HERV1-env Induces Unfolded Protein Response Activation in Autoimmune Liver Disease: A Potential Mechanism for Regulatory T Cell Dysfunction.

Regulatory T cells (Tregs) are not terminally differentiated but can acquire effector properties. Here we report an increased expression of human endogenous retrovirus 1 (HERV1-env) proteins in Tregs of patients with de novo autoimmune hepatitis and autoimmune hepatitis, which induces endoplasmic reticulum (ER) stress. HERV1-env-triggered ER stress activates all three branches (IRE1, ATF6, and PERK) of the unfolded protein response (UPR). Our coimmunoprecipitation studies show an interaction between HERV1-env proteins and the ATF6 branch of the UPR. The activated form of ATF6α activates the expression of RORC and STAT3 by binding to promoter sequences and induces IL-17A production. Silencing of HERV1-env results in recovery of Treg suppressive function. These findings identify ER stress and UPR activation as key factors driving Treg plasticity (species: human).

An update on clinical presentation and responses to therapy of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH).

Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics and Genomics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.

Targeting the NAT10/NPM1 axis abrogates PD-L1 expression and improves the response to immune checkpoint blockade therapy.

BACKGROUND: PD-1/PD-L1 play a crucial role as immune checkpoint inhibitors in various types of cancer. Although our previous study revealed that NPM1 was a novel transcriptional regulator of PD-L1 and stimulated the transcription of PD-L1, the underlying regulatory mechanism remains incompletely characterized. METHODS: Various human cancer cell lines were used to validate the role of NPM1 in regulating the transcription of PD-L1. The acetyltransferase NAT10 was identified as a facilitator of NPM1 acetylation by coimmunoprecipitation and mass spectrometry. The potential application of combined NAT10 inhibitor and anti-CTLA4 treatment was evaluated by an animal model. RESULTS: We demonstrated that NPM1 enhanced the transcription of PD-L1 in various types of cancer, and the acetylation of NPM1 played a vital role in this process. In particular, NAT10 facilitated the acetylation of NPM1, leading to enhanced transcription and increased expression of PD-L1. Moreover, our findings demonstrated that Remodelin, a compound that inhibits NAT10, effectively reduced NPM1 acetylation, leading to a subsequent decrease in PD-L1 expression. In vivo experiments indicated that Remodelin combined with anti-CTLA-4 therapy had a superior therapeutic effect compared with either treatment alone. Ultimately, we verified that the expression of NAT10 exhibited a positive correlation with the expression of PD-L1 in various types of tumors, serving as an indicator of unfavorable prognosis. CONCLUSION: This study suggests that the NAT10/NPM1 axis is a promising therapeutic target in malignant tumors.

Psychosocial evaluation of living liver donors-State of current practices in the United States.

We surveyed living donor liver transplant programs in the United States to describe practices in the psychosocial evaluation of living donors focused on (1) composition of psychosocial team; (2) domains, workflow, and tools of the psychosocial assessment; (3) absolute and relative mental health-related contraindications to donation; and (4) postdonation psychosocial follow-up. We received 52 unique responses, representing 33 of 50 (66%) of active living donor liver transplant programs. Thirty-one (93.9%) provider teams included social workers, 22 (66.7%) psychiatrists, and 14 (42.4%) psychologists. Validated tools were rarely used, but domains assessed were consistent. Respondents rated active alcohol (93.8%), cocaine (96.8%), and opioid (96.8%) use disorder, as absolute contraindications to donation. Active suicidality (97%), self-injurious behavior (90.9%), eating disorders (87.9%), psychosis (84.8%), nonadherence (71.9%), and inability to cooperate with the evaluation team (78.1%) were absolute contraindications to donation. There were no statistically significant differences in absolute psychosocial contraindications to liver donation between geographical areas or between large and small programs. Programs conduct postdonation psychosocial follow-up (57.6%) or screening (39.4%), but routine follow-up of declined donors is rarely conducted (15.8%). Psychosocial evaluation of donor candidates is a multidisciplinary process. The structure of the psychosocial evaluation of donors is not uniform among programs though the domains assessed are consistent. Psychosocial contraindications to living liver donation vary among the transplant programs. Mental health follow-up of donor candidates is not standardized.

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.

Clinical predictive value of renalase in post-ERCP pancreatitis.

BACKGROUND AND AIMS: Plasma levels of renalase decrease in acute experimental pancreatitis. We aimed to determine if decreases in plasma renalase levels after ERCP predict the occurrence of post-ERCP pancreatitis (PEP). METHODS: In this prospective cohort study conducted at a tertiary hospital, plasma renalase was determined before ERCP (baseline) and at 30 and 60 minutes after ERCP. Native renalase levels, acidified renalase, and native-to-acidified renalase proportions were analyzed over time using a longitudinal regression model. RESULTS: Among 273 patients, 31 developed PEP. Only 1 PEP patient had a baseline native renalase >6.0 µg/mL, whereas 38 of 242 without PEP had a native renalase > 6.0 µg/mL, indicating a sensitivity of 97% (30/31) and specificity of 16% (38/242) in predicting PEP. Longitudinal models did not show differences over time between groups. CONCLUSIONS: Baseline native renalase levels are very sensitive for predicting PEP. Further studies are needed to determine the potential clinical role of renalase in predicting and preventing PEP.

Long-term Changes in Low Anterior Resection Syndrome in Survivors of Rectal Cancer: Longitudinal Follow-up of a Randomized Controlled Trial.

BACKGROUND: Postoperative bowel dysfunction, also known as low anterior resection syndrome, is common in rectal cancer survivors and significantly impacts quality of life. Although long-term longitudinal follow-up is lacking, improvement of the syndrome is commonly believed to happen only within the first 2 years. OBJECTIVE: This study aimed to depict the longitudinal evolvement of low anterior resection syndrome beyond 3 years and explore factors associated with changes. DESIGN: Longitudinal long-term follow-ups were performed for the single center with the largest cohort within the multicenter FOWARC randomized controlled trial. SETTING: A quaternary referral center. PATIENTS: Individuals diagnosed with rectal cancer who received long-course neoadjuvant chemotherapy or chemoradiotherapy, followed by sphincter-preserving radical proctectomy. MAIN OUTCOME MEASUREMENTS: Change of low anterior resection syndrome score and stoma status. RESULTS: Of the 220 patients responding to the first follow-up at a median of 39 months, 178 (80.9%) responded to the second follow-up after a median of 83 months. During this interval, the mean low anterior resection syndrome score improved from 29.5 (95% CI, 28.3-30.7) to 18.6 (95% CI, 16.6-20.6). Fifty-six (31.5%) patients reported improvement from major to no/minor severity, and 6 (3.4%) patients had new stomas because of severe bowel dysfunction. Neoadjuvant radiotherapy ( p = 0.016) was independently and negatively associated with improvement of the score. LIMITATIONS: Loss of follow-up during the long-term follow-ups. CONCLUSIONS: Most rectal cancer survivors with low anterior resection syndrome continued to improve beyond 3 years after proctectomy. Neoadjuvant radiotherapy was negatively associated with long-term improvement of low anterior resection syndrome. See Video Abstract . CAMBIO A LARGO PLAZO DEL SNDROME DE RESECCIN ANTERIOR BAJA EN SUPERVIVIENTES DE CNCER DE RECTO SEGUIMIENTO LONGITUDINAL DE UN ENSAYO CONTROLADO ALEATORIO: ANTECEDENTES:La disfunción intestinal posoperatoria, también conocida como síndrome de resección anterior baja, es común en los sobrevivientes de cáncer de recto y afecta significativamente la calidad de vida. Aunque falta un seguimiento longitudinal a largo plazo, comúnmente se cree que la mejoría del síndrome ocurre sólo dentro de los primeros dos años.OBJETIVO:Este estudio tiene como objetivo representar la evolución longitudinal del síndrome de resección anterior baja más allá de los 3 años y explora los factores asociados con el cambio.DISEÑO:Se realizaron seguimientos longitudinales a largo plazo para el único centro con la cohorte más grande dentro del ensayo controlado aleatorio multicéntrico FOWARC.AJUSTE:Un centro de referencia cuaternario.PACIENTES:Individuos diagnosticados con cáncer de recto que recibieron quimioterapia neoadyuvante de larga duración o quimiorradioterapia, seguida de proctectomía radical con preservación del esfínter.PRINCIPALES MEDICIONES DE RESULTADO:Cambio en la puntuación del síndrome de resección anterior baja y el estado del estoma.RESULTADOS:De los 220 pacientes que respondieron al primer seguimiento con una mediana de 39 meses, 178 (80,9%) respondieron al segundo seguimiento después de una mediana de 83 meses. Durante el intervalo, la puntuación media del síndrome de resección anterior baja mejoró de 29,5 (intervalo de confianza [IC] del 95%: 28,3-30,7) a 18,6 (IC del 95%: 16,6-20,6). 56 (31,5%) pacientes informaron una mejoría de mayor a ninguna gravedad, y 6 (3,4%) pacientes tuvieron un nuevo estoma debido a una disfunción intestinal grave. La radiación neoadyuvante (p = 0,016) se asoció de forma independiente y negativa con la mejora de la puntuación.LIMITACIONES:Pérdida de seguimiento durante los seguimientos a largo plazo.CONCLUSIÓN:La mayoría de los sobrevivientes de cáncer de recto con síndrome de resección anterior baja continuaron mejorando más allá de los 3 años después de la proctectomía. La radiación neoadyuvante se asoció negativamente con la mejora a largo plazo del síndrome de resección anterior baja. (Traducción-Dr Yolanda Colorado ).

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.

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.

In-person validation of the Ichthyosis Scoring System.

BACKGROUND: Ichthyoses are a heterogeneous group of skin disorders characterized by scaling and erythema. Recognizing the variability of scale and erythema by region and ichthyosis subtype, we developed the Ichthyosis Scoring System (ISS) to quantify severity. We previously found ISS to have high inter- and intrarater reliability in evaluating photographic images. To confirm ISS clinical utility, we examined its performance at the 2022 Foundation for Ichthyosis and Related Skin Types conference. METHODS: Sixty-five participants were evaluated by 3 of 9 medical professionals trained to score ichthyosis scale and erythema using ISS. Intrarater and interrater intraclass correlation coefficients (ICC) were analyzed using one-way and two-way random effects models, respectively. RESULTS: Intrarater reliability was excellent (ICC = 0.931, 95% CI, 0.921-0.940) for scale and good (ICC = 0.876, 95% CI, 0.853-0.899) for erythema scoring. Compared to photo validation with excellent intrarater reliability ratings for both scale (ICC = 0.956, 95% CI, 0.925-0.974) and erythema (ICC = 0.913, 95% CI, 0.855-0.949), ISS demonstrated equivalent reliability for live use. Overall interrater reliability for 10 body sites showed excellent (ICC >0.9) and good (ICC >0.75) agreement and consistency for both scale and erythema. Palms were an exception, demonstrating moderate (ICC >0.5) interrater agreement and consistency for erythema evaluation. CONCLUSIONS: ISS is a reliable measure of global and regional ichthyosis severity during in-person evaluations. Ease-of-use, accessibility, and content validity in both live and photographic evaluation endorse ISS as a standard for ichthyosis severity analysis.

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.

Human Immunodeficiency Virus Is Associated With Poor Overall Survival Among Patients With Head and Neck Cancer.

BACKGROUND: Head and neck squamous cell cancer (HNSCC) occurs at higher rates among persons with HIV (PWH). This study compares the impact of sociodemographic and clinicopathologic characteristics on outcomes among PWH-HNSCC compared with HNSCC patients without HIV. METHODS: Patient data from HNSCC individuals were collected at a single academic hospital center between 2002 and 2018. Forty-eight patients with HIV (HIV-HNSCC) and 2894 HNSCC patients without HIV were included. Multivariate analysis determined predictors of survival using Cox proportional hazards regression model. HIV-positive and -negative tumors were analyzed by quantitative immunofluorescence for expression of CD4, CD8, CD20 and PD-L1. RESULTS: HIV-HNSCC patients had a lower median overall survival than HNSCC patients without HIV (34 [18-84] vs 94 [86-103] months; P < .001). In multivariate analysis that included age, sex, race/ethnicity, stage, site, tobacco use, time to treatment initiation, and insurance status, HIV was an independent predictor of poorer survival, with a hazard ratio of 1.98 (95% CI: 1.32-2.97; P < .001). PWH with human papillomavirus (HPV)-positive oropharyngeal tumors also had worse prognosis than HPV-positive oropharyngeal tumors in the population without HIV (P < .001). The tumor microenvironment among HIV-HNSCC patients revealed lower intratumoral CD8 infiltration among HIV+ HPV+ tumors compared with HIV- HPV+ tumors (P = .04). CONCLUSIONS: HIV-HNSCC patients had worse prognosis than the non-HIV population, with HIV being an independent predictor of poor clinical outcomes when accounting for important sociodemographic and clinicopathologic factors. Our findings highlight differences in tumor biology that require further detailed characterization in large cohorts and increased inclusion of PWH in immunotherapy trials.

China special issue on gastrointestinal tumors-Radiological features of pathological complete response in mismatch repair deficient colorectal cancer after neoadjuvant PD-1 blockade: A post hoc analysis of the PICC phase II trial.

Neoadjuvant programmed cell death protein 1 (PD-1) blockade exhibits promising efficacy in patients with mismatch repair deficient (dMMR) colorectal cancer (CRC). However, discrepancies between radiological and histological findings have been reported in the PICC phase II trial (NCT03926338). Therefore, we strived to discern radiological features associated with pathological complete response (pCR) based on computed tomography (CT) images. Data were obtained from the PICC trial that included 36 tumors from 34 locally advanced dMMR CRC patients, who received neoadjuvant PD-1 blockade for 3 months. Among the 36 tumors, 28 (77.8%) tumors achieved pCR. There were no statistically significant differences in tumor longitudinal diameter, the percentage change in tumor longitudinal diameter from baseline, primary tumor sidedness, clinical stage, extramural venous invasion status, intratumoral calcification, peritumoral fat infiltration, intestinal fistula and tumor necrosis between the pCR and non-pCR tumors. Otherwise, tumors with pCR had smaller posttreatment tumor maximum thickness (median: 10 mm vs 13 mm, P = .004) and higher percentage decrease in tumor maximum thickness from baseline (52.9% vs 21.6%, P = .005) compared to non-pCR tumors. Additionally, a higher proportion of the absence of vascular sign (P = .003, odds ratio [OR] = 25.870 [95% CI, 1.357-493.110]), nodular sign (P < .001, OR = 189.000 [95% CI, 10.464-3413.803]) and extramural enhancement sign (P = .003, OR = 21.667 [2.848-164.830]) was observed in tumors with pCR. In conclusion, these CT-defined radiological features may have the potential to serve as valuable tools for clinicians in identifying patients who have achieved pCR after neoadjuvant PD-1 blockade, particularly in individuals who are willing to adopt a watch-and-wait strategy.

Efficacy and Safety of Avapritinib in Treating Unresectable or Metastatic Gastrointestinal Stromal Tumors: A Phase I/II, Open-Label, Multicenter Study.

BACKGROUND: Avapritinib is a type 1 kinase inhibitor designed to potently and selectively inhibit oncogenic KIT/PDGFRA mutants by targeting the kinase active conformation. This multicenter, single-arm, open-label, phase I/II bridging study of NAVIGATOR in Chinese patients evaluated the safety and the antineoplastic activity of avapritinib in Chinese patients with unresectable/metastatic gastrointestinal stromal tumors (GIST). METHODS: Phase I comprised dose escalation for safety and phase II dose determination. Phase II comprised dose expansion for safety/efficacy evaluations in patients with PDGFRA D842V mutations or patients having received at least 3 lines of therapy without PDGFRA D842V mutations. The primary endpoints were recommended phase II dose, safety, and Independent Radiology Review Committee (IRRC)-assessed objective response rate (ORR). RESULTS: No dose-limiting toxicities occurred (n = 10); the recommended phase II dose was avapritinib 300 mg once daily orally. Fifty-nine patients initially received avapritinib 300 mg. Common grade ≥3 treatment-related adverse events were anemia, decreased white blood cell count, increased blood bilirubin levels, and decreased neutrophil count. In patients with PDGFRA D842V mutations, IRRC- and investigator-assessed ORRs were 75% and 79%, respectively; clinical benefit rates were both 86%. Median duration of response/progression-free survival were not reached. IRCC- and investigator-assessed ORRs in patients in the fourth- or later-line setting were 22% and 35%, respectively. Median progression-free survivals were 5.6 months for both. Overall survival data were immature and not calculated. CONCLUSION: Avapritinib was generally well tolerated and showed marked anti-tumor activity in Chinese patients with GIST bearing PDGFRA D842V mutations and notable efficacy as fourth- or later-line monotherapy (ClinicalTrials.gov Identifier: NCT04254939).

A new function of thymol nanoemulsion for reversing colistin resistance in Salmonella enterica serovar Typhimurium infection.

BACKGROUND: Adjuvant addition of approved drugs or foodborne additives to colistin might be a cost-effective strategy to overcome the challenge of plasmid-mediated mobile colistin resistance gene emergence, which poses a threat in the clinic and in livestock caused by infections with Gram-negative bacteria, especially carbapenem-resistant Enterobacteriaceae. METHODS: Chequerboard assay was applied to screen the colistin adjuvants from natural compounds. The killing-time curve, combined disc test and membrane permeation assay were conducted to identify the synergy efficacy of thymol and colistin in vitro. Thin-layer chromatography (TLC), LC-MS and fluorescence spectra were used to indicate the interaction of thymol and MCR-1. The potential binding sites were then investigated by molecular simulation dynamics. Finally, a thymol nanoemulsion was prepared with high-pressure homogenization as the clinical dosage form. RESULTS: Thymol presented an excellent synergistic effect in vitro with colistin against Salmonella enterica serovar Typhimurium and Escherichia coli bacteria. Thymol addition, forming a complex with MCR-1, might interfere with the efficacy of MCR-1. Moreover, thymol strengthened colistin activity associated with potentiating membrane damage, destroying the biofilm and enhancing reactive oxygen species-mediated oxidative damage. Thymol nanoemulsion combined with colistin remarkably prevented the intestinal damage caused by S. Typhimurium infection, resulting in a survival rate higher than 60%. CONCLUSIONS: This study achieved a promising thymol oral formulation as colistin adjuvant to combat S. Typhimurium infection, which could be used to extend the lifespan of colistin in clinical veterinary medicine.

CT-based deep learning model for the prediction of DNA mismatch repair deficient colorectal cancer: a diagnostic study.

BACKGROUND: Stratification of DNA mismatch repair (MMR) status in patients with colorectal cancer (CRC) enables individual clinical treatment decision making. The present study aimed to develop and validate a deep learning (DL) model based on the pre-treatment CT images for predicting MMR status in CRC. METHODS: 1812 eligible participants (training cohort: n = 1124; internal validation cohort: n = 482; external validation cohort: n = 206) with CRC were enrolled from two institutions. All pretherapeutic CT images from three dimensions were trained by the ResNet101, then integrated by Gaussian process regression (GPR) to develop a full-automatic DL model for MMR status prediction. The predictive performance of the DL model was evaluated using the area under the receiver operating characteristic curve (AUC) and then tested in the internal and external validation cohorts. Additionally, the participants from institution 1 were sub-grouped by various clinical factors for subgroup analysis, then the predictive performance of the DL model for identifying MMR status between participants in different groups were compared. RESULTS: The full-automatic DL model was established in the training cohort to stratify the MMR status, which presented promising discriminative ability with the AUCs of 0.986 (95% CI 0.971-1.000) in the internal validation cohort and 0.915 (95% CI 0.870-0.960) in the external validation cohort. In addition, the subgroup analysis based on the thickness of CT images, clinical T and N stages, gender, the longest diameter, and the location of tumors revealed that the DL model showed similar satisfying prediction performance. CONCLUSIONS: The DL model may potentially serve as a noninvasive tool to facilitate the pre-treatment individualized prediction of MMR status in patients with CRC, which could promote the personalized clinical-making decision.

Isorhamnetin as a novel inhibitor of pneumolysin against Streptococcus pneumoniae infection in vivo/in vitro.

The increasing incidence of Streptococcus pneumoniae (S. pneumoniae) infection severely threatened the global public heath, causing a significant fatality in immunocompromised hosts. Notably, pneumolysin (PLY) as a pore-forming cytolysin plays a crucial role in the pathogenesis of pneumococcal pneumonia and lung injury. In this study, a natural flavonoid isorhamnetin was identified as a PLY inhibition to suppress PLY-induced hemolysis by engaging the predicted residues and attenuate cytolysin PLY-mediated A549 cells injury. Underlying mechanisms revealed that PLY inhibitor isorhamnetin further contributed to decrease the formation of bacterial biofilms without affecting the expression of PLY. In vivo S. pneumoniae infection confirmed that the pathological injury of lung tissue evoked by S. pneumoniae was ameliorated by isorhamnetin treatment. Collectively, these results presented that isorhamnetin could inhibit the biological activity of PLY, thus reducing the pathogenicity of S. pneumoniae. In summary, our study laid a foundation for the feasible anti-virulence strategy targeting PLY, and provided a promising PLY inhibitor for the treatment of S. pneumoniae infection.

Neoadjuvant Modified FOLFOXIRI With Selective Radiotherapy in Locally Advanced Rectal Cancer: Long-term Outcomes of Phase II Study and Propensity-Score-Matched Comparison With Chemoradiotherapy.

BACKGROUND: Neoadjuvant modified FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) chemotherapy with selective radiotherapy did not compromise pathologic complete response and tumor downstaging in locally advanced rectal cancer. OBJECTIVE: The study aimed to analyze disease-free survival and local recurrence of neoadjuvant chemotherapy with modified FOLFOXIRI (mFOLFOXIRI). DESIGN: This was a prospective single-arm phase II study. A propensity score-adjusted method was implemented to compare outcomes against historical controls of chemoradiotherapy. SETTINGS: The study was conducted at single institutions. PATIENTS: One hundred 6 patients with stage II and III rectal cancers were included. INTERVENTION: All patients received neoadjuvant mFOLFOXIRI chemotherapy before total mesorectal excision. Patients with mesorectal fascia-positive or ycT4a/b after reevaluation with MRI received radiation before surgery. Otherwise, immediate total mesorectal excision would be performed. MAIN OUTCOME AND MEASURES: The primary end point was tumor downstaging (ypStage 0-I) rate, which was reported previously. Disease-free survival and local recurrence rate were the main outcomes for the current study. RESULTS: After a median follow-up of 43.3 months, the 2-year disease-free survival rate was 85.6% and the 3-year disease-free survival rate was 78.9%. The local recurrence rate was 7.8% after surgery. After propensity score matching, 73 patients were available for comparison in each group. The pathologic complete response rate was 23.3% and 13.7% ( p = 0.14), the proportion of ypStage 0-I was 45.2% vs 39.7% ( p = 0.5), the 3-year disease-free survival was 87.6% vs 75.8% (HR = 0.46; 95% CI, 0.22-0.95, p = 0.037). The local recurrence rate in the mFOLFOXIRI group was 5.5% and in the chemoradiotherapy group was 4.1% ( p = 0.70). Patients receiving mFOLFOXIRI had a lower incidence of anastomotic fistula compared with the chemoradiotherapy group (5.5% vs 17.8%, p = 0.02). LIMITATIONS: This was a single-arm, nonrandomized phase II study. CONCLUSIONS: Neoadjuvant mFOLFOXIRI with selective radiotherapy was feasible and safe, and it improved 3-year disease-free survival compared with propensity score-matched historical controls who received chemoradiotherapy. See Video Abstract at http://links.lww.com/DCR/B989 .Trial registration: NCT02217020. FOLFOXIRI MODIFICADO NEOADYUVANTE CON RADIOTERAPIA SELECTIVA EN CNCER DE RECTO LOCALMENTE AVANZADO RESULTADOS A LARGO PLAZO DEL ESTUDIO DE FASE II Y COMPARACIN EMPAREJADA POR PUNTUACIN DE PROPENSIN CON QUIMIORRADIOTERAPIA: ANTECEDENTES:La quimioterapia neoadyuvante con FOLFOXIRI modificado (ácido folínico, 5-fluoruracilo, oxaliplatino e irinotecan) con radioterapia selectiva no comprometió la respuesta patológica completa ni la reducción del estadio del tumor en el cáncer de recto localmente avanzado.OBJETIVO:El estudio tuvo como objetivo analizar la sobrevida libre de enfermedad y la recurrencia local de la quimioterapia neoadyuvante con FOLFOXIRI modificado (mFOLFOXIRI).DISEÑO:Este fue un estudio prospectivo de fase II de un solo brazo. Se implementó un método ajustado por puntaje de propensión para comparar los resultados con los controles históricos de quimiorradioterapia.ESCENARIO:El estudio se realizó en instituciones individuales.PACIENTES:Se incluyeron 106 pacientes con cáncer de recto en estadio II y III.INTERVENCIÓN:Todos los pacientes recibieron quimioterapia neoadyuvante con mFOLFOXIRI antes de la escisión total del mesorrecto. Los pacientes con fascia mesorrectal positiva o ycT4a/b después de la reevaluación con MRI recibirían radiación antes de la cirugía. En caso contrario, se realizaría una escisión mesorrectal total inmediata.PRINCIPALES RESULTADOS Y MEDIDAS:El criterio principal de valoración fue la tasa de disminución del estadio del tumor (ypEstadio 0-I), que se informó anteriormente. La sobrevida libre de enfermedad y la tasa de recurrencia local son los principales resultados del estudio actual.RESULTADOS:Después de una mediana de seguimiento de 43,3 meses, las tasas de sobrevida libre de enfermedad a 2 y 3 años fueron del 85,6 % y 78,9 %, respectivamente. La tasa de recidiva local fue del 7,8% tras la cirugía. Después del emparejamiento por puntaje de propensión, 73 pacientes estaban disponibles para la comparación en cada grupo. La tasa de respuesta patológica completa fue de 23,3 % y de 13,7 % (p = 0,14), la proporción de ypEstadio 0-I fue del 45,2 % frente al 39,7 % (p = 0,5), la SLE a los 3 años fue del 87,6 % frente al 75,8 % (HR = 0,46, IC del 95 % 0,22-0,95, p = 0,037) y la tasa de recurrencia local fue del 5,5 % y del 4,1 % (p = 0,70) en el grupo de mFOLFOXIRI frente al grupo de quimiorradioterapia, respectivamente. Los pacientes que recibieron mFOLFOXIRI tuvieron una menor incidencia de fístula anastomótica en comparación con el grupo de quimiorradioterapia (5,5 % frente a 17,8 %, p = 0,02).LIMITACIONES:Este fue un estudio de fase II no aleatorizado de un solo brazo.CONCLUSIONES:El mFOLFOXIRI neoadyuvante con radioterapia selectiva fue factible y seguro, y mejoró la SSE a los 3 años en comparación con los controles históricos emparejados por puntaje de propensión que recibieron quimiorradioterapia. Consulte Video Resumen en http://links.lww.com/DCR/B989 . (Traducción-Dr. Felipe Bellolio ).

A survey of transplant providers regarding attitudes, barriers, and facilitators to living donor liver transplantation in the United States.

INTRODUCTION: A successful living donor liver transplant (LDLT) is the culmination of a multifaceted process coordinated among key stakeholders. METHODS: We conducted an electronic survey of US liver transplant (LT) centers (August 26, 2021-October 10, 2021) regarding attitudes, barriers, and facilitators of LDLT to learn how to expand LDLT safely and effectively in preparation for the American Society of Transplantation Living Donor Liver Transplant Consensus Conference. RESULTS: Responses were received from staff at 58 programs (40.1% of US LT centers). There is interest in broadening LDLT (100% of LDLT centers, 66.7% of non-LDLT centers) with high level of agreement that LDLT mitigates donor shortage (93.3% of respondents) and that it should be offered to all suitable candidates (87.5% of respondents), though LDLT was less often endorsed as the best first option (29.5% of respondents). Key barriers at non-LDLT centers were institutional factors and surgical expertise, whereas those at LDLT centers focused on waitlist candidate and donor factors. Heterogeneity in candidate selection for LDLT, candidate reluctance to pursue LDLT, high donor exclusion rate, and disparities in access were important barriers. CONCLUSION: Findings from this study may help guide current and future expansion of LDLT more efficiently in the US. These efforts require clear and cohesive messaging regarding LDLT benefits, engagement of the public community, and dedicated resources to equitably increase LDLT access.

Characteristics of phenotypic antibiotic resistance of Helicobacter pylori and its correlation with genotypic antibiotic resistance: A retrospective study in Ningxia.

BACKGROUND: Geographic differences exist in the antibiotic resistance patterns of Helicobacter pylori. Personalized treatment regimens based on local or individual resistance data are essential. We evaluated the current status of H. pylori resistance in Ningxia, analyzed resistance-related factors, and assessed the concordance of phenotypic and genotypic resistance. METHODS: Strains were isolated from the gastric mucosa of patients infected with H. pylori in Ningxia and relevant clinical information was collected. Phenotypic antibiotic susceptibility assays (Kirby-Bauer disk diffusion) and antibiotic resistance gene detection (Sanger sequencing) were performed. RESULTS: We isolated 1955 H. pylori strains. The resistance rates of H. pylori to amoxicillin, levofloxacin, clarithromycin, and metronidazole were 0.9%, 42.4%, 40.4%, and 94.2%, respectively. Only five tetracycline-resistant and one furazolidone-resistant strain were identified. Overall, 3.3% of the strains were sensitive to all six antibiotics. Multidrug-resistant strains accounted for 22.9%, of which less than 20% were from Wuzhong. Strains isolated from women and patients with nonulcerative disease had higher rates of resistance to levofloxacin and clarithromycin. Higher rates of resistance to metronidazole, levofloxacin, and clarithromycin were observed in the older age group than in the younger age group. The kappa coefficients of phenotypic resistance and genotypic resistance for levofloxacin and clarithromycin were 0.830 and 0.809, respectively, whereas the remaining antibiotics showed poor agreement. CONCLUSION: H. pylori antibiotic resistance is severe in Ningxia. Therefore, furazolidone, amoxicillin, and tetracycline are better choices for the empirical therapy of H. pylori infection in this region. Host sex, age, and the presence of ulcerative diseases may affect antibiotic resistance of the bacteria. Personalized therapy based on genetic testing for levofloxacin and clarithromycin resistance may be a future direction for the eradication therapy of H. pylori infection in Ningxia.