromosomal disorder associated with intellectual and physical disabilities and has historically been viewed by health care providers through a negative lens when considering the effect the condition has on the individual, family, and community. The purpose of this scoping review was to provide an overview of recent research concerning adaptation in families of individuals with DS with a focus on family adaptation rather than individual or dyadic adaptation. Three literature indexes were searched from 2017 to 2022, with 41 articles included. Foci of the studies included strength/resilience, stress/coping, and negative/challenge. Thirteen studies reported using a family framework. Multiple methodological approaches and family measures were used in the studies and are outlined. Findings from this review show there has been a shift in focus when researching families of individuals with DS from a negative and challenging experience to one of strength and resilience. [ABSTRACT FROM AUTHOR]

Gastroentero-pancreatic Neuroendocrine Neoplasms (GEP-NENs) are a diverse group of rare tumors that arise from neuroendocrine cells in the gastrointestinal tract and pancreas, and they can vary significantly in terms of clinical behavior and prognosis. Immunotherapy, particularly immune checkpoint inhibitors, has shown remarkable success in various malignancies by harnessing the body's immune system to target and eliminate cancer cells. Immune checkpoint inhibitor clinical studies in GEP-NENs have yielded promising outcomes, particularly in individuals with advanced and refractory disease. Objective responses and disease stabilization have been observed in some cases, even in those previously unresponsive to traditional treatments like chemotherapy or targeted therapies. However, it's important to note that the efficacy of immunotherapy in GEP-NENs can vary widely depending on tumor characteristics, the immune microenvironment, and patient factors. As such, identifying predictive biomarkers to select the most suitable patients for immunotherapy remains an ongoing challenge. Immunotherapy has considerable potential for treating GEP-NENs, but research is still in its early stages. Several combinations are being explored to enhance the effectiveness of immunotherapy and improve the outcomes of treatment, such as combining immunotherapy with other targeted therapies or chemotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: This comprehensive review explores evolving systemic combination regimens for advanced well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with evidence provided by clinical trials and prospective studies. Phase 1 and 2 trials predominated, with few phase 3 trials impacting clinical practice. Results showed variability in anti-tumor activity of combination regimens, with some showing promising outcomes. Among others, treatments with a peptide receptor radionuclide therapy backbone displayed favorable results and warrant further investigation. In contrast, immune-checkpoint inhibitor-based combinations had limited applicability in this patient population. More extensive trials are needed to determine optimal treatment strategies. There is an evolving landscape of systemic combination regimens for patients with advanced well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). In this review, we provide a comprehensive outline of the existing clinical trials/prospective studies investigating these combinations. PubMed was searched using key relevant terms to identify articles referring to GEP-NETs and combination treatments. No systematic search of the literature or metanalysis of the data was performed, and we focused on the most recent literature results. Primarily, phase 1 and 2 clinical trials were available, with a smaller number of phase 3 trials, reporting results from combination treatments across a wide range of antiproliferative agents. We identified significant variability in the anti-tumor activity of the reported combinations, with occasional promising results, but only a very small number of practice-changing phase 3 clinical trials. Overall, the peptide receptor radionuclide therapy (PRRT)-based combinations (with chemotherapy, dual PPRT, and targeted agents) and anti-vascular endothelial growth factor (VEGF) agent combinations with standard chemotherapy were found to have favorable results and may be worth investigating in future, larger-scale trials. In contrast, the immune-checkpoint inhibitor-based combinations were found to have limited applicability in advanced, well-differentiated GEP-NETs. [ABSTRACT FROM AUTHOR]

Simple Summary: Recently immunotherapy has been approved in first line for patients with MPM. However, the benefit of immunotherapy in MPM is modest, and recognizing the immune landscape of this tumor could guide the optimal therapeutic strategy. In some tumors dynamic changes of TILs has been reported after chemotherapy, endocrine therapy and immunotherapy. We investigated the changes in expression of TILs in human MPM tumor tissue using immunohistochemistry and patterns of gene expression from paired samples. We included samples of patients treated with chemotherapy, immunotherapy and patients without any treatment between the samples. In our series, after systemic treatment or at progressive disease we observed a decrease of the number of TILs and a downregulation of the immune-related genes. In patients without any treatment between the samples we found an increase of immune cells. We suggest that the immune system tends to turn off during the evolution of disease of after treatment. MPM is an aggressive disease with an immunosuppressive tumor microenvironment, and interest in exploring immunotherapy in this disease has been increasing. In the first line of treatment, the combination of nivolumab and ipilimumab demonstrated an improvement in survival over chemotherapy. The presence of TILs has been recognized as a marker of antitumor immune response to chemotherapy in solid tumors. The aim of our study is to identify the effect of treatment on immune cells and the immune gene profile in MPM. We investigated the changes in expression of TILs in 10 human MPM paired tumor tissues using immunohistochemistry and gene expression analysis from paired untreated and treated samples. In this small series, we demonstrated that during the evolution of disease without any treatment there was an increase in the inflammatory component in tumor samples. After systemic treatment there was a decrease in the number of TILs. We observed that after systemic treatment or disease progression immune gene signatures were suppressed. Our integrated analysis of paired samples with immune profile and genomic changes on MPM suggested that during the evolution of the disease the immune system tends to switch, turning off with treatment. [ABSTRACT FROM AUTHOR]

The SPARC gene plays multiple roles in extracellular matrix synthesis and cell shaping, associated with tumor cell migration, invasion, and metastasis. The SPARC gene is also involved in the epithelial-mesenchymal transition (EMT) process, which is a critical phenomenon leading to a more aggressive cancer cell phenotype. SPARC gene overexpression has shown to be associated with poor survival in the mesothelioma (MESO) cohort from the TCGA database, indicating that this gene may be a powerful prognostic factor in MESO. Its overexpression is correlated with the immunosuppressive tumor microenvironment. Here, we summarize the omics advances of the SPARC gene, including the summary of SPARC gene expression associated with prognosis in pancancer and MESO, the immunosuppressive microenvironment, and cancer cell stemness. In addition, SPARC might be targeted by microRNAs. Notably, despite the controversial functions on angiogenesis, SPARC may directly or indirectly contribute to tumor angiogenesis in MESO. In conclusion, SPARC is involved in tumor invasion, metastasis, immunosuppression, cancer cell stemness, and tumor angiogenesis, eventually impacting patient survival. Strategies targeting this gene may provide novel therapeutic approaches to the treatment of MESO. [ABSTRACT FROM AUTHOR]

Purpose of Review: The management of isocitrate dehydrogenase (IDH)-wildtype glioblastomas is an area of unmet need. Despite multimodal therapy incorporating maximal safe resection, radiotherapy, and temozolomide, clinical outcomes remain poor. At disease progression or relapse, available systemic agents such as temozolomide, lomustine, and bevacizumab have limited efficacy. We review the recent advances in the treatment of IDH-wildtype glioblastomas. Recent Findings: A broad repertoire of systemic agents is in the early stages of development, encompassing the areas of precision medicine, immunotherapy, and repurposed medications. The use of medical devices may present opportunities to bypass the blood–brain barrier. Novel clinical trial designs aim to efficiently test treatment options to advance the field. Summary: There are a number of emerging treatment options for IDH-wildtype glioblastomas which are undergoing evaluation in clinical trials. Advances in our scientific understanding of IDH-wildtype glioblastomas offer hope and the prospect of incremental improvements in clinical outcomes. [ABSTRACT FROM AUTHOR]

Malignant pleural mesothelioma (MPM) is a rare cancer usually caused by asbestos exposure and associated with a very poor prognosis. After more than a decade without new therapeutic options, immune checkpoint inhibitors (ICIs) demonstrated superiority over standard chemotherapy, with improved overall survival in the first and later-line settings. However, a significant proportion of patients still do not derive benefit from ICIs, highlighting the need for new treatment strategies and predictive biomarkers of response. Combinations with chemo-immunotherapy or ICIs and anti-VEGF are currently being evaluated in clinical trials and might change the standard of care in the near future. Alternatively, some non-ICI immunotherapeutic approaches, such as mesothelin targeted CAR-T cells or denditric-cells vaccines, have shown promising results in early phases of trials and are still in development. Finally, immunotherapy with ICIs is also being evaluated in the peri-operative setting, in the minority of patients presenting with resectable disease. The goal of this review is to discuss the current role of immunotherapy in the management of malignant pleural mesothelioma, as well as promising future therapeutic directions. [ABSTRACT FROM AUTHOR]

Malignant peritoneal mesothelioma (MPeM) is a type of rare and highly lethal tumor. Immune checkpoint blockade (ICB)-based therapy has shown encouraging clinical activity for MPeM. However, no definitive biomarkers have been identified for predicting which patients with MPeM will benefit from ICB-based therapy. At present, there are several novel potential biomarkers proposed for predicting the response to ICB-based therapy, and biomarkers available in MPeM cells and in the tumor microenvironment have been identified with the potential to predict the efficacy of ICB-based therapy in MPeM. According to the molecular characteristics of MPeM itself, the feasibility of biomarkers in practice, and the body of available evidence, we hypothesize that the following five types of biomarkers can be used to predict the response of ICB-based therapy in patients with MPeM: Tertiary lymphoid structures, immune checkpoints and their ligands, fusion gene neoantigen burden, BRCA1-associated protein-1 haploinsufficiency and transcriptome-based biomarkers. The present review discusses the value and limitations of each type of biomarker, and potential solutions to address the limitations are proposed. The aim of the present review is to provide a background for future studies on ICB-based therapy for MPeM. [ABSTRACT FROM AUTHOR]