Risk factors indicating immune-related adverse events with combination chemotherapy with immune checkpoint inhibitors and platinum agents in patients with non-small cell lung cancer: a multicenter retrospective study.

PURPOSE: Immune checkpoint inhibitors (ICI) ushered in a new era for the treatment of non-small cell lung cancer (NSCLC). However, they carry the risk of immune-related adverse events (irAEs). Recently, various studies have been conducted on the predictive factors for irAEs, but there are no reports focusing only on ICI plus platinum agents. The present study aimed to identify the risk factors for irAEs due to ICI combined with platinum-based induction immunochemotherapy in NSCLC patients, focusing only on the period of combined therapy and excluding the period of ICI maintenance therapy. METHODS: This retrospective study included 315 NSCLC patients who started ICI combined with platinum-based chemotherapy treatment at 14 hospitals between December 2018 and March 2021. A logistic regression analysis was used to explore the predictive factors. RESULTS: Fifty patients (15.9%) experienced irAEs. A multivariate analysis revealed that squamous cell carcinoma (P = 0.021; odds ratio [OR]: 2.30; 95% confidence interval [Cl]: 1.14-4.65), anti-programmed death 1 antibody (anti-PD-1) plus anti-cytotoxic T-lymphocyte antigen-4 antibody (anti-CTLA-4) regimens (P < 0.01; OR: 22.10; 95% Cl: 5.60-87.20), and neutrophil-to-lymphocyte rate (NLR) < 3 (P < 0.01; OR: 2.91; 95% Cl: 1.35-6.27) were independent predictive factors for irAEs occurrence. CONCLUSION: Squamous cell carcinoma, anti-PD-1 plus anti-CTLA-4 regimens, and NLR < 3 may be predictive factors for the occurrence of irAEs due to induction immunochemotherapy in patients with NSCLC. By focusing on the potential risk of irAEs in patients with these factors, irAEs can be appropriately managed from an early stage.

Vancomycin pharmacokinetics in critically ill patients receiving continuous haemodiafiltration with a polyethyleneimine-coated polyacrylonitrile membrane.

WHAT IS KNOWN AND OBJECTIVE: We investigated the elimination efficiency and pharmacokinetics (PK) parameters of vancomycin (VCM) in patients undergoing continuous haemodiafiltration (CHDF) using a polyethyleneimine-coated polyacrylonitrile membrane (AN69ST) for dosage adjustment. METHODS: We conducted a retrospective study of CHDF patients treated with VCM from December 2017 to August 2019. We calculated PK parameters of VCM and determined the 24-hour dose required to maintain the target trough concentration of VCM (VCM_trough ). RESULTS AND DISCUSSION: The average (95% CI) volume of distribution and total clearance of VCM were 75.5 L (63.7-87.3 L) and 1.84 L/h (1.38-2.30 L/h), respectively, and the elimination rate constant and half-life were 0.026/h (0.017-0.034/h) and 31.2 h (22.8-39.5 h), respectively. The average AN69ST clearance of VCM (CL_CHDF ) was 0.69 L/h (0.52-0.86 L/h). The estimated average doses required to maintain VCM_trough of 10, 15 and 20 µg/mL were 623.1 mg (379.8-866.4 mg), 934.6 mg (569.7-1299.5 mg) and 1246.2 mg (759.6-1732.8 mg), respectively. WHAT IS NEW AND CONCLUSION: The PK of VCM and CL_CHDF of AN69ST were clarified. These results suggest that it is possible to adjust the dose of VCM in using AN69ST, which efficiently removes cytokines, and contributes to improvement of serious infections.

Characterization of rabbit morphine 6-dehydrogenase and two NAD(+)-dependent 3α(17ß)-hydroxysteroid dehydrogenases.

Mammalian morphine 6-dehydrogenase (M6DH)(1) converts morphine into a reactive electrophile, morphinone. M6DH belongs to the aldo-keto reductase (AKR) superfamily, but its endogenous substrates and entire amino acid sequence remain unknown. A recent rabbit genomic sequencing predicts three genes for novel AKRs (1C26, 1C27 and 1C28) that share >87% amino acid sequence identity and are similar to the partial sequence of rabbit liver M6DH. We isolated cDNAs for the three AKRs, and compared the properties of their recombinant enzymes. Like M6DH, only AKR1C26 that shares the highest sequence identity with hepatic M6DH oxidized morphine. The three AKRs showed NAD(+)-dependent dehydrogenase activity towards other non-steroidal alicyclic alcohols and 3α/17ß-hydroxy-C(18)/C(19)/C(21)-steroids, and their mRNAs were ubiquitously expressed in rabbit tissues. The kinetic constants for the substrates suggest that at least AKR1C26 and AKR1C28 act as NAD(+)-dependent 3α/17ß-hydroxysteroid dehydrogenases. AKR1C27 differed from AKR1C28 in its high K(m) values for the substrates and low sensitivity towards competitive inhibitors (ikarisoside A, hinokitiol, hexestrol and zearalenone), despite their 95% sequence identity. The site-directed mutagenesis of Tyr118 and Phe310 in AKR1C27 to the corresponding residues (Phe and Ile, respectively) in AKR1C28 produced an enzyme that was similar to AKR1C28, suggesting their key roles in ligand binding.

Predictors for the Clinical Efficacy of Tramadol for Cancer Pain.

CONTEXT: Tramadol is conditionally recommended for cancer pain and is a less expensive drug compared to strong opioids. Thus, tramadol may help reduce health care costs. OBJECTIVES: To investigate factors that predict the clinical efficacy of tramadol for cancer pain. METHODS: A retrospective study using electronic medical records was conducted on patients who received tramadol for cancer pain from January 2016 to December 2020. Patients who continued tramadol for >28 days or discontinued tramadol before 28 days owing to pain improvement were considered as clinical efficacy cases. RESULTS: We identified 183 eligible patients; 104 cases had clinical efficacy. The median starting tramadol daily dose was 100 mg, and the median administration duration was 22 days. Overall, 169 patients (92.3%) discontinued tramadol; pain improvement was the most common reason (34.9%). Age (>70 years), a performance status of 0-1, and an albumin-bilirubin grade of 1 were independent predictors for the clinical efficacy of tramadol. Patients with multiple predictors had significantly higher achievement rates than those without. CONCLUSION: Tramadol could have greater clinical efficacy for cancer pain in patients who are elderly, have good performance status, and have good liver function.

Impact of the pretreatment prognostic nutritional index on the survival after first-line immunotherapy in non-small-cell lung cancer patients.

BACKGROUND: Immunotherapy has become a standard-of-care for patients with non-small-cell lung cancer (NSCLC). Although several biomarkers, such as programmed cell death-1, have been shown to be useful in selecting patients likely to benefit from immune checkpoint inhibitors (ICIs), more useful and reliable ones should be investigated. The prognostic nutritional index (PNI) is a marker of the immune and nutritional status of the host, and is derived from serum albumin level and peripheral lymphocyte count. Although several groups reported its prognostic role in patients with NSCLC receiving a single ICI, there exist no reports which have demonstrated its role in the first-line ICI combined with or without chemotherapy. MATERIALS AND METHODS: Two-hundred and eighteen patients with NSCLC were included in the current study and received pembrolizumab alone or chemoimmunotherapy as the first-line therapy. Cutoff value of the pretreatment PNI was set as 42.17. RESULTS: Among 218 patients, 123 (56.4%) had a high PNI (≥42.17), while 95 (43.6%) had a low PNI (<42.17). A significant association was observed between the PNI and both the progression-free survival (PFS; hazard ratio [HR] = 0.67, 95% confidence interval [CI]: 0.51-0.88, p = 0.0021) and overall survival (OS; HR = 0.46, 95% CI: 0.32-0.67, p < 0.0001) in the entire population, respectively. The multivariate analysis identified the pretreatment PNI as an independent prognosticator for the PFS (p = 0.0011) and OS (p < 0.0001), and in patients receiving either pembrolizumab alone or chemoimmunotherapy, the pretreatment PNI remained an independent prognostic factor for the OS (p = 0.0270 and 0.0006, respectively). CONCLUSION: The PNI might help clinicians appropriately identifying patients with better treatment outcomes when receiving first-line ICI therapy.

Characterization of rabbit aldose reductase-like protein with 3ß-hydroxysteroid dehydrogenase activity.

In this study, we isolated the cDNA for a rabbit aldose reductase-like protein that shared an 86% sequence identity to human aldo-keto reductase (AKR)(1) 1B10 and has been assigned as AKR1B19 in the AKR superfamily. The purified recombinant AKR1B19 was similar to AKR1B10 and rabbit aldose reductase (AKR1B2) in the substrate specificity for various aldehydes and α-dicarbonyl compounds. In contrast to AKR1B10 and AKR1B2, AKR1B19 efficiently reduced 3-keto-5α/ß-dihydro-C19/C21/C24-steroids into the corresponding 3ß-hydroxysteroids, showing K(m) of 1.3-9.1 µM and k(cat) of 1.1-7.6 min(-1). The stereospecific reduction was also observed in the metabolism of 5α- and 5ß-dihydrotestosterones in AKR1B19-overexpressing cells. The mRNA for AKR1B19 was ubiquitously expressed in rabbit tissues, and the enzyme was co-purified with 3ß-hydroxysteroid dehydrogenase activity from the lung. Thus, AKR1B19 may function as a 3-ketoreductase, as well as a defense system against cytotoxic carbonyl compounds in rabbit tissues. The molecular determinants for the unique 3-ketoreductase activity were investigated by replacement of Phe303 and Met304 in AKR1B19 with Gln and Ser, respectively, in AKR1B10. Single and double mutations (F303Q, M304S and F303Q/M304S) significantly impaired this activity, suggesting the two residues play critical roles in recognition of the steroidal substrate.

Association between pretreatment neutrophil-to-lymphocyte ratio and immune-related adverse events due to immune checkpoint inhibitors in patients with non-small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced or recurrent non-small cell lung cancer (NSCLC). They cause immune-related adverse events (irAEs), but the underlying mechanisms and predictors remain to be fully elucidated. In this retrospective study, we investigated the association between pretreatment neutrophil-to-lymphocyte ratio (NLR) and the occurrence of irAEs. METHODS: The study involved 115 patients with NSCLC who started ICI-only treatment in our hospital between January 2016 and April 2020. RESULTS: Forty-five patients (39.1%) had irAEs, and pretreatment NLR was significantly lower in the irAEs group than in the non-irAEs group (2.8 vs. 4.1; p = 0.036). The cutoff value of the NLR was 2.86 (area under curve, 0.62; sensitivity, 0.56; specificity, 0.71), and the incidence rate of irAEs was significantly higher in the NLR < 2.86 group than in the NLR ≥2.86 group (p = 0.004; odds ratio [OR]: 3.12; 95% confidence interval [CI]: 1.43-6.84). The multivariate analysis showed that the NLR was significantly associated with the occurrence of irAEs (p = 0.016; OR: 2.69; 95% CI: 1.21-6.01). CONCLUSIONS: Low pretreatment NLR may be a predictive factor for the occurrence of irAEs. By focusing on the potential risk of irAEs in patients with a low pretreatment NLR, irAEs can be appropriately managed from an early period.

Modulation of activity and inhibitor sensitivity of rabbit aldose reductase-like protein (AKR1B19) by oxidized glutathione and SH-reagents.

Rabbit aldo-keto reductase (AKR) 1B19 is an ortholog of human aldose reductase-like protein (ARLP), AKR1B10, showing 86% amino acid sequence identity. AKR1B19 exhibits the highest catalytic efficiency for 4-oxo-2-nonenal, a major product of lipid peroxidation, compared to known reductases of this aldehyde. In this study, we found that the reductase activity of AKR1B19 was activated to about 5-fold immediately after the addition of 10 µM SH-reagents (p-chloromercuriphenylsulfonic acid and p-chloromercuribenzoic acid) in the absence or presence of NADPH. In addition, a maximum of 3-fold activation of AKR1B19 was induced by incubation with glutathione disulfide (GSSG) for 1h. The activated enzyme was converted into the native enzyme by further incubation with dithiothreitol and glutathione. The activation was abolished by the C299S mutation of AKR1B19, and the glutathionylated Cys299 was identified by mass spectrometry analysis. The Cys299-modified enzyme displayed different kinetic alterations depending on substrates and inhibitors. In the reduction of 4-oxo-2-nonenal, the catalytic efficiency was increased. Thus, AKR1B10 may be modulated by cellular ratio of GSSG/glutathione and more efficiently act as a detoxifying enzyme for the cytotoxic aldehyde under oxidatively stressed conditions. Furthermore, such an activity alteration by GSSG was not detected in AKR1B10 and rat ARLPs, suggesting the presence of a GSSG-binding site near Cys299 in AKR1B19.