Efficacy and safety of zimberelimab (GLS-010) monotherapy in patients with recurrent or metastatic cervical cancer: a multicenter, single-arm, phase II study.

OBJECTIVE: There is an unmet need to improve clinical outcomes for patients with recurrent/metastatic cervical cancer. Checkpoint inhibitors represent a promising treatment strategy. We evaluated the safety and anti-tumor activity of zimberelimab, an anti-programmed cell death protein-1 antibody, in patients with previously treated, recurrent, metastatic cervical cancer. METHODS: This phase II, single-arm, open-label study used a Simon two-stage minimax design. Eligible patients were women aged 18-75 years with programmed death ligand-1-positive recurrent or metastatic cervical cancer that had progressed after first- or subsequent-line chemotherapy (Eastern Cooperative Oncology Group (ECOG) performance status 0-1). Patients received intravenous zimberelimab (240 mg every 2 weeks) for 2 years until disease progression, intolerable adverse effects, or withdrawal from the study. The primary endpoint was objective response rate assessed per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, by an independent review committee. RESULTS: A total of 105 patients were enrolled. Median age was 51 (range, 31-75) years; 63.8% had an ECOG performance status of 1. The median number of previous treatment lines was 1 (range, 1-4). Median follow-up was 16.9 (range, 16.3-18.4) months. The objective response rate was 27.6%, and the disease control rate was 55.2%. Median duration of response was not reached. Median overall survival was 16.8 months, and median progression-free survival was 3.7 months. The incidence of treatment-related adverse events of any grade was 78.1%, of which the most common were hypothyroidism (26.7%) and anemia (19.0%). CONCLUSION: Zimberelimab monotherapy demonstrated durable anti-tumor activity and an acceptable safety profile in patients with cervical cancer. CLINICAL TRIAL REGISTRATION: NCT03972722.

Cross-resistance pattern to ACCase-inhibiting herbicides in a novel Trp1999Leu mutation American sloughgrass (Beckmannia syzigachne) population.

The plastid acetyl coenzyme carboxylase (ACCase) Trp1999Leu mutation was identified in a Beckmannia syzigachne population resistant to fenoxaprop-p-ethyl. The pattern of cross-resistance for the Trp1999Leu mutation is still ambiguous. In this paper, mutant homozygote (1999Leu/Leu, RR) and wild type (1999Trp/Trp, SS) B. syzigachne plants with the same genetic background were purified from the JS-26 population using the dCAPS method. The activity of ACCase in RR and SS was determined. Then, the cross-resistance pattern to ACCase inhibiting herbicides of the Trp1999Leu mutation was determined using the whole-plant method. ACCase activity showed that the Trp1999Leu mutation decreased ACCase sensitivity to fenoxaprop-p-ethyl by 2.73-fold. A dose-response experiment indicated that the Trp1999Leu mutation conferred high resistance to quizalofop-p-ethyl (20.29-fold), metamifop (12.22-fold) and pinoxaden (18.60-fold), moderate resistance to fenoxaprop-p-ethyl (8.20-fold) and sethoxydim (6.38-fold), low resistance to cyhalofop-butyl (2.73-fold) and no resistance to clodinafop-propargyl (1.42 fold) and clethodim (1.59-fold). This is the first report of the role of Trp1999Leu in fenoxaprop-p-ethyl resistance and of the patterns of cross-resistance to ACCase-inhibiting herbicides in B. syzigachne.

Involvement of H2O2 in fluazifop-P-butyl-induced cell death in bristly starbur seedlings.

In order to understand the action mechanism of fluazifop-P-butyl (FB) in bristly starbur (Acanthospermum hispidum D.C.), a susceptible plant, the role of active oxygen species (ROS) in herbicide-induced cell death in shoots was investigated. FB-induced phytotoxicity was not reduced by the antioxidants, 1,4-diazabicyclooctane (dabaco), sodium azide, l-tryptophan, d-tryptophan, hydroquinone and dimethyl pyridine N-oxide (DMPO). The activities of superoxide dismutase (SOD) and catalase (CAT), in bristly starbur seedlings were significantly increased by FB at 12 HAT and 24 HAT, while ascorbate peroxidase (APX) and glutathione reductase (GR) activities increased only at 12 HAT. The contents of H2O2 in FB-treated bristly starbur seedlings were significantly higher to that of control between 8 and 24 HAT. According to the analysis of potassium iodide - starch or 3,3-diaminobenzidine, the accumulation of hydrogen peroxide was observed in the apical growing point, stem, petiole and veins of FB-treated bristly starbur seedlings at 24 HAT. The cell viability of bristly starbur seedlings treated by 10µM FB decreased at 18 HAT. These results suggested that FB-induced cell death in bristly starbur shoots may be caused by ROS (O2- and H2O2) generation and lipid peroxidation.

Fluazifop-P-butyl induced ROS generation with IAA (indole-3-acetic acid) oxidation in Acanthospermum hispidum D.C.

Acanthospermum hispidum D.C. was particularly susceptible to fluazifop-P-butyl, an aryloxyphenoxypropionate herbicide, and the primary action site for the herbicide was shoot apical meristem, which is also the main site of indole-3-acetic acid (IAA) biosynthesis and action. Membrane lipid peroxidation caused by increasing levels of reactive oxygen species (ROS) was considered as an action mechanism of fluazifop-P-butyl in A. hispidum. To further clarify the ROS inducing mechanism of fluazifop-P-butyl in the plant, the interactions between fluazifop-P-butyl and auxin compounds IAA or 2,4-dichlorophenoxyacetic acid (2,4-D) were studied. Haloxyfop-P-methyl, an AOPP herbicide which is inactive on A. hispidum, was used for comparison. The results showed that the growth inhibition and malondialdehyde or H2O2 increases induced by fluazifop-P-butyl on A. hispidum were reversed by IAA or 2,4-D. The IAA content was decreased but the contents of three IAA oxidation metabolites, indole-3-methanol, indole-3-aldehyde and indole-3-carboxylic acid were increased by fluazifop-P-butyl in A. hispidum, but not by haloxyfop-P-methyl. The growth of A. hispidum was not inhibited by three IAA oxidative compounds. Moreover, the activities of IAA oxidase and peroxidase were increased by fluazifop-P-butyl but not by haloxyfop-P-methyl, and the increase was reversed by IAA or 2,4-D. We suggest that there is an antagonistic effect between fluazifop-P-butyl and IAA or 2,4-D, and the IAA oxidation may be involved in the action mechanism of fluazifop-P-butyl in A. hispidum.

New evidence for primordial action site of Fluazifop-P-butyl on Acanthospermum hispidum seedlings: From the effects on chlorophyll fluorescence characteristics and histological observation.

Acanthospermum hispidum DC, an Asteraceae weed species, was very susceptible to fluazifop-P-butyl, but tolerant to other aryloxyphenoxypropionate herbicides, such as haloxyfop-P-methyl. However, other Asteraceae weeds including Bidens pilosa were all tolerant to fluazifop-P-butyl. Membrane lipid peroxidation by increasing the levels of reactive oxygen species (ROS) was proposed as an action mechanism of fluazifop-P-butyl in A. hispidum. To further clarify the primordial action site of fluazifop-P-butyl in this species, the effects on chlorophyll fluorescence characteristics and cytohistology of apical meristems were studied. Chlorophyll fluorescence characteristics (CFC) in sensitive A. hispidum seedlings were markedly affected by 10µM fluazifop-P-butyl, with the dark fluorescence yield (Fo), maximal fluorescence yield (Fm), maximal PS II quantum yield (Fv/Fm), effective photosystem II (PS II) quantum yield [Y(II)], and quantum yield of regulated energy dissipation [Y(NPQ)] declining, quantum yield of nonregulated energy dissipation [Y(NO)] rising, but these measures were not affected in Bidens pilosa. The effects of fluazifop-P-butyl on chlorophyll fluorescence properties were observed on the growing point before the mature leaves by about 4-6h. Haloxyfop-P-methyl, a control herbicide, had no effects on CFC of either A. hispidum or B. pilosa. In addition, damage to apical meristem cells of A. hispidum was observed at 6 HAT prior to changes in chlorophyll fluorescence parameters suggesting that the primary action site of fluazifop-P-butyl in this species is in the apical meristem and the effects on CFC may be the results of secondary action.

Inhibition of SRC-3 enhances sensitivity of human cancer cells to histone deacetylase inhibitors.

SRC-3 is widely expressed in multiple tumor types and involved in cancer cell proliferation and apoptosis. Histone deacetylase (HDAC) inhibitors are promising antitumor drugs. However, the poor efficacy of HDAC inhibitors in solid tumors has restricted its further clinical application. Here, we reported the novel finding that depletion of SRC-3 enhanced sensitivity of breast and lung cancer cells to HDAC inhibitors (SAHA and romidepsin). In contrast, overexpression of SRC-3 decreased SAHA-induced cancer cell apoptosis. Furthermore, we found that SRC-3 inhibitor bufalin increased cancer cell apoptosis induced by HDAC inhibitors. The combination of bufalin and SAHA was particular efficient in attenuating AKT activation and reducing Bcl-2 levels. Taken together, these accumulating data might guide development of new breast and lung cancer therapies.

Laparoscopic surgery is feasible for the treatment of rectal cancer after neoadjuvant chemoradiotherapy.

This case-control study aimed to clarify the short- and long-term outcomes of laparoscopic surgery for rectal cancer after neoadjuvant chemo radiotherapy compared with conventional open resection. Between January 2008 and December 2014, a series of 227 patients with rectal cancer underwent radical surgery after neoadjuvant chemo radiotherapy. Age, gender, American Society of Anesthesiologists score, clinical stage, and type of resection were matched by propensity scoring and 106 patients (53 patients with laparoscopic total mesorectal excision and 53 patients with open resection) were selected for analysis. There were no significant differences in the clinicopathological features between the two groups. With regard to short-term outcomes, blood loss, postoperative analgesia and hospital stay were significantly shorter in the laparoscopy group than in the open group, whereas operative time was significantly longer in the laparoscopy group than in the open group. The overall morbidity was similar in the two groups. There were no significant differences in the 5-year overall and disease-free survival rates between the two groups. In summary, laparoscopic surgery may be both feasible and efficient compared with open resection for rectal cancer after neoadjuvant chemo radiotherapy.

A novel benzoxazine/cyanate ester blend with sea-island phase structures.

A novel cardanol-based benzoxazine (C-BOZ)/bisphenol A dicyanate ester (BADCy) blend with sea-island phase structures was successfully prepared via reaction-induced phase separation. The introduction of a long-chain alkyl group on the benzene ring significantly enhanced the thermodynamic differences between C-BOZ and BADCy. With the increase of the BADCy content, the Flory-Huggins interaction parameter (χ) of the blend decreased. By adjusting the ratio of the two components, sea-island phase separations were observed in C-BOZ/BADCy blends during the curing process. The dispersed phase was a C-BOZ rich phase, while the matrix was the crosslinked network composed of triazine rings and ring-opened C-BOZ. On the DMA curves of 9/1, 8/2 and 7/3 cured blends, there were two distinct Tgs. But with the increase of the BADCy content, the extent of phase separation was reduced. When the ratio reached 5/5, there was only one Tg because the viscosity of the blend was too high for phase separation to occur.

Atypical lipoma of the right piriformis muscle: a case report and review of the literature.

BACKGROUND: Piriformis muscle mass is rare, which is particular for intrapiriformis lipoma. Thus far, only 11 cases of piriformis muscle mass have been reported in the English literature. Herein, we encountered one patient with intrapiriformis lipoma who was initially misdiagnosed. CASE PRESENTATION: The patient is a 50-year-old Chinese man. He complained of osphyalgia, right buttock pain, and radiating pain from the right buttock to the back of the right leg. Both ultrasound and magnetic resonance imaging demonstrated a cyst-like mass in the right piriformis muscle. Ultrasonography-guided aspiration was performed on this patient first, but failed. He was then recommended to undergo mass resection and neurolysis of sciatic nerve. Surprisingly, final histology revealed the diagnosis of intrapiriformis lipoma. The patient exhibited significant relief of symptoms 3 days post-surgery. CONCLUSION: Diagnosis and differential diagnosis of radicular pain are potentially challenging but necessary. Atypical lipoma is prone to be misdiagnosed, especially in rare sites. It is notable for clinicians to be aware of the presence of intrapiriformis lipoma to avoid misdiagnosis and inappropriate treatment.

Low-Cyclic Reversed Loading Tests on Full-Scale Precast Concrete Composite Wall Connected by Tooth Groove and Grouted Sleeve.

In this paper, a novel precast concrete composite wall connected by tooth groove and grouted sleeve was introduced, which is produced in factories by means of structure-insulation integrated prefabrication, and the prefabrication and assembly process were presented minutely. To verify the feasibility and reliability of this novel tooth groove and grouted sleeve connection method and explore the joint connection performance and the seismic performance of the precast concrete composite wall connected by tooth groove and grouted sleeve, low-cyclic reversed loading tests with an axial compressive ratio of 0.1 were performed on two full-scale precast concrete composite walls. Moreover, the failure mode, hysteretic curve, skeleton curve, stiffness degradation, displacement ductility, energy dissipation capacity, and reinforcement strain were comprehensively discussed. The research results showed that under the vertical axial load and low-cyclic reversed load, the distributed reinforcements in the wall panel only played a structural role, while the connecting reinforcements at horizontal joints can always effectively transfer stress without bond failure, and the tooth groove and grouted sleeve connection performance was reliable. In addition, the hysteretic curves of the precast concrete composite wall connected by tooth groove and grouted sleeve were full, showing good ductile deformation capacity and energy dissipation capacity. In general, the precast concrete composite wall connected by tooth groove and grouted sleeve not only possessed favorable seismic performance but also showed obvious advantages such as green energy saving, high assembly rate, and less on-site wet operation, which can be applied to practical engineering under reasonable design.

Ultrasound-propelled nanomotors for efficient cancer cell ferroptosis.

Ferroptosis is a non-apoptotic form of cell death that is dependent on the accumulation of intracellular iron that causes elevation of toxic lipid peroxides. Therefore, it is crucial to improve the levels of intracellular iron and reactive oxygen species (ROS) in a short time. Here, we first propose ultrasound (US)-propelled Janus nanomotors (Au-FeOx/PEI/ICG, AFPI NMs) to accelerate cellular internalization and induce cancer cell ferroptosis. This nanomotor consists of a gold-iron oxide rod-like Janus nanomotor (Au-FeOx, AF NMs) and a photoactive indocyanine green (ICG) dye on the surface. It not only exhibits accelerating cellular internalization (∼4-fold) caused by its attractive US-driven propulsion but also shows good intracellular motion behavior. In addition, this Janus nanomotor shows excellent intracellular ROS generation performance due to the synergistic effect of the "Fenton or Fenton-like reaction" and the "photochemical reaction". As a result, the killing efficiency of actively moving nanomotors on cancer cells is 88% higher than that of stationary nanomotors. Unlike previous passive strategies, this work is a significant step toward accelerating cellular internalization and inducing cancer-cell ferroptosis in an active way. These novel US-propelled Janus nanomotors with strong propulsion, efficient cellular internalization and excellent ROS generation are suitable as a novel cell biology research tool.

A study on the effect of using the video teach-back method in continuous nursing care of stroke patients.

Objective: To explore the effect of a video teach-back method on continuous family nursing care of stroke patients. Methods: Stroke patients hospitalized in our hospital between March 2020 and March 2023 who met the inclusion criteria were randomly divided into an intervention group (n = 45), who received routine health education plus video teach-back training of caregivers, and a control group (n = 45), who received routine health education only. The effects on nursing-related variables were compared between the two groups. Results: Total scores representing the caring ability of caregivers in the intervention group increased significantly over time relative to baseline and were higher than those of the control group. Scores representing the care burden of caregivers in the intervention group decreased significantly over time and were lower than those of the control group. Conclusion: The teach-back method combined with video education improves the nursing ability of family caregivers and can improve the self-care ability of stroke patients.

Capecitabine or Capecitabine Plus Oxaliplatin Versus Fluorouracil Plus Cisplatin in Definitive Concurrent Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma (CRTCOESC): A Multicenter, Randomized, Open-Label, Phase 3 Trial.

PURPOSE: This phase 3 trial aimed to compare the efficacy and safety of capecitabine or capecitabine plus oxaliplatin (XELOX) with those of fluorouracil plus cisplatin (PF) in definitive concurrent chemoradiotherapy (DCRT) for inoperable locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Patients were randomly assigned to receive two cycles of capecitabine, XELOX, or PF along with concurrent intensity-modulated radiation therapy. Patients in each arm were again randomly assigned to receive two cycles of consolidation chemotherapy or not. The primary end points were 2-year overall survival (OS) rate and incidence of grade ≥3 adverse events (AEs). RESULTS: A total of 246 patients were randomly assigned into the capecitabine (n = 80), XELOX (n = 85), and PF (n = 81) arms. In capecitabine, XELOX, and PF arms, the 2-year OS rate was 75%, 66.7%, and 70.9% (capecitabine v PF: hazard ratio [HR], 0.91 [95% CI, 0.61 to 1.35]; nominal P = .637; XELOX v PF: 0.86 [95% CI, 0.58 to 1.27]; P = .444); the median OS was 40.9 (95% CI, 34.4 to 49.9), 41.9 (95% CI, 28.6 to 52.1), and 35.4 (95% CI, 30.4 to 45.4) months. The incidence of grade ≥3 AEs during the entire treatment was 28.8%, 36.5%, and 45.7%, respectively. Comparing the consolidation chemotherapy with the nonconsolidation chemotherapy groups, the median OS was 41.9 (95% CI, 34.6 to 52.8) versus 36.9 (95% CI, 28.5 to 44) months (HR, 0.71 [95% CI, 0.52 to 0.99]; nominal P = .0403). CONCLUSION: Capecitabine or XELOX did not significantly improve the 2-year OS rate over PF in DCRT for inoperable locally advanced ESCC. Capecitabine showed a lower incidence of grade ≥3 AEs than PF did.

Degradation of Steel Rebar Tensile Properties Affected by Longitudinal Non-Uniform Corrosion.

Rebar corrosion is the primary cause of the durability degradation of reinforced concrete (RC) structures, where non-uniform corrosion is the typical pattern in engineering. This study experimentally and numerically investigated the tensile degradation properties of non-uniform corroded rebars. Corrosion morphology was accurately determined by three-dimensional (3D) laser scanning techniques, studying the characteristics of longitudinal non-uniform corrosion. The results showed that the non-uniformity of corrosion increased with an increase in corrosion levels. From tensile tests, the differences in nominal stress-strain curves among rebars with similar average corrosion levels indicated that corrosion non-uniformity has appreciable effects on the tensile behavior of rebars. The residual load-bearing capacity of corroded rebars was dominated by the reduced critical cross-section, while residual ductility was associated with the cross-section loss throughout the entire length of rebars. The degradation relations of nominal yield and ultimate strength, ultimate strain, and elongation after fracture were better correlated to the maximum cross-section loss than to the average volume loss. Additionally, numerical calculation based on the cross-sectional areas of corroded rebars was conducted to evaluate the tensile behavior of non-uniform corroded rebars. Equivalent distribution models simulating the longitudinal non-uniform corrosion were proposed, on the basis of probability characteristics of cross-sectional areas, for practical application of the numerical method.

Study on Joint Connection Performance of an Innovative Tooth Groove Connection and Vertical Reinforcement Lapping in Reserved Hole.

In order to explore the horizontal joint connection performance of the innovative tooth groove connection and vertical reinforcement lapping in the reserved hole, five horizontal joint specimens were designed and constructed in this paper. Through the combination of monotonic horizontal load tests and finite element simulation analysis, the effects of axial compression ratio, vertical reinforcement connection degree, reserved hole type, mortar strength, and tooth groove depth on the horizontal joint connection performance of innovative tooth groove connections and vertical reinforcement lapping in reserved holes were comprehensively analyzed and discussed. The results indicated that the specimens were subjected to penetration failure at the tooth groove joint, but the vertical reinforcements and UHPC in reserved holes can effectively transfer the stress, ensuring satisfactory connection performance. With the increase in axial compression ratio and vertical reinforcement connection degree, the joint connection performance enhanced gradually, while the reserved hole type had little effect on the joint connection performance. In addition, it was found that increasing the mortar strength and the tooth groove depth can significantly improve the peak bearing capacity through finite element analysis. Finally, the optimization design suggestions for this innovative tooth groove connection and vertical reinforcement lapping in the reserved hole were given considering factors such as joint connection performance and construction assembly.

Structural Response of High-Strength Wire-Reinforced UHPC Slabs Subjected to Bending.

Using high strength wire (HSW) as a longitudinal reinforcement in UHPC can make full use of the outstanding properties of UHPC. In this paper, the flexural test was carried out on normal rebar-reinforced UHPC (NRRU) and HSW reinforced UHPC (HSWRU) slabs. The cracking resistance, failure modes, bearing capacity and deformation characteristics of specimens were investigated. The test results indicated that both HSWRU and NRRU specimens exhibited excellent flexural performance under concentrated loads. Fewer inclined cracks and a slower cracking development process were observed for HSWRU specimens, and brittle failure did not occur during the whole loading process. As compared to HSWRU specimens, the cracking and ultimate load of NRRU specimens increased by 24.64% and 85.47%, respectively, due to a higher reinforcement ratio. Then the theoretical method available for flexural capacity and ductility calculation was proposed, and the feasibility was substantiated through test results. In addition, the traditional deformation ductility coefficient was found to be 30% conservative against the applied energy ductility coefficient. Finally, the extensive parametric analysis revealed that the increase of the reinforcement ratio and the strength of the steel rebar significantly enhanced the ultimate capacity, while the ductility coefficient was obviously weakened. Inversely, those two factors had little impact on the cracking capacity. Moreover, section height was found to be beneficial for both the flexural capacity and ductility of specimens.

Experimental Study on Seismic Behavior of PC Walls with Alveolar-Type Horizontal Joint under Pseudo-Static Loading.

There are many horizontal joints on precast concrete (PC) wall panel structures, which certainly has a significant impact on the seismic behavior of structures. This paper proposes a novel alveolar-type horizontal joint, which has advantages of convenient and rapid assembly. Six precast concrete wall specimens with alveolar-type joints were designed and constructed, and they were weakly connected by spliced rebars anchored into grouted sleeves to meet the requirements of structural performance. The pseudo-static loading tests on these specimens were conducted to investigate the effects of influencing factors, such as the axial compression ratio, the thickness of wall (interface contact area), and the addition of a vertical grouted sleeve connection at the horizontal joint, on the seismic performance of PC walls. Analyses and comparisons were conducted in terms of the cracking propagation pattern, failure modes, force-displacement hysteretic curves, skeleton curves, bearing capacity, ductility factors, and energy dissipation of PC walls. It was concluded that the axial compression ratio and adding grouted sleeve connection had a significant influence on the cracking mode of PC walls, whereas the impact of the wall thickness was slight. The shear capacity and energy dissipation capacity of specimen dramatically enhanced by increasing the axial compression ratio or adding grouted sleeve connection. The PC wall exhibits good ductility after adding the vertical grouted sleeve connection at a horizontal joint. However, the ductility factor increases firstly and then decreases in the enhancement of the axial compression ratio. The reduction in wall thickness has remarkable impacts on the shear strength and energy dissipation capacity of specimens, but the influences on ductility were not significant. The prediction method for calculating the shear capacity of PC walls with alveolar-type horizontal joints was proposed based on the experimental data, and these calculated results are in good agreement with the experimental results.

Preliminary study of sound touch elastography in diffuse thyroid disease in children.

Objective: The purpose of this study was to evaluate the use of sound touch elastography (STE) in conjunction with conventional ultrasound in the differential diagnosis of diffuse thyroid disease (DTD) and normal thyroid in children. Methods: Studies performed on 62 children with DTD and 30 normal volunteers were reviewed. Standard gray scale ultrasound, Doppler ultrasound and STE of the examinees, and the serum test results of children with DTD were collected, analyzed and compared. Results: The STE-Mean values in the Graves' disease (GD) group, Hashimoto's thyroiditis (HT) group, and normal control group, respectively, were 19.35 ± 5.00 kPa, 19.43 ± 6.06 kPa, and 11.24 ± 1.99 kPa. With an area under the ROC curve (AUC) of 0.945, STE-Mean values differentiated DTD from normal children. The peak systolic velocity (PSV) of the superior thyroid artery separated DTD from normal children and AUC from children with GD and HT, respectively, and was 0.992 and 0.864. The PSV of superior thyroid artery revealed a somewhat favorable connection with FT3 and FT4. Conclusion: The STE results revealed that thyroid stiffness was higher in children with DTD than in normal children, but further differentiation into GD and HT subgroups lacked specificity, and the superior thyroid artery flow velocity might be a good supplement to distinguish both.

A phase I study of FCN-411, a pan-HER inhibitor, in EGFR-mutated advanced NSCLC after progression on EGFR tyrosine kinase inhibitors.

BACKGROUND: There are no approved epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for EGFR-mutated non-small cell lung cancer (NSCLC) without EGFR T790M mutation after progression on first- or second-generation EGFR-TKIs. METHODS: We conducted this phase I, open-label, multicenter, dose-escalation/dose-expansion study to evaluate the safety, tolerability, antitumor activity, and pharmacokinetics of FCN-411, a TKI targeting EGFR, HER2, and HER4, in patients with EGFR-mutated advanced NSCLC whose disease had progressed during treatment of EGFR-TKIs. Adult patients with stage IIIB-IV NSCLC harboring EGFR mutations (exon 18/19/20/21) who had progressed on prior EGFR-TKIs were enrolled. In the dose-escalation phase, patients received 4 mg, 8 mg, 12 mg, and 16 mg FCN-411 once daily until the maximum tolerated dose (MTD). In the dose-expansion phase, patients received FCN-411 at the recommended phase II dose (RP2D) continuously in 21-day cycles. The primary endpoints were safety, tolerability, MTD, and RP2D. RESULTS: From July 23, 2018 to September 29, 2020, 77 patients were enrolled, including 30 with EGFR T790M mutation in tumor tissues. The cut-off date was February 1, 2021. No dose-limiting toxicities were observed. The most common grade ≥ 3 treatment-emergent adverse events among all patients were diarrhea (8; 10.4%) and dermatitis acneiform (7; 9.1%). Ten of 67 evaluable patients achieved confirmed partial response, with an objective response rate (ORR) of 14.9% (95% confidence interval [CI], 8.3-24.0); the ORR was 33.3%, 14.0%, 0, and 25.0% at 4 mg, 8 mg, 12 mg, and 16 mg, respectively. Besides, the ORR in patients without and with EGFR T790M mutation was 20.5% and 7.4%, respectively. Moreover, 39 patients achieved stable disease across all doses, and the disease control rate was 73.1% (95% CI, 60.9-83.2). Median progression-free survival was 4.1 (95% CI, 2.9-5.3) months. Median duration of response and overall survival have not been reached. CONCLUSIONS: FCN-411 was well tolerated and demonstrated preliminary antitumor activity in patients with EGFR-mutated NSCLC after progression on EGFR-TKIs, especially in those without EGFR T790M mutation. The RP2D was defined as 8 mg once daily. Future studies are warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03420079.

Pan-Cancer Analysis Reveals the Signature of TMC Family of Genes as a Promising Biomarker for Prognosis and Immunotherapeutic Response.

Transmembrane Channel-like (TMC) genes are critical in the carcinogenesis, proliferation, and cell cycle of human cancers. However, the multi-omics features of TMCs and their role in the prognosis and immunotherapeutic response of human cancer have not been explored. We discovered that TMCs 4-8 were commonly deregulated and correlated with patient survival in a variety of cancers. For example, TMC5 and TMC8 were correlated with the relapse and overall survival rates of breast cancer and skin melanoma, respectively. These results were validated by multiple independent cohorts. TMCs were regulated by DNA methylation and somatic alterations, such as TMC5 amplification in breast cancer (523/1062, 49.2%). Six algorithms concordantly uncovered the critical role of TMCs in the tumor microenvironment, potentially regulating immune cell toxicity and lymphocytes infiltration. Moreover, TMCs 4-8 were correlated with tumor mutation burden and expression of PD-1/PD-L1/CTLA4 in 33 cancers. Thus, we established an immunotherapy response prediction (IRP) score based on the signature of TMCs 4-8. Patients with higher IRP scores showed higher immunotherapeutic responses in five cohorts of skin melanoma (area under curve [AUC] = 0.90 in the training cohort, AUCs range from 0.70 to 0.83 in the validation cohorts). Together, our study highlights the great potential of TMCs as biomarkers for prognosis and immunotherapeutic response, which can pave the way for further investigation of the tumor-infiltrating mechanisms and therapeutic potentials of TMCs in cancer.