Safety, antitumor activity and biomarkers of sugemalimab in Chinese patients with advanced solid tumors or lymphomas: results from the first-in-human phase 1 trial.

BACKGROUND: This first-in-human phase 1 trial is to evaluate the safety, pharmacokinetics, preliminary efficacy, and biomarkers of sugemalimab, a full-length, fully human anti-PD-L1 monoclonal antibody, in Chinese patients with advanced malignancies. METHODS: Eligible patients with unresectable advanced or metastatic solid tumors or lymphomas were enrolled in phase 1a to receive sugemalimab following a modified 3 + 3 design. The primary endpoints included safety, tolerability, and the recommended Phase 2 dose (RP2D). In phase 1b, patients with 7 selected types of tumor received sugemalimab at the RP2D alone (monotherapy cohorts) or in combination with standard-of-care (SOC) chemotherapy (combination cohorts). The primary endpoint of phase 1b was investigator-assessed objective response rate (ORR). RESULTS: As of 19 February 2020, 29 and 178 patients were treated in phase 1a and 1b, respectively. No dose-limiting toxicities were observed in phase 1a, and the RP2D of sugemalimab was determined as 1200 mg fixed dose once every 3 weeks. Sugemalimab-related adverse events (AEs) were mostly (75.9%) grade 1-2 in phase 1a. Antitumor activity was observed across dose levels with an ORR of 24.1%. In phase 1b, 15.9% and 40.4% of patients in the monotherapy and combination cohorts, respectively, reported grade 3-5 sugemalimab-related AEs. Promising efficacy was observed in all combination cohorts, with ORRs ranging from 47.6 to 75.0%. Exploratory biomarker analysis did not indicate significant differences in responses at different PD-L1 expression/tumor mutation burden levels. CONCLUSIONS: Sugemalimab was well-tolerated and showed promising antitumor activity as monotherapy or in combination with SOC chemotherapy in advanced malignancies. This trial was registered with ClinicalTrials.gov on Oct 18, 2017, number NCT03312842.

Efficacy and safety of adrenergic beta-antagonist combined with lasers in the treatment of infantile hemangiomas: a meta-analysis.

To investigate the efficacy and safety of combined therapy with adrenergic beta-antagonist and lasers in infantile hemangiomas (IH). A search of Pubmed, Cochrane, Embase, Wanfang Date, CNKI (China National Knowledge Infrastructure) and CBM (China Biology Medicine) databases was conducted to identify studies that examined response to combined therapy with adrenergic beta-antagonist and laser in IH patients. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) in random-effects or fixed-effects models were calculated with Review Manger 5.3. Efficacy of combined therapy with oral propranolol and lasers was significantly better than that of propranolol (OR 5.79, 95% CI 2.52-13.31, P < 0.00001) or lasers (OR 5.09, 95% CI 3.04-8.54, P < 0.00001) alone. Combined therapy with topical timolol and lasers was more effective than topical timolol (OR 3.71, 95% CI 2.46-5.59, P < 0.00001) or lasers (OR 10.92, 95% CI 1.90-62.70, P = 0.007) alone. We did not observe statistically significant differences of adverse reactions between combined therapy with oral propranolol and lasers and propranolol (OR 1.09, 95% CI 0.64-1.84, P = 0.75) or lasers (OR 0.83, 95% CI 0.28-2.50, P = 0.74). The incidence of adverse reactions in combined therapy with topical timolol and lasers and monotherapy with topical timolol therapy (OR 0.50, 95% CI 0.14-1.80, P = 0.75) or lasers (OR 0.29, 95% CI 0.06-1.55, P = 0.15) has no significant difference. The average treatment duration of combined therapy may be shorter than that of monotherapy. Combination therapy of adrenergic beta-antagonist and lasers on IH is significantly more effective than monotherapy, while the safety of combination therapy was not significantly higher than that of monotherapy.

[Effect of progesterone on the pathogenesis and development of hemangioma in nude mice].

OBJECTIVE: To explore the role of progesterone in the pathogenesis and development of hemangioma in nude mice.
 Methods: The hemangioma model was established. Progesterone was injected intramuscularly at different doses (0.2, 0.4, and 0.8 mg/d) for one week. Camellia oil (0.4 mL/d) was injected intramuscularly as control. The size of hemangioma was observed dynamically. The subcutaneous implants were harvested on the 14th and 28th days. The expression of vascular endothelial growth factor in the tumor tissues were evaluated using immunohistochemistry and microvessel density (MVD) was counted under the microscope.
 Results: On the 14th day, the expression of vascular endothelial growth factor (P<0.01 and P<0.05, respectively) was higher, the volume of tumors (All P<0.01) and MVD (All P<0.01) were greater in the high-dose progesterone group than those in the control and low-dose progesterone group. On the 28th day, there was no significant difference in the volume of tumors among 4 groups (P>0.05). The expression of vascular endothelial growth factor (P<0.01) was lower, and MVD (All P<0.05) were less in the middle-dose and high-dose progesterone group than those in the control and low-dose progesterone group.
 Conclusion: Progesterone promotes angiogenesis via upregulation of vascular endothelial growth factor expression, promotion of hemangiomas proliferation, suggesting that excessive progesterone supplementation may be one of the initial factors for early hemangioma formation.

[Usage and efficacy of timolol maleate eye drops in treatment of superficial infantile hemangioma].

OBJECTIVE: To determine drug dose and usage of timolol maleate eye drops in the treatment of superficial infantile hemangioma.
 Methods: A total of 250 superficial hemangioma infants were recruited and assigned into 5 groups (n=50 for each group): an external application group and 4 exterior coating groups (2, 4, 6, 8 times per day). We evaluated the therapeutic effect of different methods for drug application (external application or exterior coating) and the frequency for drug administration on superficial infantile hemangioma.
 Results: The external application group (twice a day and 0.5 hour per time) showed better effect than that in the exterior coating group with twice a day (P<0.001). The difference in therapeutic effect between the exterior coating group with 6 times a day and exterior coating group with twice a day or with 3 times a day was significant (P<0.001). The differences in drug efficacy were not found among the exterior coating group with 6 times a day, the exterior coating group with 8 times a day, or the external application group with twice a day (All P>0.05).
 Conclusion: Drug dose may affect the therapeutic effect of timolol maleate eye drops in superficial hemangioma infants, and exterior coating with 6 times a day may achieve the best curative effect.

[Survey on changes in the proportion for facial aesthetics].

OBJECTIVE: To explore the proportion for facial aesthetics that may be recognized by the potential group who will do plastic surgery in the future. 
 Methods: We measured the celebrity photos, who were born before 1980 recognizable by the people over 40 years old or by high school students. The proportions for facial aesthetics recognizable by these two generations were obtained and compared. 
 Results: Compared the new generation of male celebrities with the older generation of male celebrities, the difference was statistically significant by the independent samples t test (t=-2.502, P<0.05), while other ratios were not statistically significant (P>0.05). Compared the new generation of female celebrities with the older generation of female celebrities, the difference was statistically significant by the independent samples t test. The ratios between inter-canthic diameter and eyeslit breadth, mouth breadth and eyeslit breadth, stirnhohe and 1/3 of the physiognomic facial height, nasal height and 1/3 of the physiognomic facial height were significantly different (P<0.05), while other ratios were not significantly different (P>0.05).
 Conclusion: The young new generation loves more larger eyeslit breadth for men, while a larger eyeslit breadth, smaller bizygomatic breadth and sharper chin for women.

Ivosidenib in Chinese patients with relapsed or refractory isocitrate dehydrogenase 1 mutated acute myeloid leukemia: a registry study.

Ivosidenib, an isocitrate dehydrogenase 1 (IDH1) inhibitor, has demonstrated clinical benefits in a pivotal study (AG120-C-001) in patients with IDH1-mutated (mIDH1) acute myeloid leukemia (AML). A registry study (CS3010-101: NCT04176393) was conducted to assess the pharmacokinetic (PK) characteristics, safety, and efficacy of ivosidenib in Chinese patients with relapsed or refractory (R/R) mIDH1 AML. Patients received ivosidenib 500 mg once daily for 28-day cycles until disease progression. Ten subjects underwent intensive PK/progressive disease (PD) assessments. All subjects had the clinical response assessed at screening, every 28 days through month 12, and then every 56 days. Between November 12, 2019, and April 2, 2021, 30 patients were enrolled; 26 (86.7%) had de novo AML and 18 (60.0%) were transfusion-dependent at baseline. Following single and repeated doses of ivosidenib, median time to maximum plasma concentration (T max) was 4.0 and 2.0 hours, respectively. The inter-individual variability of pharmacokinetic exposure was moderate to high (coefficient of variation [CV], 25%-53%). No obvious accumulation was observed after repeated doses at cycle 2 day 1. Regarding the clinical response, the CR + CRh rate was 36.7% (95% confidence interval [CI]: 19.9%-56.1%), the median duration of CR + CRh was 19.7 months (95% CI: 2.9 months-not reached [NR]), and median duration of response (DoR) was 14.3 months (95% CI: 6.4 months-NR). Consistent clinical benefits and safety of ivosidenib were consistently observed at the final data cutoff with median follow-up time 26.0 months, as compared with primary data cutoff, and the data from Chinese R/R mIDH1 AML patients were also consistent with results from pivotal study.

First-line sugemalimab with chemotherapy for advanced esophageal squamous cell carcinoma: a randomized phase 3 study.

Although antiprogrammed death 1 antibody plus chemotherapy has recently been approved for first-line esophageal squamous cell carcinoma (ESCC), antiprogrammed death-ligand 1 antibody may offer another combination option in this setting. In this multicenter, randomized, double-blinded phase 3 trial a total of 540 adults (aged 18-75 years) with unresectable, locally advanced, recurrent or metastatic ESCC and who had not received systemic treatment were enrolled. All patients were randomized at 2:1 to receive either sugemalimab (an anti-PD-L1 antibody; 1,200 mg) or placebo every 3 weeks for up to 24 months, plus chemotherapy (cisplatin 80 mg m-2 on day 1 plus 5-fluorouracil 800 mg m-2 day-1 on days 1-4) every 3 weeks for up to six cycles. At the prespecified interim analysis this study had met dual primary endpoints. With a median follow-up of 15.2 months, the prolongation of progression-free survival was statistically significant with sugemalimab plus chemotherapy compared with placebo plus chemotherapy (median 6.2 versus 5.4 months, hazard ratio 0.67 (95% confidence interval 0.54-0.82), P = 0.0002) as assessed by blinded independent central review. Overall survival was also superior with sugemalimab chemotherapy (median 15.3 versus 11.5 months, hazard ratio 0.70 (95% confidence interval 0.55-0.90, P = 0.0076). A significantly higher objective response rate (60.1 versus 45.2%) as assessed by blinded independent central review was observed with sugemalimab chemotherapy. The incidence of grade 3 or above treatment-related adverse events (51.3 versus 48.4%) was comparable between the two groups. Sugemalimab plus chemotherapy significantly prolonged progression-free survival and overall survival in treatment-naïve patients with advanced ESCC, with no unexpected safety signal. The ClinicalTrials.gov identifier is NCT04187352 .

The Expression of ZNF268 and Its Role in The Cisplatin-based Chemoresistance of Breast Cancer.

Objective: Breast cancer is one of the most prevalent cancers in females worldwide and is one of the leading causes of cancer death and disability in women. Multiple therapies have been applied to breast cancer treatment; however, the long-term survival rate remains low. Although cisplatin has been widely utilized for cancer therapy, chemoresistance still influences the outcome. Methods: After collecting the breast cancer cell line MDA-MB-231 treated with or without cisplatin and sample information from The Cancer Genome Atlas Program (TCGA), we screened out their common parameters and influences on the prognoses of patients' potential targets. Surgical excisional tissue sections of patients with breast cancer who were admitted and treated in the Department of Breast and Thyroid Surgery, Liuzhou People's Hospital from 2017 to 2020 was collected and follow up. After a series of assays combined with clinical information, we tested the reliability of the target. Results: We found that a high expression level of ZNF268 in breast cancer cell lines significantly enhances the sensitivity to cisplatin, contrary to the effects of low expression. Furthermore, a significantly worse prognosis was observed in patients with a high expression of ZNF268 after cisplatin chemotherapy. Conclusion: The expression level of ZNF268 in breast cancer patients after cisplatin chemotherapy may become a potential target to predict the chemoresistance of patients to cisplatin. This study provides a novel idea for improving breast cancer treatment and survival rates.

Sugemalimab Monotherapy for Patients With Relapsed or Refractory Extranodal Natural Killer/T-Cell Lymphoma (GEMSTONE-201): Results From a Single-Arm, Multicenter, Phase II Study.

PURPOSE: Relapsed or refractory extranodal natural killer/T-cell lymphoma (R/R ENKTL) is a rare and aggressive type of non-Hodgkin lymphoma with limited treatment options. This phase II study evaluated the efficacy and safety of sugemalimab, an anti-PD-L1 monoclonal antibody, in R/R ENKTL. METHODS: Eligible patients received sugemalimab 1,200 mg intravenously once every 3 weeks for up to 24 months or until progression, death, or study withdrawal. The primary end point was objective response rate (ORR) assessed by an independent radiologic review committee. Key secondary end points included ORR assessed by the investigators, complete response rate, duration of response, and safety. RESULTS: At the data cutoff (February 23, 2022), 80 patients were enrolled and followed for a median of 18.7 months. At baseline, 54 (67.5%) had stage IV disease and 39 (48.8%) had received ≥2 lines of prior systemic therapy. Independent radiologic review committee-assessed ORR was 44.9% (95% CI, 33.6 to 56.6); 28 (35.9%) patients achieved a complete response and seven (9.0%) achieved a partial response, with a 12-month duration of response rate of 82.5% (95% CI, 62.0 to 92.6). Investigator-assessed ORR was 45.6% (95% CI, 34.3 to 57.2), and 24 (30.4%) patients achieved a complete response. Most treatment-emergent adverse events were grade 1-2 in severity, and grade ≥ 3 events were reported in 32 (40.0%) patients. CONCLUSION: Sugemalimab showed robust and durable antitumor activity in R/R ENKTL. Treatment was well tolerated with expected safety profile for this drug class.

Decoupled Electrochemical Hydrazine "Splitting" via a Rechargeable Zn-Hydrazine Battery.

Hydrogen generation via electrochemical splitting plays an important role to achieve hydrogen economy. However, the large-scale application is highly limited by high cost and low efficiency. Herein, a new type of rechargeable Zn-hydrazine (Zn-Hz) battery is proposed and realized by a bifunctional electrocatalyst based on two separate cathodic reactions of hydrogen evolution (discharge: 2H2 O + 2e-  â†’ H2  + 2OH- ) and hydrazine oxidation (charge: 1 / 2 N 2 H 4 + 2 OH - → 1 / 2 N 2 + 2 H 2 O + 2 e - $1{\rm{/}}2\,{{\rm{N}}_2}{{\rm{H}}_4}{\bm{ + }}2{\rm{O}}{{\rm{H}}^{\bm{ - }}}{\bm{ \to }}1{\rm{/}}2\,{{\rm{N}}_2}{\bm{ + }}2{{\rm{H}}_2}{\rm{O}}{\bm{ + }}2{e^{\bm{ - }}}$ ). This Zn-Hz battery, driven by temporally decoupled electrochemical hydrazine splitting on the cathode during discharge and charge processes, can generate separated hydrogen without purification. When the highly active bifunctional cathode of 3D Mo2 C/Ni@C/CS is paired with Zn foil, the Zn-Hz battery can achieve efficient hydrogen generation with a low energy input of less than 0.4 V (77.2 kJ mol-1 ) and high energy efficiency of 96%. Remarkably, this battery exhibits outstanding long-term stability for 600 cycles (200 h), achieving continuous hydrogen production on demand, which presents great potential for practical application.

Critical role of DNA checkpoints in mediating genotoxic-stress-induced filamentous growth in Candida albicans.

The polymorphic fungus Candida albicans switches from yeast to filamentous growth in response to a range of genotoxic insults, including inhibition of DNA synthesis by hydroxyurea (HU) or aphidicolin (AC), depletion of the ribonucleotide-reductase subunit Rnr2p, and DNA damage induced by methylmethane sulfonate (MMS) or UV light (UV). Deleting RAD53, which encodes a downstream effector kinase for both the DNA-replication and DNA-damage checkpoint pathways, completely abolished the filamentous growth caused by all the genotoxins tested. Deleting RAD9, which encodes a signal transducer of the DNA-damage checkpoint, specifically blocked the filamentous growth induced by MMS or UV but not that induced by HU or AC. Deleting MRC1, the counterpart of RAD9 in the DNA-replication checkpoint, impaired DNA synthesis and caused cell elongation even in the absence of external genotoxic insults. Together, the results indicate that the DNA-replication/damage checkpoints are critically required for the induction of filamentous growth by genotoxic stress. In addition, either of two mutations in the FHA1 domain of Rad53p, G65A, and N104A, nearly completely blocked the filamentous-growth response but had no significant deleterious effect on cell-cycle arrest. These results suggest that the FHA domain, known for its ability to bind phosphopeptides, has an important role in mediating genotoxic-stress-induced filamentous growth and that such growth is a specific, Rad53p-regulated cellular response in C. albicans.