A Toll pathway effector protects Drosophila specifically from distinct toxins secreted by a fungus or a bacterium.

The Drosophila systemic immune response against many Gram-positive bacteria and fungi is mediated by the Toll pathway. How Toll-regulated effectors actually fulfill this role remains poorly understood as the known Toll-regulated antimicrobial peptide (AMP) genes are active only against filamentous fungi and not against Gram-positive bacteria or yeasts. Besides AMPs, two families of peptides secreted in response to infectious stimuli that activate the Toll pathway have been identified, namely Bomanins and peptides derived from a polyprotein precursor known as Baramicin A (BaraA). Unexpectedly, the deletion of a cluster of 10 Bomanins phenocopies the Toll mutant phenotype of susceptibility to infections. Here, we demonstrate that BaraA is required specifically in the host defense against Enterococcus faecalis and against the entomopathogenic fungus Metarhizium robertsii, albeit the fungal burden is not altered in BaraA mutants. BaraA protects the fly from the action of distinct toxins secreted by these Gram-positive and fungal pathogens, respectively, Enterocin V and Destruxin A. The injection of Destruxin A leads to the rapid paralysis of flies, whether wild type (WT) or mutant. However, a larger fraction of wild-type than BaraA flies recovers from paralysis within 5 to 10 h. BaraAs' function in protecting the host from the deleterious action of Destruxin is required in glial cells, highlighting a resilience role for the Toll pathway in the nervous system against microbial virulence factors. Thus, in complement to the current paradigm, innate immunity can cope effectively with the effects of toxins secreted by pathogens through the secretion of dedicated peptides, independently of xenobiotics detoxification pathways.

The Toll pathway mediates Drosophila resilience to Aspergillus mycotoxins through specific Bomanins.

Host defense against infections encompasses both resistance, which targets microorganisms for neutralization or elimination, and resilience/disease tolerance, which allows the host to withstand/tolerate pathogens and repair damages. In Drosophila, the Toll signaling pathway is thought to mediate resistance against fungal infections by regulating the secretion of antimicrobial peptides, potentially including Bomanins. We find that Aspergillus fumigatus kills Drosophila Toll pathway mutants without invasion because its dissemination is blocked by melanization, suggesting a role for Toll in host defense distinct from resistance. We report that mutants affecting the Toll pathway or the 55C Bomanin locus are susceptible to the injection of two Aspergillus mycotoxins, restrictocin and verruculogen. The vulnerability of 55C deletion mutants to these mycotoxins is rescued by the overexpression of Bomanins specific to each challenge. Mechanistically, flies in which BomS6 is expressed in the nervous system exhibit an enhanced recovery from the tremors induced by injected verruculogen and display improved survival. Thus, innate immunity also protects the host against the action of microbial toxins through secreted peptides and thereby increases its resilience to infection.

Phase 1 trial of navitoclax and sorafenib in patients with relapsed or refractory solid tumors with hepatocellular carcinoma expansion cohort.

Navitoclax (ABT-263) is an oral BCL2 homology-3 mimetic that binds with high affinity to pro-survival BCL2 proteins, resulting in apoptosis. Sorafenib, an oral multi kinase inhibitor also promotes apoptosis and inhibits tumor angiogenesis. The efficacy of either agent alone is limited; however, preclinical studies demonstrate synergy with the combination of navitoclax and sorafenib. In this phase 1 study, we evaluated the combination of navitoclax and sorafenib in a dose escalation cohort of patients with refractory solid tumors, with an expansion cohort in hepatocellular carcinoma (HCC). Maximum tolerated dose (MTD) was determined using the continual reassessment method. Navitoclax and sorafenib were administered continuously on days 1 through 21 of 21-day cycles. Ten patients were enrolled in the dose escalation cohort and 15 HCC patients were enrolled in the expansion cohort. Two dose levels were tested, and the MTD was navitoclax 150 mg daily plus sorafenib 400 mg twice daily. Among all patients, the most common grade 3 toxicity was thrombocytopenia (5 patients, 20%): there were no grade 4 or 5 toxicities. Patients received a median of 2 cycles (range 1-36 cycles) and all patients were off study treatment at data cut off. Six patients in the expansion cohort had stable disease, and there were no partial or complete responses. Drug-drug interaction between navitoclax and sorafenib was not observed. The combination of navitoclax and sorafenib did not increase induction of apoptosis compared with navitoclax alone. Navitoclax plus sorafenib is tolerable but showed limited efficacy in the HCC expansion cohort. These findings do not support further development of this combination for the treatment of advanced HCC. This phase I trial was conducted under ClinicalTrials.gov registry number NCT01364051.

Immune-Related Adverse Events in Patients with Lung Cancer.

PURPOSE OF REVIEW: Immune checkpoint inhibitors (ICI) have been widely adopted for the treatment of lung cancer since receiving first U.S Food and Drug Administration (FDA) approval in 2015. However, along with their use, the occurrence of immune-related adverse events (irAEs) has presented a challenge for both patients and oncology providers. In this manuscript, we reviewed the clinical trials that led to the approval of ICI by the FDA for the treatment of lung cancer between 2015 and 2023 to establish the frequency of irAEs in this patient population. Among the adverse events associated with ICI, we focused on the most common and relevant ones, including hypothyroidism, pneumonitis, diarrhea/colitis, skin rash, and hepatitis. RECENT FINDINGS: We thoroughly examined the available literature, including society guidelines concerning these complications, to discuss various aspects such as their pathophysiology, epidemiology, diagnostic process, grading system, and clinical management. Additionally, we explored the association between irAEs and disease response. The management of irAEs is a crucial aspect of oncologic care, particularly due to their potential to cause severe and life-threatening clinical manifestations. We present each pertinent aspect in a concise and organized manner to provide guidance and assistance to oncology providers managing these patients in both outpatient and inpatient settings.

High volatility of superbase-derived eutectic solvents used for CO2 capture.

High volatility would lead to a highly flammable hazard, explosion danger, low regeneration efficiency and air pollution. Eutectic solvents (ESs) are assumed to be nonvolatile; however, the assumption is not correct. Here, we, for the first time, find that superbase-derived ESs are highly volatile. Even at room temperature (i.e., 25 °C) and atmospheric pressure, the mass loss of ESs could reach as high as 43.5% after 20 h of exposure. Superbase-derived ESs are promising solvents for CO2 capture, and they are also highly volatile after CO2 capture. We found that typical ethylene glycol : 1,8-diazabicyclo[5.4.0]undec-7-ene (EG : DBU (4 : 1)) has a three-stage volatilizing mechanism. EG and DBU volatilize first by breaking weak hydrogen-bonding interactions (1st stage), followed by the destruction of strong hydrogen-bonding interactions (2nd stage), and finally by destroying much stronger hydrogen-bonding interactions (3rd stage). This work presents a new horizon that ESs and their mixture with CO2 are highly volatile, which is helpful for mitigating laboratory explosion, combustion hazards, air pollution and designing new types of ESs with negligible volatility.

Immunogenicity of Del19 EGFR mutations in Chinese patients affected by lung adenocarcinoma.

BACKGROUND: Mutant peptides presented by cancer cells are superior vaccine candidates than self peptides. The efficacy of mutant K-Ras, P53 and EGFR (Epidermal Growth Factor Receptor) peptides have been tested as cancer vaccines in pancreatic, colorectal, and lung cancers. The immunogenicity of EGFR Del19 mutations, frequent in Chinese lung adenocarcinoma patients, remains unclear. RESULTS: We predicted the HLA binding epitopes of Del19 mutations of EGFR in Chinese lung adenocarcinoma patients with NetMHC software. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the EGFR-reactive IgG in lung cancer patients. Del19 mutations may be presented by multiple HLA Class I molecules, with delE746_A750 presented by 37.5% of Chinese population. For HLA Class II molecules, Del19 mutations of EGFR may be presented by multiple HLA-DRB1 molecules, with delE746_A750 presented by 58.1% of Chinese population. Serum reactivity to wild type EGFR protein was significantly higher in patients with Del19 EGFR mutations than those with EGFR L858R point mutation or with EGFR wild type genotype. CONCLUSIONS: These findings suggest that Del19 mutations of EGFR, with an estimated frequency of 40% in Chinese lung adenocarcinoma patients, may serve as unique targets for immunotherapy in Chinese lung cancer patients.

Sex Differences in Tolerability to Anti-Programmed Cell Death Protein 1 Therapy in Patients with Metastatic Melanoma and Non-Small Cell Lung Cancer: Are We All Equal?

BACKGROUND: Immune-related adverse events (irAEs) have emerged as a serious clinical issue in the use of immune checkpoint inhibitors (ICIs). Risk factors for irAEs remain controversial. Therefore, we studied sex differences in irAEs in patients treated with anti-programmed cell death protein 1 (PD-1) therapy. MATERIALS AND METHODS: All patients with metastatic melanoma and non-small cell lung cancer (NSCLC) treated with anti-PD-1 therapy at Mayo Clinic Rochester and Florida from 2015 to 2018 were reviewed. Kaplan-Meier method and log-rank test was used for time-to-event analysis. RESULTS: In 245 patients with metastatic melanoma, premenopausal women were more likely to experience irAEs (all grades) compared with postmenopausal women and men (67% vs. 60% vs. 46%), primarily because of an increase in endocrinopathies (33% vs. 12% vs. 10%, respectively). In patients with NSCLC (231 patients), women (all ages) were also more likely to develop irAEs of all grades (48% vs. 31%). Women with NSCLC were more likely to develop pneumonitis (11% vs. 4%) and endocrinopathies (14% vs. 5%). No differences in grade ≥3 toxicities were seen across sexes in both cohorts, but women were more likely to receive systemic steroids for the treatment of irAEs compared with men. Better progression-free-survival was observed in women with NSCLC and irAEs (10 months vs. 3.3 months) compared with women without irAEs. CONCLUSION: Women with metastatic melanoma and NSCLC are more likely to experience irAEs compared with men. We also observed differences between sexes in the frequency of certain irAEs. Larger studies are needed to investigate the mechanisms underlying these associations. IMPLICATIONS FOR PRACTICE: The results of this study suggest that women may be at a higher risk for immune-related adverse events (irAEs) compared with men when treated with anti-programmed cell death protein 1 therapy. In addition, women were more likely to develop certain irAEs, including endocrinopathies and pneumonitis. Close follow-up of women undergoing treatment with immune checkpoint inhibitors will allow clinicians to diagnose these treatment-related complications early, potentially reducing their associated morbidity and mortality. In addition, a possible association between irAEs and response to therapy was observed.

Sustainable wastewater treatment by deep eutectic solvents and natural silk for radioactive iodine capture.

The pollution from nuclear leaks and nuclear disasters (e.g. radioactive iodine) would cause serious harm to human beings and ecosystems for many years. Cocoon silk and deep eutectic solvents (DESs) are both green substances. DESs are easily synthesized, cheap, highly biocompatible and highly biodegradable. Here, we combine the removal of organic dyes and the capture of radioactive iodine by using green DES-pretreated cocoon silk. It is the first time organic dyes have been removed from wastewater by DES-disrupted silk for the purpose of favourably removing iodine. Organic dyes-captured DES-pretreated cocoon silk could be used to capture iodine efficiently. It opens a new route to dispose of one waste from nuclear energy with organic dyes from wastewater captured by green solvents-pretreated natural silk.

MHC class II restricted neoantigen peptides predicted by clonal mutation analysis in lung adenocarcinoma patients: implications on prognostic immunological biomarker and vaccine design.

BACKGROUND: Mutant peptides presented by MHC (major histocompatibility complex) Class II in cancer are important targets for cancer immunotherapy. Both animal studies and clinical trials in cancer patients showed that CD4 T cells specific to tumor-derived mutant peptides are essential for the efficacy of immune checkpoint blockade therapy by PD1 antibody. RESULTS: In this study, we analyzed the next generation sequencing data of 147 lung adenocarcinoma patients from The Cancer Genome Atlas and predicted neoantigens presented by MHC Class I and Class II molecules. We found 18,175 expressed clonal somatic mutations, with an average of 124 per patient. The presentation of mutant peptides by an HLA(human leukocyte antigen) Class II molecule, HLA DRB1, were predicted by NetMHCIIpan3.1. 8804 neo-peptides, including 375 strong binders and 8429 weak binders were found. For HLA DRB1*01:01, 54 strong binders and 896 weak binders were found. The most commonly mutated genes with predicted neo-antigens are KRAS, TTN, RYR2, MUC16, TP53, USH2A, ZFHX4, KEAP1, STK11, FAT3, NAV3 and EGFR. CONCLUSIONS: Our results support the feasibility of discovering individualized HLA Class II presented mutant peptides as candidates for immunodiagnosis and immunotherapy of lung adenocarcinoma.

The role of immunotherapy sensitizers and novel immunotherapy modalities in the treatment of cancer.

The importance of the immune system in the response against cancer has always been a subject of intense investigation. The advent of immune checkpoint inhibitors has transformed the landscape of oncologic treatments, while expanding the understanding of this disease's pathophysiology. Consequently, many therapies are being investigated, with interventions directed at different steps and pathways of the immune response. Relevantly, immunotherapy sensitizers have arisen as approaches focused on the synergistic effects of immunotherapy combination, or the combination of immunotherapy and other treatment modalities, such as chemotherapy or radiation therapy. Concomitantly, novel immunotherapy modalities are also in development. Approaches focusing from the tumor intrinsic pathways to the tumor microenvironment and ex-vivo interventions, such as CAR-T cell therapies and tumor-infiltrating lymphocytes are important examples. Although many of those interventions were initially envisioned as standalone options, their combination has demonstrated promising results in early-phase in vitro studies and clinical trials. The possibility of coupling different immunotherapy modalities, as well as with other techniques, further strengthen the concept of sensitizers, allowing for deeper and more robust responses in cancer treatment. This review aims to present an overview of the concepts of these sensitizing mechanisms that are the basis for the synergistic effects of immunotherapy combination, or the combination of immunotherapy and a multitude of therapeutic strategies. Novel immunotherapy modalities are also presented, focusing on the potential of combining them with sensitizer interventions. Understanding the complexity underlying these principles may be the key for future breakthroughs and improved patient outcomes.

Clinical outcomes of atezolizumab versus standard-of-care docetaxel with and without ramucirumab in patients with advanced non-small-cell lung cancer who received prior immunotherapy.

Background: Atezolizumab is superior to docetaxel for patients with advanced non-small-cell lung cancer (NSCLC) who are pretreated with platinum-based chemotherapy based on the POPLAR and OAK trials. However, patients who received prior immunotherapy were excluded from these trials. The standard of care second-line therapy for these patients remains to be docetaxel with or without ramucirumab. The efficacy and safety of atezolizumab as a subsequent therapy in immunotherapy-pretreated patients are unknown. Methods: We conducted a retrospective study of all patients with locally advanced or metastatic NSCLC who were pretreated with immunotherapy at Mayo Clinic Jacksonville and Rochester from 2016 to 2022. Patients who received subsequent therapy of atezolizumab alone (Atezo), docetaxel (Doce), or docetaxel + ramucirumab (Doce+Ram) were included. Results: In this cohort of 165 patients, 12.7% (n=21), 49.1% (n=81), and 38.2% (n=63) patients received subsequent Atezo, Doce, and Doce+Ram, respectively. 1-year landmark progression-free survival (PFS) were 23.8%, 6.2%, and 3.2% (p=0.006), and 2-year landmark PFS were 14.3%, 0%, and 0% (p<0.0001), in the Atezo, Doce, and Doce+Ram groups, respectively. About 20% patients with positive PD-L1 had durable response to atezolizumab. The Atezo group showed significantly greater overall survival (OS) improvement over Doce group (median OS 17.7 vs. 7.7 months, HR 0.47, 95% CI 0.29 - 0.76, p=0.008), and over Doce+Ram group (median OS 17.7 vs. 8.9 months, HR 0.55, 95% CI 0.32 - 0.95, p=0.047). 4 of 21 (19%) patients in the Atezo group developed immune-related adverse events (irAE). Conclusion: We observed statistically significant and clinically meaningful overall survival benefits of atezolizumab monotherapy compared with docetaxel +/- ramucirumab in patients with advanced NSCLC who were pretreated with immunotherapy. The survival benefit seems to be mainly from PD-L1 positive patients. Subsequent immunotherapy with Atezolizumab did not increase irAE rate.

Identification and preliminary analysis of hub genes associated with bladder cancer progression by comprehensive bioinformatics analysis.

Bladder cancer (BC) is a crisis to human health. It is necessary to understand the molecular mechanisms of the development and progression of BC to determine treatment options. Publicly available expression data were obtained from TCGA and GEO databases to spot differentially expressed genes (DEGs) between cancer and normal bladder tissues. Weighted co-expression networks were constructed, and Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Associations in hub genes, immune infiltration, and immune therapy were evaluated separately. Protein-protein interaction (PPI) networks for the genes identified in the normal and tumor groups were launched. 3461 DEGs in the TCGA dataset and 1069 DEGs in the GSE dataset were identified, including 87 overlapping genes between cancer and normal bladder groups. Hub genes in the tumor group were mainly enriched for cell proliferation, while hub genes in the normal group were related to the synthesis and secretion of neurotransmitters. Based on survival analysis, CDH19, RELN, PLP1, and TRIB3 were considerably associated with prognosis (P < 0.05). CDH19, RELN, PLP1, and TRIB3 may play important roles in the development of BC and are potential biomarkers in therapy and prognosis.

Sex- and Age-Associated Differences in Genomic Alterations among Patients with Advanced Non-Small Cell Lung Cancer (NSCLC).

Genomic mutations impact non-small cell lung cancer (NSCLC) biology. The influence of sex and age on the distribution of these alterations is unclear. We analyzed circulating-tumor DNA from individuals with advanced NSCLC from March 2018 to October 2020. EGFR, KRAS, ALK, ROS1, BRAF, NTRK, ERBB2, RET, MET, PIK3CA, STK11, and TP53 alterations were assessed. We evaluated the differences by sex and age (<70 and ≥70) using Fisher's exact test. Of the 34,277 samples, 30,790 (89.83%) had a detectable mutation and 19,923 (58.12%) had an alteration of interest. The median age of the ctDNA positive population was 69 (18-102), 16,756 (54.42%) were female, and 28,835 (93.65%) had adenocarcinoma. Females had more alterations in all the assessed EGFR mutations, KRAS G12C, and ERBB2 ex20 ins. Males had higher numbers of MET amp and alterations in STK11 and TP53. Patients <70 years were more likely to have alterations in EGFR exon 19 del/exon 20 ins/T790M, KRAS G12C/D, ALK, ROS1, BRAF V600E, ERBB2 Ex20ins, MET amp, STK11, and TP53. Individuals ≥70 years were more likely to have alterations in EGFR L861Q, MET exon 14 skipping, and PIK3CA. We provided evidence of sex- and age-associated differences in the distribution of genomic alterations in individuals with advanced NSCLC.

Early discontinuation of immune checkpoint inhibitor therapy prior to disease progression in patients with metastatic non-small cell lung cancer: a survival analysis.

Introduction: Limited survival data are available for patients with metastatic non-small cell lung cancer (mNSCLC) who stop immune checkpoint inhibitor therapy (ICI) early for reasons other than progression of disease (POD), such as immune-related adverse events (irAEs). Methods: We conducted a retrospective observational study of all patients with mNSCLC treated with ICIs, with or without combination chemotherapy, at 3 Mayo Clinic sites between 2011 and 2022. Separate analyses were conducted at 6- and 12-month intervals. Patients who discontinued ICI due to POD prior to these time points were excluded from the analysis. Results: A total of 246 patients with stage IV NSCLC used ICIs. Patients were then excluded if they had experienced POD prior to 6 or 12 months, resulting in 81 and 63 patients, respectively, for each timepoint. Sixty-four patients continued treatment beyond 6 months and were found to have longer progression-free survival (PFS) compared to the 17 patients who discontinued treatment (22.8 months vs 11.8 months, P =1.1E-04), as well as a significant increase in overall survival (OS) (33.9 months vs 14.4 months, P =7.2E-08). Forty patients continued treatment beyond 12 months and had longer PFS compared to the 23 patients that discontinued treatment (27.9 months vs 14.8 months, P =1.1E-04), as well as a significant increase in OS (39.7 months vs 18.0 months, P =2.0E-07). The most common reason for ICI discontinuation was irAEs. Other common reasons for stopping ICI were non-irAEs and stable disease. At both time points, 12 patients continued or restarted ICI after experiencing an irAE, and 2 patients experienced recurrent/new grade 1-2 irAEs. More patients continued/rechallenged with ICI after experiencing an irAE in the groups that continued ICI compared to those that discontinued ICI. Conclusions: Patients with mNSCLC and no POD who continued ICI beyond 6 months and 12 months, experienced significantly increased PFS and OS compared to patients who discontinued ICI, with larger increases in those who continued ICI past 12 months. Oncology providers should discuss the survival benefits of continuing ICI and offer support to overcome obstacles to continuation of treatment, if possible, particularly management of grade 1 and 2 irAEs.

Adagrasib Treatment After Sotorasib-Related Hepatotoxicity in Patients With KRASG12C-Mutated Non-Small Cell Lung Cancer: A Case Series and Literature Review.

PURPOSE: KRAS is the most commonly mutated driver oncogene in non-small cell lung cancer (NSCLC). Sotorasib and adagrasib, KRASG12C inhibitors, have been granted accelerated US approval; however, hepatotoxicity is a common side effect with higher rates in patients treated with sotorasib proximal to checkpoint inhibitor (CPI) therapy. The aim of this study was to assess the feasibility and safety of adagrasib after discontinuation of sotorasib because of treatment-related grade 3 hepatotoxicity through real-world and clinical cases. METHODS: Medical records from five patients treated in real-world settings were retrospectively reviewed. Patients had locally advanced or metastatic KRASG12C-mutated NSCLC and received adagrasib after sotorasib in the absence of extracranial disease progression. Additional data were collected for 12 patients with KRASG12C-mutated NSCLC enrolled in a phase Ib cohort of the KRYSTAL-1 study and previously treated with sotorasib. The end points associated with both drugs included timing and severity of hepatotoxicity, best overall response, and duration of therapy. RESULTS: All patients were treated with CPIs followed by sotorasib (initiated 0-64 days after CPI). All five real-world patients experienced hepatotoxicity with sotorasib that led to treatment discontinuation, whereas none experienced treatment-related hepatotoxicity with subsequent adagrasib treatment. Three patients from KRYSTAL-1 transitioned from sotorasib to adagrasib because of hepatotoxicity; one experienced grade 3 ALT elevation on adagrasib that resolved with therapy interruption and dose reduction. CONCLUSION: Adagrasib may have a distinct hepatotoxicity profile from sotorasib and is more easily combined with CPIs either sequentially or concurrently. These differences may be used to inform clinical decisions regarding an initial KRASG12C inhibitor for patients who recently discontinued a CPI or experience hepatotoxicity on sotorasib.

A Phase I Study of sequences of the CDK4/6 Inhibitor, Ribociclib Combined with Gemcitabine in Patients with Advanced Solid Tumors.

Background: Based on preclinical data showing addition of CDK4/6 inhibitors to gemcitabine is synergistic, ribociclib was evaluated in combination with gemcitabine to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Methods: In this single arm multicohort phase I trial, we evaluated the safety and efficacy of Ribociclib plus Gemcitabine in patients with advanced solid tumors. Patients received Gemcitabine intravenously on days 1 and 8 followed by Ribociclib days 8-14, with treatment repeated every 3 weeks. Results: The study enrolled 43 patients between October 2017 and September 2019. The escalation phase (19 patients) determined the MTD and recommended phase II dose (RP2D) to be ribociclib 800mg daily and gemcitabine 1000mg/m2 for the expansion phase (24 patients). One patient experienced Grade 4 thrombocytopenia. Eleven patients experienced Grade 3 adverse events (AE), the most common being neutropenia, thrombocytopenia, and anemia. No partial or complete responses were observed. 15/22 (68%) of efficacy evaluable patients who received the MTD achieved best response of stable disease. Conclusions: The addition of Ribociclib to Gemcitabine was tolerated well and yielded stability of tumors in both cohorts. Ribociclib and gemcitabine could have synergistic activity in certain tumor types, and our data provides support for the combination. Clinical Trial Registration: NCT03237390.

Metastatic Non-Small Cell Lung Cancer Mimicking Metaplastic Breast Cancer: A Case Report.

NGS used to diagnose and treat NSCLC patient with initial concern for metaplastic breast cancer.

Clinical Benefit from Docetaxel +/- Ramucirumab Is Not Associated with Mutation Status in Metastatic Non-Small-Cell Lung Cancer Patients Who Progressed on Platinum Doublets and Immunotherapy.

Docetaxel +/- ramucirumab remains the standard-of-care therapy for patients with metastatic non-small-cell lung cancer (NSCLC) after progression on platinum doublets and immune checkpoint inhibitors (ICIs). The aim of our study was to investigate whether the cancer gene mutation status was associated with clinical benefits from docetaxel +/- ramucirumab. We also investigated whether platinum/taxane-based regimens offered a better clinical benefit in this patient population. A total of 454 patients were analyzed (docetaxel +/- ramucirumab n=381; platinum/taxane-based regimens n=73). Progression-free survival (PFS) and overall survival (OS) were compared among different subpopulations with different cancer gene mutations and between patients who received docetaxel +/- ramucirumab versus platinum/taxane-based regimens. Among patients who received docetaxel +/- ramucirumab, the top mutated cancer genes included TP53 (n=167), KRAS (n=127), EGFR (n=65), STK11 (n=32), ERBB2 (HER2) (n=26), etc. None of these cancer gene mutations or PD-L1 expression was associated with PFS or OS. Platinum/taxane-based regimens were associated with a significantly longer mQS (13.00 m, 95% Cl: 11.20-14.80 m versus 8.40 m, 95% Cl: 7.12-9.68 m, LogRank P=0.019) than docetaxel +/- ramcirumab. Key prognostic factors including age, histology, and performance status were not different between these two groups. In conclusion, in patients with metastatic NSCLC who have progressed on platinum doublets and ICIs, the clinical benefit from docetaxel +/- ramucirumab is not associated with the cancer gene mutation status. Platinum/taxane-based regimens may offer a superior clinical benefit over docetaxel +/- ramucirumab in this patient population.

RefAI: a GPT-powered retrieval-augmented generative tool for biomedical literature recommendation and summarization.

OBJECTIVES: Precise literature recommendation and summarization are crucial for biomedical professionals. While the latest iteration of generative pretrained transformer (GPT) incorporates 2 distinct modes-real-time search and pretrained model utilization-it encounters challenges in dealing with these tasks. Specifically, the real-time search can pinpoint some relevant articles but occasionally provides fabricated papers, whereas the pretrained model excels in generating well-structured summaries but struggles to cite specific sources. In response, this study introduces RefAI, an innovative retrieval-augmented generative tool designed to synergize the strengths of large language models (LLMs) while overcoming their limitations. MATERIALS AND METHODS: RefAI utilized PubMed for systematic literature retrieval, employed a novel multivariable algorithm for article recommendation, and leveraged GPT-4 turbo for summarization. Ten queries under 2 prevalent topics ("cancer immunotherapy and target therapy" and "LLMs in medicine") were chosen as use cases and 3 established counterparts (ChatGPT-4, ScholarAI, and Gemini) as our baselines. The evaluation was conducted by 10 domain experts through standard statistical analyses for performance comparison. RESULTS: The overall performance of RefAI surpassed that of the baselines across 5 evaluated dimensions-relevance and quality for literature recommendation, accuracy, comprehensiveness, and reference integration for summarization, with the majority exhibiting statistically significant improvements (P-values <.05). DISCUSSION: RefAI demonstrated substantial improvements in literature recommendation and summarization over existing tools, addressing issues like fabricated papers, metadata inaccuracies, restricted recommendations, and poor reference integration. CONCLUSION: By augmenting LLM with external resources and a novel ranking algorithm, RefAI is uniquely capable of recommending high-quality literature and generating well-structured summaries, holding the potential to meet the critical needs of biomedical professionals in navigating and synthesizing vast amounts of scientific literature.