Tislelizumab in previously treated, locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid tumors.

Objective: The open-label, phase II RATIONALE-209 study evaluated tislelizumab (anti-programmed cell death protein 1 antibody) as a tissue-agnostic monotherapy for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) tumors. Methods: Adults with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled. Patients received tislelizumab 200 mg intravenously every 3 weeks. Objective response rate (ORR; primary endpoint), duration of response (DoR), and progression-free survival (PFS) were assessed by independent review committee (Response Evaluation Criteria in Solid Tumors v1.1). Results: Eighty patients were enrolled and treated; 75 (93.8%) patients had measurable disease at baseline. Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease (n=79; 98.8%). At primary analysis (data cutoff July 8, 2021; median follow-up 15.2 months), overall ORR [46.7%; 95% confidence interval (95% CI), 35.1-58.6; one-sided P<0.0001] and ORR across tumor-specific subgroups [colorectal (n=46): 39.1% (95% CI, 25.1-54.6); gastric/gastroesophageal junction (n=9): 55.6% (95% CI, 21.2-86.3); others (n=20): 60.0% (95% CI, 36.1-80.9)] were significantly greater with tislelizumab vs. a prespecified historical control ORR of 10%; five (6.7%) patients had complete responses. Median DoR, PFS, and overall survival were not reached with long-term follow-up (data cutoff December 5, 2022; median follow-up 28.9 months). Tislelizumab was well tolerated with no unexpected safety signals. Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 53.8% of patients; 7.5% of patients discontinued treatment due to TRAEs. Conclusions: Tislelizumab demonstrated a significant ORR improvement in patients with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.

Temperature Control Parameters Are Important: Earlier Preinduction Is Associated With Improved Outcomes Following Out-of-Hospital Cardiac Arrest.

STUDY OBJECTIVE: Temperature control trials in cardiac arrest patients have not reliably conferred neuroprotective benefit but have been limited by inconsistent treatment parameters. To evaluate the presence of a time dependent treatment effect, we assessed the association between preinduction time and clinical outcomes. METHODS: In this retrospective, single academic center study between 2014 and 2022, consecutive out-of-hospital cardiac arrest (OHCA) patients treated with temperature control were identified. Preinduction was defined as the time from hospital arrival to initiation of a closed-loop temperature feedback device [door to temperature control initiation time], and early door to temperature control device time was defined a priori as <3 hours. We assessed the association between good neurologic outcome (cerebral performance category 1 to 2) and door to temperature control device time using logistic regression. The proportion of patients who survived to hospital discharge was evaluated as a secondary outcome. A sensitivity analysis using inverse probability treatment weighting, created using a propensity score, was performed to minimize measurable confounding. RESULTS: Three hundred and forty-seven OHCA patients were included; the early door to temperature control device cohort included 75 (21.6%) patients with a median (interquartile range) door to temperature control device time of 2.50 (2.03 to 2.75) hours, whereas the late door to temperature control device cohort included 272 (78.4%) patients with a median (interquartile range) door to temperature control device time of 5.18 (4.19 to 6.41) hours. In the multivariable logistic regression model, early door to temperature control device time was associated with improved good neurologic outcome and survival before [adjusted odds ratio (OR) (95% confidence interval) 2.36 (1.16 to 4.81) and 3.02 (1.54 to 6.02)] and after [adjusted OR (95% confidence interval) 1.95 (1.19 to 3.79) and 2.14 (1.33 to 3.36)] inverse probability of treatment weighting, respectively. CONCLUSION: In our study of OHCA patients, a shorter preinduction time for temperature control was associated with improved good neurologic outcome and survival. This finding may indicate that early initiation in the emergency department will confer benefit. Our findings are hypothesis generating and need to be validated in future prospective trials.

Outcomes Following Implementation of an Electronic Model for Perioperative Hematologic Consultation.

INTRODUCTION: Electronic consultations (e-consults) for periprocedural hematologic questions were introduced at the VA Connecticut Healthcare System in 2011. We sought to explore the relationship between the availability of e-consults, referral patterns, and surgical outcomes. METHODS: A single-center retrospective study of all perioperative hematologic consultations from 2006 to 2018 was conducted. Patient characteristics, indications, and outcomes were analyzed. Primary outcome measures were time from consult to surgery and operative morbidity via Clavien-Dindo classification. Secondary outcomes included consult volume and procedural outcomes of interest. RESULTS: Of 357 consultations, 62% were conducted via e-consults. 68.3% had associated procedural data and constituted the study cohort. Annual consult volume increased from 7 in 2006 to 41 in 2018, a 5.8-fold increase. E-consults comprised 20% of consults in 2011 but had risen to 92.3% in 2018. Time to resolution of e-consults after 2011 improved compared to pre-face-to-face (FTF-pre, P = 0.001) and FTF-post (P = 0.002). Time from consult to surgery remained unchanged. 8.4% had major complications (Clavien-Dindo >2) with readmission or reoperation occurring in 4.0% and 3.7%, respectively. Intraoperative and postoperative transfusions were required in 15.2% and 13.1% of cases, respectively. Hematologic complications (i.e., deep vein thrombosis/pulmonary embolism) occurred in 3.5%. Comparison between FTF and e-consults revealed no significant differences in these outcomes (P > 0.05, all). CONCLUSIONS: E-consults for perioperative hematologic issues were rapidly adopted and addressed more quickly than FTF consultation while time to surgery was unchanged despite increased consult volume. Adoption of the e-consult model was not associated with changes in the assessed operative outcomes.

Psychosocial Evaluation of Living Kidney Donors: A Survey of Current Practices in the United States.

BACKGROUND: Best practices in psychosocial evaluation and care of living donor candidates and donors are not well established. METHODS: We surveyed 195 living kidney donor (LKD) transplant centers in United States from October 2021 to April 2022 querying (1) composition of psychosocial teams, (2) evaluation processes including clinical tools and domains assessed, (3) selection criteria, and (4) psychosocial follow-up post-donation. RESULTS: We received 161 responses from 104 programs, representing 53% of active LKD programs and 67% of LKD transplant volume in 2019. Most respondents (63%) were social workers/independent living donor advocates. Over 90% of respondents indicated donor candidates with known mental health or substance use disorders were initially evaluated by the psychosocial team. Validated psychometric or transplant-specific tools were rarely utilized but domains assessed were consistent. Active suicidality, self-harm, and psychosis were considered absolute contraindications in >90% of programs. Active depression was absolute contraindication in 50% of programs; active anxiety disorder was excluded 27%. Conditions not contraindicated to donation include those in remission: anxiety (56%), depression (53%), and posttraumatic stress disorder (41%). There was acceptance of donor candidates using alcohol, tobacco, or cannabis recreationally, but not if pattern met criteria for active use disorder. Seventy-one percent of programs conducted post-donation psychosocial assessment and use local resources to support donors. CONCLUSIONS: There was variation in acceptance of donor candidates with mental health or substance use disorders. Although most programs conducted psychosocial screening post-donation, support is not standardized and unclear if adequate. Future studies are needed for consensus building among transplant centers to form guidelines for donor evaluation, acceptance, and support.

Single-Nucleus RNA-Seq Reveals Spermatogonial Stem Cell Developmental Pattern in Shaziling Pigs.

Normal testicular development ensures the process of spermatogenesis, which is a complex biological process. The sustained high productivity of spermatogenesis throughout life is predominantly attributable to the constant proliferation and differentiation of spermatogonial stem cells (SSCs). The self-renewal and differentiation processes of SSCs are strictly regulated by the SSC niche. Therefore, understanding the developmental pattern of SSCs is crucial for spermatogenesis. The Shaziling pig is a medium-sized indigenous pig breed originating from central China. It is renowned for its superior meat quality and early male sexual maturity. The spermatogenic ability of the boars is of great economic importance to the pig industry. To investigate testicular development, particularly the pattern of SSC development in Shaziling pigs, we used single-cell transcriptomics to identify gene expression patterns in 82,027 individual cells from nine Shaziling pig testes at three key postnatal developmental stages. We generated an unbiased cell developmental atlas of Shaziling pig testicular tissues. We elucidated the complex processes involved in the development of SSCs within their niche in the Shaziling pig. Specifically, we identified potential marker genes and cellular signaling pathways that regulate SSC self-renewal and maintenance. Additionally, we proposed potential novel marker genes for SSCs that could be used for SSC isolation and sorting in Shaziling pigs. Furthermore, by immunofluorescence staining of testicular tissues of different developmental ages using marker proteins (UCHL1 and KIT), the developmental pattern of the spermatogonia of Shaziling pigs was intensively studied. Our research enhances the comprehension of the development of SSCs and provides a valuable reference for breeding Shaziling pigs.

First-line serplulimab in metastatic colorectal cancer: Phase 2 results of a randomized, double-blind, phase 2/3 trial.

BACKGROUND: Whether or not the addition of immunotherapy to current standard-of-care treatments can improve efficacy in proficient mismatch repair (pMMR)/microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), the predominant type of mCRC, is unclear. METHODS: This randomized, double-blind, phase 2 part of a phase 2/3 trial was conducted at 23 hospitals across China (ClinicalTrials.gov: NCT04547166). Patients with unresectable metastatic/recurrent colorectal adenocarcinoma and no prior systemic therapy were randomly assigned 1:1 to receive every-3-weeks intravenous serplulimab (300 mg) plus HLX04 (7.5 mg/kg) and XELOX (serplulimab group) or placebo (300 mg) plus bevacizumab (7.5 mg/kg) and XELOX (placebo group). The primary endpoint was independent radiology review committee (IRRC)-assessed progression-free survival (PFS). Secondary endpoints included other efficacy endpoints and safety. FINDINGS: Between July 16, 2021, and January 20, 2022, 114 patients were enrolled and randomly assigned to the serplulimab (n = 57) or placebo (n = 57) group. All patients had stage IV CRC, and 95.7% of the patients with available microsatellite instability (MSI) status were MSS. With a median follow-up duration of 17.7 months, median PFS was prolonged in the serplulimab group (17.2 vs. 10.7 months; hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.31-1.14). Although the median overall survival (OS) was not reached for either group, a trend of an OS benefit was observed for the serplulimab group (HR, 0.77; 95% CI, 0.41-1.45). 36 (65.5%) and 32 (56.1%) patients in the serplulimab and placebo groups had grade ≥3 treatment-related adverse events, respectively. CONCLUSIONS: Serplulimab plus HLX04 and XELOX exhibits promising efficacy and is safe and tolerable in patients with treatment-naive mCRC. FUNDING: This work was funded by Shanghai Henlius Biotech, Inc.

Fruquintinib plus paclitaxel versus placebo plus paclitaxel for gastric or gastroesophageal junction adenocarcinoma: the randomized phase 3 FRUTIGA trial.

The vascular endothelial growth factor pathway plays a key role in the pathogenesis of gastric cancer. In the multicenter, double-blind phase 3 FRUTIGA trial, 703 patients with advanced gastric or gastroesophageal junction adenocarcinoma who progressed on fluorouracil- and platinum-containing chemotherapy were randomized (1:1) to receive fruquintinib (an inhibitor of vascular endothelial growth factor receptor-1/2/3; 4 mg orally, once daily) or placebo for 3 weeks, followed by 1 week off, plus paclitaxel (80 mg/m2 intravenously on days 1/8/15 per cycle). The study results were positive as one of the dual primary endpoints, progression-free survival (PFS), was met (median PFS, 5.6 months in the fruquintinib arm versus 2.7 months in the placebo arm; hazard ratio 0.57; 95% confidence interval 0.48-0.68; P < 0.0001). The other dual primary endpoint, overall survival (OS), was not met (median OS, 9.6 months versus 8.4 months; hazard ratio 0.96, 95% confidence interval 0.81-1.13; P = 0.6064). The most common grade ≥3 adverse events were neutropenia, leukopenia and anemia. Fruquintinib plus paclitaxel as a second-line treatment significantly improved PFS, but not OS, in Chinese patients with advanced gastric or gastroesophageal junction adenocarcinoma and could potentially be another treatment option for these patients. ClinicalTrials.gov registration: NCT03223376 .

Novel functions of o-cymen-5-ol nanoemulsion in reversing colistin resistance in multidrug-resistant Klebsiella pneumoniae infections.

Multidrug resistance (MDR) Klebsiella pneumoniae (K. pneumoniae) is a major emerging threat to human health, and leads to very high mortality rate. The effectiveness of colistin, the last resort against MDR Gram-negative bacteria, is significantly compromised due to the widespread presence of plasmid- or chromosome-mediated resistance genes. In this study, o-cymen-5-ol has been found to greatly restore colistin sensitivity in MDR K. pneumoniae. Importantly, this compound does not impact bacterial viability, induce resistance, or cause any noticeable cell toxicity. Various routes disclosed the potential mechanism of o-cymen-5-ol potentiating colistin activity against MDR K. pneumoniae. These include inhibiting the activity of plasmid-mediated mobile colistin resistance gene (mcr-1), accelerating lipopolysaccharide (LPS) - mediated membrane damage, and promoting the ATP-binding cassette (ABC) transporter pathway. To enhance the administration and bioavailability of o-cymen-5-ol, a nanoemulsion has been designed, which significantly improves the loading efficiency and solubility of o-cymen-5-ol, resulting in antimicrobial potentiation of colistin against K. pneumoniae infection. This study has revealed a new understanding of the o-cymen-5-ol nanoemulsion as a means to enhance the effectiveness of colistin against resistant factors. The finding also suggests that o-cymen-5-ol nanoemulsion could be a promising approach in the development of potential treatments for multidrug-resistant Gram-negative bacterial infections.

Intravascular Ultrasound Use is Associated with Improved Patency in Lower Extremity Peripheral Arterial Interventions.

BACKGROUND: Intravascular ultrasound (IVUS) facilitates detailed visualization of endoluminal anatomy not adequately appreciated on conventional angiography. However, it is unclear if IVUS use improves clinical outcomes of peripheral vascular interventions (PVIs) for peripheral arterial disease. This study aimed to evaluate the impact of IVUS on 1-year outcomes of PVI in the vascular quality initiative (VQI). METHODS: The VQI-PVI modules were reviewed (2016-2020). All patients with available 1-year follow-up after lower extremity PVI were included and grouped as IVUS-PVI or non-IVUS PVI based on use of IVUS. Propensity matching (1:1) was performed using demographics and comorbidities. One-year major amputation and patency rates were compared. A generalized estimating equation model was used to identify predictors of 1-year outcomes. Subgroup analysis based on Trans-Atlantic Intersociety Consensus (TASC) classification, treatment length and treatment modalities were performed using same modeling approaches. RESULTS: There were 56,633 procedures (non-IVUS PVI = 55,302 vs. IVUS-PVI = 1,331) in 44,042 patients. Propensity matching yielded a total cohort of 1,854 patients matched (1:1), with no baseline differences. Lower extremity revascularization for claudication was performed in 60.4%, while one-third (33.9%) had chronic limb threatening ischemia (CLTI). IVUS was more commonly used for lesions >15 cm in length (46.6% vs. 43.3%) and for aortoiliac disease (31.8% vs. 27.2%). Rates of atherectomy and stenting were significantly higher with IVUS-PVI (21.1% vs. 16.8%), while balloon angioplasty was less common (13.5% vs. 24.4%). One-year patency was better with IVUS-PVI (97.7% vs. 95.2%, P = 0.004). On subgroup analysis, IVUS (odds ratio [OR] 2.20, 95% confidence interval [CI] 1.29-3.75) was associated with improved patency in CLTI patients, TASC C or D lesions, and treatment length >15 cm. Adjunctive IVUS use during PVI did not significantly impact 1-year amputation (OR 1.7, 95% CI 0.78-3.91). On multivariable regression, adjunctive use of IVUS (OR 2.46 95% CI 1.43-4.25) and aortoiliac interventions (OR 2.91, 95% CI 1.09-7.75) were independent predictors of patency. Treatment modalities such as atherectomy, stenting or balloon angioplasty did not significantly impact patency at 1-year. CONCLUSIONS: IVUS during lower extremity PVI is associated with improved 1-year patency, when compared to angiography alone. Certain subgroups, such as CLTI patients, lesions>15 cm, and TASC C or D lesions might benefit from adjunctive use of IVUS.

Enhancing the effectiveness of Polymyxin E with a Fisetin Nanoemulsion against a Colistin-resistant Salmonella typhimurium infection.

BACKGROUND: Polymyxin E is widely recognized as a last resort for treating multidrug-resistant gram-negative bacteria. Unfortunately, the effectiveness of polymyxin E is significantly reduced when treating life-threatening bacterial infections due to plasmid-mediated polymyxin E resistance. The synergistic effect of applying a polymyxin E adjuvant is a promising strategy for overcoming the growing threat of antibiotic-resistant pathogens. PURPOSE: To evaluate the synergistic effect of fisetin and polymyxin E on S. typhimurium infections in vivo and further elucidate the underlying mechanism of this effect. METHODS: The effect of combining fisetin and polymyxin E to treat mobilized colistin resistance-1-positive (MCR-1-positive) gram-negative bacteria in vitro was examined using various methods, such as checkerboard assays, growth curves and time‒kill curves. To elucidate the mechanism by which fisetin affects MCR-1, we employed ultraviolet (UV) absorption spectroscopy, thin layer chromatography (TLC), and western blot analysis to investigate its effect at the protein level. Subsequently, molecular dynamics simulations (MDS) and metabolomics analysis were utilized to determine the site of interaction between fisetin and MCR-1 as well as the potential pathways and mechanisms involved. A new nanoemulsion of fisetin was produced using high-pressure homogenization, and its stability was tested. Finally, two animal models of S. typhimurium HYM2 infection were established to evaluate the synergistic effect of polymyxin E and fisetin in vivo. RESULTS: Our study revealed that fisetin exhibited a synergistic effect when combined with polymyxin E against MCR-1-positive S. typhimurium. The TLC results demonstrated that fisetin could inhibit the phosphoethanolamine (PEA) transfer of the MCR-1 protein, thereby restoring the activity of polymyxin E in strains against MCR-1. The MDS analysis indicated robust and immediate binding between fisetin and the MCR-1 protein, with both hydrophobic and polar effects playing significant roles in determining the binding energy of the former. Metabolomic studies demonstrated that the addition of fisetin significantly modulated bacterial metabolites. Moreover, it effectively inhibited the activity of ABC transporters in bacteria, thereby mitigating bacterial drug resistance and enhancing the therapeutic efficacy of polymyxin E. Furthermore, in mouse and chick models of infection, intragastric administration of the fisetin nanoemulsion together with polymyxin E resulted in significant therapeutic benefits, including increased survival rates, reduced bacterial colonization, and decreased levels of inflammatory factors. CONCLUSION: Fisetin, an MCR-1 inhibitor and a promising synergistic partner of polymyxin E, has significant potential for clinical application in the treatment of S. typhimurium infections, particularly those resulting extensively from drug-resistant MCR-1-positive strains.

Effect of free and bound proanthocyanidins from Chinese quince on heterocyclic aromatic amine formation and quality in fried chicken.

The abilities of Chinese quince free proanthocyanidins (FP) and bound proanthocyanidins (BP) at different levels (0.1%, 0.15%, and 0.3%) to mitigate heterocyclic aromatic amine (HAA) formation in fried chicken patties were investigated for the first time and compared with vitamin C (Vc). FP and BP reduced HAAs in a dose-dependent manner. Significantly, high concentrations of FP (0.3%) resulted in a reduction of PhIP, harman, and norharman levels by 59.84%, 22.91%, and 38.21%, respectively, in chicken patties. The addition of proanthocyanidins significantly (p < 0.05) reduced the weight loss of fried chicken patties. Furthermore, a positive correlation was observed among pH, weight loss, and total HAA formation in all three groups (FP, BP, and Vc). Multivariate analysis showed that FP had a more pronounced effect than BP from the perspective of enhancing the quality of fried chicken patties and reducing the formation of HAAs. These results indicate that proanthocyanidins, both BP and FP, but especially FP, from Chinese quince can inhibit the formation of carcinogenic HAAs when added to protein-rich foods that are subsequently fried.

Gender-specific effects of polystyrene nanoplastic exposure on triclosan-induced reproductive toxicity in zebrafish (Danio rerio).

Nanoplastics (NPs) and triclosan (TCS) are ubiquitous emerging environmental contaminants detected in human samples. While the reproductive toxicity of TCS alone has been studied, its combined effects with NPs remain unclear. Herein, we employed Fourier transform infrared spectroscopy and dynamic light scattering to characterize the coexposure of polystyrene nanoplastics (PS-NPs, 50 nm) with TCS. Then, adult zebrafish were exposed to TCS at environmentally relevant concentrations (0.361-48.2 µg/L), with or without PS-NPs (1.0 mg/L) for 21 days. TCS biodistribution in zebrafish tissues was investigated using ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry. Reproductive toxicity was assessed through gonadal histopathology, fertility tests, changes in steroid hormone synthesis and gene expression within the hypothalamus-pituitary-gonad-liver (HPGL) axis. Transcriptomics and proteomics were applied to explore the underlying mechanisms. The results showed that PS-NPs could adsorb TCS, thus altering the PS-NPs' physical characteristics. Our observations revealed that coexposure with PS-NPs reduced TCS levels in the ovaries, livers, and brains of female zebrafish. Conversely, in males, coexposure with PS-NPs increased TCS levels in the testes and livers, while decreasing them in the brain. We found that co-exposure mitigated TCS-induced ovary development inhibition while exacerbated TCS-induced spermatogenesis suppression, resulting in increased embryonic mortality and larval malformations. This co-exposure influenced the expression of genes linked to steroid hormone synthesis (cyp11a1, hsd17ß, cyp19a1) and attenuated the TCS-decreased estradiol (E2) in females. Conversely, testosterone levels were suppressed, and E2 levels were elevated due to the upregulation of specific genes (cyp11a1, hsd3ß, cyp19a1) in males. Finally, the integrated analysis of transcriptomics and proteomics suggested that the aqp12-dctn2 pathway was involved in PS-NPs' attenuation of TCS-induced reproductive toxicity in females, while the pck2-katnal1 pathway played a role in PS-NPs' exacerbation of TCS-induced reproductive toxicity in males. Collectively, PS-NPs altered TCS-induced reproductive toxicity by disrupting the HPGL axis, with gender-specific effects.

Gastrointestinal Incomplete Degradation Exacerbates Neurotoxic Effects of PLA Microplastics via Oligomer Nanoplastics Formation.

Biodegradable plastics, hailed for their environmental friendliness, may pose unforeseen risks as they undergo gastrointestinal degradation, forming oligomer nanoplastics. Despite this, the influence of gastrointestinal degradation on the potential human toxicity of biodegradable plastics remains poorly understood. To this end, the impact of the murine in vivo digestive system is investigated on the biotransformation, biodistribution, and toxicity of PLA polymer and PLA oligomer MPs. Through a 28-day repeated oral gavage study in mice, it is revealed that PLA polymer and oligomer microplastics undergo incomplete and complete degradation, respectively, in the gastrointestinal tract. Incompletely degraded PLA polymer microplastics transform into oligomer nanoplastics, heightening bioavailability and toxicity, thereby exacerbating overall toxic effects. Conversely, complete degradation of PLA oligomer microplastics reduces bioavailability and mitigates toxicity, offering a potential avenue for toxicity reduction. Additionally, the study illuminates shared targets and toxicity mechanisms in Parkinson's disease-like neurotoxicity induced by both PLA polymer and PLA oligomer microplastics. This involves the upregulation of MICU3 in midbrains, leading to neuronal mitochondrial calcium overload. Notably, neurotoxicity is mitigated by inhibiting mitochondrial calcium influx with MCU-i4 or facilitating mitochondrial calcium efflux with DBcAMP in mice. These findings enhance the understanding of the toxicological implications of biodegradable microplastics on human health.

PD-1 blockade plus COX inhibitors in dMMR metastatic colorectal cancer: Clinical, genomic, and immunologic analyses from the PCOX trial.

BACKGROUND: Approximately 20% of patients with DNA mismatch repair deficiency (dMMR) metastatic colorectal cancer do not respond to anti-programmed death-1 (PD-1) ligand therapy, and baseline biomarkers of response are lacking. METHODS: We conducted a phase 2 study to evaluate the efficacy of cyclooxygenase (COX) inhibitors in combination with anti-PD-1 therapy in patients with dMMR metastatic colorectal cancer. The primary endpoint was objective response rate. The secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate, duration of response, and safety. FINDINGS: A total of 30 patients were enrolled, and the objective response rate was 73.3%, meeting the predefined endpoint of 68%. The median PFS and median OS were not reached at a median follow-up period of 50.8 months. Disease control was achieved in 28 patients (93.3%). The median duration of response was not reached. The combination was well tolerated. Multiomics analysis revealed that the antigen processing and presentation pathway was positively associated with treatment response and PFS. Higher TAPBP expression was predictive of better PFS (log-rank p = 0.003), and this prognostic significance was confirmed in an immunotherapy validation cohort. CONCLUSIONS: Thus, COX inhibitors combined with PD-1 blockade may be effective and safe treatment options for patients with dMMR metastatic colorectal cancer, and TAPBP may serve as a biomarker for immune checkpoint inhibitor therapy (this study was registered at ClinicalTrials.gov: NCT03638297). FUNDING: Funded by the National Natural Science Foundation of China (81974369) and the program of Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004).

Predictors of Health-Related Quality of Life Among Women Participating in an Appointment-Based Cardiac Rehabilitation Program.

BACKGROUND: An alternative patient-centered appointment-based cardiac rehabilitation (CR) program has led to significant improvements in health outcomes for patients with cardiovascular disease. However, less is known about the effects of this approach on health-related quality of life (HRQoL), particularly for women. OBJECTIVE: We examined the effects of a patient-centered appointment-based CR program on HRQoL by sex and examined predictors of HRQoL improvements specifically for women. METHODS: Data were used from an urban single-center CR program at Yale New Haven Health (2012-2017). We collected information on patient demographics, socioeconomic status, and clinical characteristics. The Outcome Short-Form General Health Survey (SF-36) was used to measure HRQoL. We evaluated sex differences in SF-36 scores using t tests and used a multivariate linear regression model to examine predictors of improvements in HRQoL (total SF-36 score) for women. RESULTS: A total of 1530 patients with cardiovascular disease (23.7% women, 4.8% Black; mean age, 64 ± 10.8 years) were enrolled in the CR program. Women were more likely to be older, Black, and separated, divorced, or widowed. Although women had lower total SF-36 scores on CR entry, there was no statistically significant difference in CR adherence or total SF-36 score improvements between sexes. Women who were employed and those with chronic obstructive pulmonary disease were more likely to have improvements in total SF-36 scores. CONCLUSION: Both men and women participating in an appointment-based CR program achieved significant improvements in HRQoL. This approach could be a viable alternative to conventional CR to optimize secondary outcomes for patients.

First-in-human study of GFH018, a small molecule inhibitor of transforming growth factor-ß receptor I inhibitor, in patients with advanced solid tumors.

BACKGROUND: Transforming growth factor-ß (TGF-ß) is a cytokine with multiple functions, including cell growth regulation, extracellular matrix production, angiogenesis homeostasis adjustment and et al. TGF-ß pathway activation promotes tumor metastasis/progression and mediates epithelial-mesenchymal transmission suppressing immunosurveillance in advanced tumors. GFH018, a small molecule inhibitor blocking TGF-ß signal transduction, inhibits the progression and/or metastasis of advanced cancers. This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of GFH018 monotherapy in patients with advanced solid tumors. METHODS: This phase I, open-label, multicenter study used a modified 3+3 dose escalation and expansion design. Adult patients with advanced solid tumors failing the standard of care were enrolled. Starting at 5 mg, eight dose levels up to 85 mg were evaluated. Patients received GFH018 BID (14d-on/14d-off) starting on the 4th day after a single dose on cycle 1, day 1. Subsequent cycles were defined as 28 days. The study also explored the safety of 85 mg BID 7d-on/7d-off. Adverse events were graded using NCI criteria for adverse events (NCI-CTCAE v5.0). PK was analyzed using a noncompartmental method. Efficacy was evaluated using RECIST 1.1. Blood samples were collected for biomarker analysis. RESULTS: Fifty patients were enrolled and received at least one dose of GFH018. No dose-limiting toxicity occurred, and the maximum tolerated dose was not reached. Forty-three patients (86.0%) had at least one treatment-related adverse event (TRAE), and three patients (6.0%) had ≥ G3 TRAEs. The most common TRAEs (any grade/grade ≥3) were AST increased (18%/0%), proteinuria (14%/2%), anemia (14%/2%), and ALT increased (12%/0%). No significant cardiotoxicity or bleeding was observed. GFH018 PK was linear and dose-independent, with a mean half-life of 2.25-8.60 h from 5 - 85 mg. Nine patients (18.0%) achieved stable disease, and one patient with thymic carcinoma achieved tumor shrinkage, with the maximum target lesion decreased by 18.4%. Serum TGF-ß1 levels were not associated with clinical responses. The comprehensive recommended dose for Phase II was defined as 85 mg BID 14d-on/14d-off. CONCLUSIONS: GFH018 monotherapy presented a favorable safety profile without cardiac toxicity or bleeding. Modest efficacy warrants further studies, including combination strategies. TRIAL REGISTRATION: ClinicalTrial. gov ( https://www. CLINICALTRIALS: gov/ ), NCT05051241. Registered on 2021-09-02.

Neoadjuvant Chemotherapy With Oxaliplatin and Fluoropyrimidine Versus Upfront Surgery for Locally Advanced Colon Cancer: The Randomized, Phase III OPTICAL Trial.

PURPOSE: The role of neoadjuvant chemotherapy (NAC) in colon cancer remains unclear. This trial investigated whether 3 months of modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine and oxaliplatin (CAPOX) as NAC could improve outcomes in patients with locally advanced colon cancer versus upfront surgery. PATIENTS AND METHODS: OPTICAL was a randomized, phase III trial in patients with clinically staged locally advanced colon cancer (T3 with extramural spread into the mesocolic fat ≥5 mm or T4). Patients were randomly assigned 1:1 to receive six preoperative cycles of mFOLFOX6 or four cycles of CAPOX, followed by surgery and adjuvant chemotherapy (NAC group), or immediate surgery and the physician's choice of adjuvant chemotherapy (upfront surgery group). The primary end point was 3-year disease-free survival (DFS) assessed in the modified intention-to-treat (mITT) population. RESULTS: Between January 2016 and April 2021, of the 752 patients enrolled, 744 patients were included in the mITT analysis (371 in the NAC group; 373 in the upfront surgery group). At a median follow-up of 48.0 months (IQR, 46.0-50.1), 3-year DFS rates were 82.1% in the NAC group and 77.5% in the upfront surgery group (stratified hazard ratio [HR], 0.74 [95% CI, 0.54 to 1.03]). The R0 resection was achieved in 98% of patients who underwent surgery in both groups. Compared with upfront surgery, NAC resulted in a 7% pathologic complete response rate (pCR), significantly lower rates of advanced tumor staging (pT3-4: 77% v 94%), lymph node metastasis (pN1-2: 31% v 46%), and potentially improved overall survival (stratified HR, 0.44 [95% CI, 0.25 to 0.77]). CONCLUSION: NAC with mFOLFOX6 or CAPOX did not show a significant DFS benefit. However, this neoadjuvant approach was safe, resulted in substantial pathologic downstaging, and appears to be a viable therapeutic option for locally advanced colon cancer.