A PD-1 Inhibitor Induces Complete Response of Advanced Bladder Urothelial Carcinoma: A Case Report

The prognosis of patients with advanced urothelial carcinoma is dismal. Platinum-based chemotherapy is still the main first-line treatment for advanced urothelial carcinoma, while immunotherapy can be used as a first-line treatment option for people who cannot tolerate platinum. Immunotherapy is preferred in the second-line treatment of bladder urothelial carcinoma. PD-1 inhibitors (Pembrolizumab, nivolumab and atezolizumab) and PD-L1 inhibitors (Ddurvalumab and avelumab) have not been approved for the treatment of advanced urothelial cancer in China. We describe a patient with advanced urothelial carcinoma experienced disease progression after gemcitabine chemotherapy. Following a treatment of domestic PD-1 inhibitor (sintilimab), the patient achieved a durable complete response with mild toxicity. This case indicates that PD-1 inhibitor sintilimab might be a second-line treatment choice for advanced urothelial carcinoma

Selective Hydrogenation of Adiponitrile to 6-Aminocapronitrile over Ni/α-Al₂O₃ Catalysts Doped with K₂O and La₂O₃

A series of Ni/Al2O3, Ni/K2O-Al2O3 and Ni/La2O3-K2O-Al2O3 catalysts that possess high activities for partial hydrogenation of adiponitrile to 6-aminocapronitrile has been successfully synthesized by the impregnation method. The catalytic performance was investigated under atmospheric pressure and in the absence of ammonia and a significant enhancement in the activity after the introduction of potassium oxide and lanthana was observed. Aiming to study the influence of K2O and La2O3 promoters on the physicochemical properties, we characterized the catalysts by N2 adsorption/desorption, XRD, H2-TPR, H2-chemisorption, H2-TPD and TEM techniques. A combination of XRD, TEM and H2-chemisorption showed that Ni0 particles with a higher dispersion are obtained after the addition of La2O3. Compared with the Ni/Al2O3 catalyst, the Ni/La2O3-K2O-Al2O3 catalyst with an appropriate amount of promoter enjoys a more catalyst surface alkalescence, enhances the electronic density of nickel and higher dispersion of nickel and exhibits higher activity and 6-aminocapronitrile selectivity than Ni/α-Al2O3 during the hydrogenation of adiponitrile in the absence of ammonia, i.e., K2O and La2O3 improved the performance of the nickel-based catalyst

Correction: Comparison of Current Diagnostic Criteria for Acute-On-Chronic Liver Failure.

[This corrects the article DOI: 10.1371/journal.pone.0122158.]

Comparison of current diagnostic criteria for acute-on-chronic liver failure.

Currently, acute-on-chronic liver failure (ACLF) has been defined differently by Asia-Pacific Association for the Study of the Liver (APASL) and Chinese Medical Association (CMA) in the East, as well as EASL-Chronic Liver Failure (EASL-CLIF) Consortium in the West. This study aimed to compare current different diagnostic criteria for ACLF and to determine predictors of the progression into post-enrollment EASL-CLIF ACLF from ACLF at enrollment defined by APASL alone or by both APASL and CMA but not by EASL-CLIF Consortium.We retrospectively analyzed clinical data from 394 eligible cirrhotic patients fulfilling at least APASL criteria for ACLF at enrollment. Patient survival was estimated by Kaplan-Meier analysis and subsequently compared by log-rank test. Independent predictors of disease progression were determined using univariate analysis and multivariate Cox regression analysis.The 90-day mortality rate was 13.1% in patients with ACLF at enrollment defined by APASL alone, 25.3% in patients with ACLF at enrollment defined by both APASL and CMA but not EASL-CLIF Consortium, and 59.3% in patients with ACLF at enrollment defined by EASL-CLIF Consortium in addition to APASL. Baseline Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) score, and the maximum rising rates of CLIF-SOFA score, Model for End-Stage Liver Disease-Sodium (MELD-Na) score and total bilirubin were independent predictors of progression into post-enrollment EASL-CLIF ACLF from ACLF at enrollment defined by APASL alone or by both APASL and CMA but not by EASL-CLIF Consortium.Different diagnostic criteria for ACLF caused different patient prognosis. So, it is imperative to formulate a unifying diagnostic criteria for ACLF worldwide, thus attaining early identification and treatment, and eventual improvement in survival of ACLF patients. Baseline CLIF-SOFA score, and the maximum rising rates of CLIF-SOFA score, MELD-Na score and total bilirubin may early predict post-enrollment development of EASL-CLIF ACLF

Real‐world effectiveness and safety of RC48‐ADC alone or in combination with PD‐1 inhibitors for patients with locally advanced or metastatic urothelial carcinoma: A multicenter, retrospective clinical study

Abstract Introduction Previous RC48 (Disitamab Vedotin) studies established that the safety and efficacy of RC48‐antibody–drug conjugate (ADC), either alone or combined with toripalimab, for metastatic urothelial carcinoma (mUC) patients exhibiting human epidermal growth factor receptor 2 (HER2)‐positive or even HER2‐negative status after standard chemotherapy failure. Methods With locally advanced or metastatic urothelial carcinoma (la/mUC), patients who received RC48‐ADC monotherapy or a combination with programmed cell death protein 1 (PD‐1) inhibitors between August 2021 and October 2022 were enrolled in this retrospective observational study to evaluate the real‐world antitumor effectiveness and safety. Results Among the 38 enrolled patients (29 males; median age 67.5 years [38–93]), 8 received RC48‐ADC monotherapy, while 30 received combination therapy. Initially, 63.2% (24/38) of the patients had received ≥1 line of prior treatment, and 63.2% (24/38) had visceral metastasis. UC of the bladder represented the majority type in 68.4% (26/38) of cases. By the data cutoff in March 2023, the overall objective response rate (ORR) was 63.2% (95% CI, 47.1%–79.2%), with a disease control rate (DCR) of 89.5% (95% CI, 79.3%–99.7%). Median follow‐up time was 10.6 months. The median progression‐free survival (PFS) was 8.2 months (95% CI, 5.9–10.5), with a 6‐month PFS rate of 63.2% and a 12‐month PFS rate of 34.1%. Median overall survival (OS) was not reached, with a 12‐month OS rate of 76.7%. The median duration of response was 7.3 months (95% CI, 4.6–10.0) among 24 patients evaluated as partial response (PR). The most common treatment‐related adverse events (TRAEs) included anemia (71.1%), anorexia (57.9%), asthenia (52.6%), hypoesthesia (52.6%), bone marrow suppression (47.4%), alopecia (47.4%), nausea (44.7%), proteinuria (36.8%), vomiting (34.2%), and hypoalbuminemia (31.6%). No patient experienced TRAEs of Grade ≥3. One patient had an immune‐related adverse event (irAE) of rash related to toripalimab. Conclusions Both as monotherapy and in combination with PD‐1 inhibitors, RC48‐ADC exhibits promising effectiveness and manageable safety profile for mUC patients in real‐world settings

Individual Irinotecan Therapy Under the Guidance of Pre-Treated * Genotyping in Gastric Cancer

Background: Severe delayed diarrhea and hematological toxicity limit the use of irinotecan. Uridine diphosphate glucuronosyltransferase 1A1 ( UGT1A1 ) is a critical enzyme in irinotecan metabolism. The study aims to investigate the safety and efficacy of irinotecan under the guidance of the pre-treatment UGT1A1 genotype in the second-line treatment of gastric cancer. Methods: This study involved 110 patients. Irinotecan was injected intravenously every 3 weeks, and the dose of irinotecan was determined by polymorphism of the UGT1A1 gene, which was divided into three groups (125 mg/m 2 : GG type; 100 mg/m 2 : GA type; 75 mg/m 2 : AA type). The primary end point was overall survival (OS), the secondary end points were progression-free survival (PFS) and safety. Results: One hundred and seven patients received irinotecan treatment and three patients with AA type received paclitaxel treatment. Among 107 patients, there were no significant differences in PFS (4.8 m vs 4.9 m vs 4.4 m; p  = 0.5249) and OS (9.3 m vs 9.3 m vs NA; p  = 0.6821) among patients with GG/GA/AA subtypes after dose adjustment. For the patient with homozygosity mutation, treatment was switched to paclitaxel. There were no significant differences in PFS and OS among patients with different alleles or after dose adjustment ( p  > 0.05). There was a significant difference in the risk of delayed diarrhea ( p  = 0.000), leukopenia ( p  = 0.003) and neutropenia ( p  = 0.000) in patients with different UGT1A1*6 genotypes, while no difference in patients with different UGT1A1* 28 genotypes. Additionally, grade 3/4 diarrhea, neutropenia, and leukopenia were significantly more common in AA genotype patients compared to GG (2%, 19%, 24%) or GA (23%, 31%, 31%) genotype patients. Conclusion: Individual irinotecan treatment shows encouraging survival and tolerability outcomes in patients with GG/GA subtype. Irinotecan may be not suitable for patients with AA subtype

Characteristics of eligible patients at enrollment.

<p>Categorical variables expressed as number (%), non-normal continuous variables as median (Q1–Q3) and normal continuous variables as mean ± SD.</p><p>HE, hepatic encephalopathy; HRS, hepatorenal syndrome; WBC, white blood cells; PLT, platelet; ALB, albumin; ALT, alanine aminotransferase; TBIL, total bilirubin; BUN, blood urea nitrogen; Cr, creatine; INR, international normalized ratio; PT, prothrombin time; CTP, child-turcotte-pugh; MELD, model for end-stage liver disease; CLIF-SOFA, chronic liver failure-sequential organ failure assessment.</p><p>^†Organ failure was defined based on the CLIF-SOFA score.</p><p>Characteristics of eligible patients at enrollment.</p

Mortality rate at 90 days according to the grade of ACLF defined by EASL-CLIF Consortium.

<p>Among patients identified as EASL-CLIF ACLF either at enrollment or after enrollment, the 90-day mortality rate was 39.1% for grade 1, 54.1% for grade 2, 86.7% for grade 3, respectively. The 90-day mortality rate in patients without EASL-CLIF ACLF both at enrollment and after enrollment was 2.1%<b>.</b> Abbreviations: ACLF, acute-on-chronic liver failure.</p

Comparison of survival among patients with ACLF at enrollment defined by different criteria.

<p>Overall 394 eligible patients who qualified for at least APASL criteria for ACLF at enrollment were divided into 3 groups: patients satisfying APASL criteria alone for ACLF at enrollment (group A), patients satisfying both APASL and CMA criteria but not EASL-CLIF criteria for ACLF at enrollment (group B), and patients satisfying EASL-CLIF criteria in addition to APASL criteria for ACLF at enrollment (group C). In comparison with patients in group A and group B, the 90-day survival was significantly lower for patients in group C (log-rank test: P < 0.001). Besides, significantly lower survival was also observed for patients in group B, as compared to patients in group A (log-rank test: P < 0.05).</p

Comparison of baseline characteristics between patients with and without progression to post-enrollment EASL-CLIF ACLF.

<p>Categorical variables expressed as number (%), non-normal continuous variables as median (Q1–Q3) and normal continuous variables as mean ± SD.</p><p>ACLF, acute-on-chronic liver failure; HE, hepatic encephalopathy; HRS, hepatorenal syndrome; WBC, white blood cells; PLT, platelet; ALB, albumin; ALT, alanine aminotransferase; TBIL, total bilirubin; BUN, blood urea nitrogen; Cr, creatine; INR, international normalized ratio; PT, prothrombin time; CTP, child-turcotte-pugh; MELD, model for end-stage liver disease; CLIF-SOFA, chronic liver failure-sequential organ failure assessment.</p><p>^†P value of comparisons between patients with and without progression to post-enrollment EASL-CLIF ACLF.</p><p>Comparison of baseline characteristics between patients with and without progression to post-enrollment EASL-CLIF ACLF.</p