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Objective: To compare the efficacy and safety of first‐line anti‐PD‐1 combined with chemotherapy versus chemotherapy alone in patients with advanced urothelial carcinoma (UC). Method: Patients with advanced UC who received first‐line treatment of chemotherapy (n = 51, gemcitabine/paclitaxel [albumin‐bound] combined with platinum) or immunochemotherapy (n = 50, PD‐1 inhibitors plus chemotherapy) were enrolled. The efficacy and safety were analyzed between the two groups. Results: This study included data from 101 patients, including 51 patients in the chemotherapy group and 50 patients in the immunochemotherapy group. The median progression‐free survival of the immunochemotherapy group was significantly longer than that of the chemotherapy group (11.5 vs. 7.17 m, HR = 0.56, p = 0.009). The two groups' overall survival showed no significant difference (20.3 vs. 17.8 m, p = 0.204). The objective response rates and the disease control rates of the two groups were 38.0% versus 49.0% (p = 0.26) and 88.0% versus 80.4% (p = 0.29). The incidence of adverse reactions (AEs) in the immunochemotherapy group and chemotherapy group were 90.0% and 84.3% (p = 0.394), respectively, and the incidence of Grade III–IV AEs were 32.0% and 35.3% (p = 0.726), respectively. Conclusion: In the first‐line treatment of patients with advanced UC, anti‐PD‐1 therapy combined with chemotherapy might have better efficacy than chemotherapy alone, and AEs are similar between the two groups. [ABSTRACT FROM AUTHOR]

Background: Rationale exists for combining immune checkpoint inhibitors and PARP inhibitors (PARPi), and results of clinical trials in ovarian cancer are promising, but data in other cancers are limited. Method: Efficacy and safety of PARPi/anti-PD-1 in advanced solid tumors were retrospectively analyzed. The efficacy measures included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Results: This retrospective study included data from 40 patients. The ORR was 27.5% (95% CI, 13.0–42.0%), with a DCR of 85.0% (95% CI, 73.4–96.6%). Except four patients in first-line treatment (three with PR and one with SD), the ORR of ≥second-line treatment, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) was 22.2%, 23.1% and 28.6%, and the DCR was 83.3%, 84.6% and 71.4%, separately. The median PFS of all patients, ≥second-line treatment, NSCLC and SCLC was 4.6 m, 4.2 m, 4.5 m and 3.7 m. The median OS was 9.4 m, 11.4 m, 12.7 m and 5.4 m, respectively. Multivariable analysis revealed that BRCA1/2 mutation was positively correlated with ORR (P = 0.008), and LDH≥250U/L was negatively correlated with lowered DCR (P = 0.018), while lymphocyte number, ECOG and LDH significantly influenced both PFS and OS. We found that the possible resistant mechanisms were sarcomatous degeneration and secondary mutation, including BRCA2 truncation mutation, A2M, JAK1,T790M, KEAP1 and mTOR mutation. 37.5% patients had ≥grade 3 adverse events. Conclusion: PARPi/anti-PD-1 is an effective and tolerable method for patients with advanced solid tumors, and BRCA1/2 is a potential biomarker. [ABSTRACT FROM AUTHOR]

Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated great promise for treating cancers with homologous recombination (HR) defects, such as germline BRCA1/2 mutation. Further studies suggest that PARP inhibitors (PARPi) can also exhibit efficacy in HR-competent cancers, by amplifying the DNA damage and inducing immunogenic cell death, and PARPi lead to increasing tumor neoantigen, upregulation of interferons and PD-L1, and modulation of the tumor microenvironment, which may facilitate a more profound antitumor immune response. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 or CTLA-4 have achieved impressive success in the treatment of different malignancies. However, only a subset of populations derive clinical benefit, and the biomarkers and resistance mechanisms are not fully understood. Therefore, given that PARPi could potentiate the therapeutic effect of ICIs, PARPi combined with ICIs are becoming an alternative for patients who cannot benefit from ICI monotherapy. In this review, we focus on the mechanisms and immune role of PARPi and discuss the rationale and clinical studies of this combined regimen. [ABSTRACT FROM AUTHOR]

A series of Ir(III) complexes (CˆN) 2 Ir(NˆN) (NˆN are 4,4′-dihydroxy-2,2′-bipyridine and 4,4′-diamino-2,2′-bipyridine, and CˆN are phenylpyridine, benzo[h]quinolone, and 2-phenylquinoline) were synthesized and characterized. Two of the complexes were structurally characterized via X-ray crystallography. The photophysical and photochemical properties of these complexes were studied. Preliminary studies of their applications on pH sensing, and cell imaging were also performed. [ABSTRACT FROM AUTHOR]

• The first report of PLEKHM2-ALK rearrangement. • The first SCLC patient with ALK fusion with long-term benefit from ALK inhibitors. • Overall survival of more than 27 months for this case Vs 8–13 months as usual. In non-small cell lung cancer (NSCLC), anaplastic lymphoma kinase (ALK) rearrangement identifies a subgroup of patients who are sensitive to ALK tyrosine kinase inhibitors (TKIs). ALK fusion is extremely rare in small-cell lung cancer (SCLC). To the best of our knowledge, only two cases of SCLC harboring ALK fusion mutation has been reported previously, both of whom carrying EML4-ALK fusion. There are no standard treatment options for SCLC patients with ALK fusion mutations. Herein, we described a rare case of ALK-rearranged SCLC responding to ALK inhibitors. Immunohistochemistry (IHC) assay and next-generation sequencing (NGS) were performed on the biopsied tumor tissue. NGS detected a novel pleckstrin homology and RUN domain containing M2 (PLEKHM2)-ALK fusion, while the IHC analysis revealed an ALK-positive tumor. For extensive SCLC patients, median OS was about 8–13 months. The patient in this case had durable clinical benefit upon the treatment with ALK inhibitors, achieving an overall survival (OS) of more than 27 months. This case provides a meaningful reference for the treatment of SCLC patients with ALK fusion mutations. This case also provides valuable information on the response to ALK inhibitors of patients with PLEKHM2-ALK fusion and better understanding of ALK-TKI applications in the future. NGS may be used as a routine test to explore more treatment opportunities for tumor SCLC patients. [ABSTRACT FROM AUTHOR]

Purpose: Anti-programmed cell death protein 1 or its ligand (anti-PD-1/L1) monotherapy has become the standard second-line treatment in advanced lung adenocarcinoma. However, the strategy treatment of anti-PD-1/L1 plus anti-angiogenesis therapy has not been evaluated. We conducted this retrospective study to assess the efficacy and safety of anti-PD-1/L1 plus anti-angiogenesis therapy in patients with advanced lung adenocarcinoma in the second-line or later setting. Methods: Patients with advanced lung adenocarcinoma who received anti-PD-1/L1 plus anti-angiogenesis therapy or anti-PD-1/L1 monotherapy in the second-line or later treatment from March 2015 to May 2019 in PLA General Hospital were retrospectively analyzed. The progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were assessed. Multivariate analyses of PFS and OS were performed with Cox proportional hazard regression models. Results: Seventy-four patients were included in our study. Twenty-five patients were treated with anti-PD-1/L1 plus anti-angiogenesis therapy, and forty-nine patients were treated with anti-PD-1/L1 monotherapy. The disease control rate (DCR) was higher in the anti-PD-1/L1 plus anti-angiogenesis group than in the anti-PD-1/L1 monotherapy group (92.0% vs. 46.9%, P = 0.0004). The median progression-free survival (PFS) was 5.1 months vs. 2.0 months (HR 0.551 [95% confidence interval 0.337–0.902], P = 0.002) and median overall survival (OS) was 14.3 months vs. 8.4 months (HR 0.549 [95% CI 0.305–0.990], P = 0.046), respectively. Multivariate Cox proportional hazard regression models showed that anti-PD-1/L1 plus anti-angiogenesis group had prolonged PFS (HR 0.541 [95% CI 0.298–0.981], P = 0.033). The incidences of grade 3/4 adverse events were 12% (3/25) in anti-PD-1/L1 plus anti-angiogenesis group and 6% (3/49) in anti-PD-1/L1 monotherapy group. Conclusion: Compared with anti-PD-1/L1 monotherapy, anti-PD-1/L1 plus anti-angiogenesis therapy could significantly improve the clinical response and bring longer PFS and OS in patients with advanced lung adenocarcinoma who had failed first-line or later treatment. Further prospective studies are needed to validate our findings. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) represent a major breakthrough for cancer treatment. However, evidence regarding the use of ICIs in pancreatic cancer (PC) remained scarce. To assess the efficacy and safety of ICIs plus chemotherapy, patients with advanced PC were retrospectively recruited and were treated with either chemotherapy alone or chemotherapy plus ICIs. Patients previously treated with any agents targeting T-cell co-stimulation or checkpoint pathways were excluded. The primary outcome was overall survival (OS). The secondary outcomes were progression-free survival (PFS), overall response rate (ORR) and safety. In total, 58 patients were included (combination, n = 22; chemotherapy, n = 36). The combination group showed a significantly longer OS than the chemotherapy group [median, 18.1 vs 6.1 months, hazard ratio (HR) 0.46 (0.23–0.90), P = 0.021]. The median PFSs were 3.2 months in the combination group and 2.0 months in the chemotherapy group [HR 0.57 (0.32–0.99), P = 0.041]. The combination group and the chemotherapy group had similar ORRs (18.2% vs 19.4%, P = 0.906). All patients who achieved a partial response received a doublet chemotherapy regimen regardless of co-treatment with ICIs. Grade 3 or higher adverse events occurred in 31.8% of the patients in the combination group and in 16.9% of those receiving chemotherapy. Although the incidence of serious treatment-related adverse events was higher in the combination group than in the chemotherapy group, the difference was not significant (P = 0.183). Our findings suggest that the combination of ICIs with chemotherapy is both effective and tolerable for advanced PC. ICIs combined with a doublet chemotherapy regimen might be a preferable choice. [ABSTRACT FROM AUTHOR]

Background: Evidence for the efficacy of immunotherapy in biliary tract cancer (BTC) is limited and unsatisfactory. Methods: Chinese BTC patients receiving a PD-1 inhibitor with chemotherapy, PD-1 inhibitor monotherapy or chemotherapy alone were retrospectively analyzed. The primary outcome was overall survival (OS). The key secondary outcomes were progression-free survival (PFS) and safety. Patients previously treated with any agent targeting T cell costimulation or immune checkpoints were excluded. Results: The study included 77 patients (a PD-1 inhibitor plus chemotherapy, n = 38; PD-1 inhibitor monotherapy, n = 20; chemotherapy alone, n = 19). The median OS was 14.9 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 4.1 months with PD-1 inhibitor monotherapy (HR 0.37, 95% CI 0.17–0.80, P = 0.001) and the 6.0 months with chemotherapy alone (HR 0.63, 95% CI 0.42–0.94, P = 0.011). The median PFS was 5.1 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 2.2 months with PD-1 inhibitor monotherapy (HR 0.59, 95% CI 0.31–1.10, P = 0.014) and the 2.4 months with chemotherapy alone (HR 0.61, 95% CI 0.45–0.83, P = 0.003). Grade 3 or 4 treatment-related adverse events were similar between the anti-PD-1 combination group and the chemotherapy alone group (34.2% and 36.8%, respectively). Conclusions: Anti-PD-1 therapy plus chemotherapy is an effective and tolerable approach for advanced BTC. [ABSTRACT FROM AUTHOR]

Abstract: Monocarboxylate transporter‐4 (MCT4), a monocarboxylic acid transporter, demonstrates significantly increased expression in the majority of malignancies. We performed an experiment using BALB/C mice, and our results showed that ShMCT4 transfection or the pharmaceutic inhibition of MCT4 with 7acc1 strengthens the activity of NK cells. The results of a calcein assay revealed that the cytotoxicity of NK cells was strengthened via inhibition of MCT4. In addition, ELISA testing showed that the content of perforin and CD107a was increased, and PCR amplification and immunoblotting revealed that the expression of NKG2D and H60 was upregulated after the inhibition of MCT4. Further, we observed an elevated pH value, decreased extracellular lactate flow, and attenuated tumor growth. Therefore, we concluded that the inhibition of MCT4 enhanced the cytotoxicity of NK cells by blocking lactate flux and reversing the acidified tumor microenvironment. In addition to these findings, we also discovered that MCT4 depletion may have a pronounced impact on autophagy, which was surmised by observing that the inhibition of autophagy (3MA) pulled the enhanced cytotoxicity of NK cells downwards. Together, these data suggest that the key effect of MCT4 depletion on NK cells probably utilizes inductive autophagy as a compensatory metabolic mechanism to minimize the acidic extracellular microenvironment associated with lactate export in tumors. [ABSTRACT FROM AUTHOR]

Ketosis causes serious economic losses for the modern dairy industry because it is a highly prevalent metabolic disease among cows in high-producing herds during the transition period. Due to some striking similarities between diabetes in humans and ketosis in dairy cows, there is potential for the use of methylglyoxal (MGO)—commonly used in human diabetics—as a biomarker in dairy cattle. However, currently no data are available about the presence of MGO in the serum of dairy cattle or about the characteristics of its production or its potential contribution in the pathogenesis of ketosis. To determine the potential origin and pathway of formation of MGO, cows in different metabolic conditions [i.e., non-subclinically ketotic dairy cows in early lactation (n = 7), subclinically ketotic dairy cows in early lactation (n = 8), overconditioned dry cows (BCS >4.25, n = 6), and nonlactating heifers (n = 6)] were selected. Serum MGO concentrations were determined and correlated with indicators of the glucose and lipid metabolism and with haptoglobin (Hp) as an inflammatory marker. The serum MGO concentrations in subclinically ketotic cows (712.60 ± 278.77 nmol/L) were significantly greater than in nonlactating heifers (113.35 ± 38.90 nmol/L), overconditioned dry cows (259.71 ± 117.97 nmol/L), and non-subclinically ketotic cows (347.83 ± 63.56 nmol/L). In serum of lactating cows, concentrations of glucose and fructosamine were lower than in heifers and were negatively correlated with MGO concentrations. Even so, concentrations of metabolic and inflammatory markers such as dihydroxyacetone phosphate, nonesterified fatty acids, β-hydroxybutyrate, acetone, and Hp were remarkably higher in subclinically ketotic cows compared with nonlactating heifers; these metabolites were also positively correlated with MGO. In human diabetics elevated MGO concentrations are stated to originate from both hyperglycemia and the enhanced lipid metabolism, whereas higher MGO concentrations in subclinically ketotic cows were not associated with hyperglycemia. Therefore, our data suggest MGO in dairy cows to be a metabolite produced from the metabolization of acetone within the lipid metabolization pathway and from the metabolization of dihydroxyacetone phosphate. Furthermore, the highly positive correlation between MGO and Hp suggests that this reactive compound might be involved in the proinflammatory state of subclinical ketosis in dairy cows. However, more research is needed to determine the potential use of MGO as a biomarker for metabolic failure in dairy cows. [ABSTRACT FROM AUTHOR]

The efficacies of pembrolizumab and nivolumab have never been directly compared in a real-world study. Therefore, we sought to retrospectively evaluate the objective response rate (ORR) and the progression-free survival (PFS) of patients with recurrent or advanced non-small cell lung cancer (NSCLC) in a real-world setting. This study included patients with recurrent or advanced NSCLC diagnosed between September 1, 2015 and August 31, 2019, who were treated with programmed cell death 1 (PD-1) inhibitors at the Cancer Center of the Chinese People's Liberation Army. PFS was estimated for each treatment group using Kaplan–Meier curves and log-rank tests. The multivariate analysis of PFS was performed with Cox proportional hazards regression models. A total of 255 patients with advanced or recurrent NSCLC treated with PD-1 inhibitors were identified. The ORR was significantly higher in the pembrolizumab group than in the nivolumab group, while PFS was not significantly different between the two groups. Subgroup analysis showed that the ORR was significantly higher for pembrolizumab than for nivolumab in patients in the first-line therapy subgroup and in those in the combination therapy as first-line therapy subgroup. Survival analysis of patients receiving combination therapy as second- or further-line therapy showed that nivolumab had better efficacy than pembrolizumab. However, the multivariate analysis revealed no significant difference in PFS between patients treated with pembrolizumab and those treated with nivolumab regardless of the subgroup. In our study, no significant difference in PFS was noted between patients treated with pembrolizumab and those treated with nivolumab in various clinical settings. This supports the current practice of choosing either pembrolizumab or nivolumab based on patient preferences. [ABSTRACT FROM AUTHOR]