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Machine learning identifies the risk of complications after laparoscopic radical gastrectomy for gastric cancer.
Hong, QQ, Yan, S, Zhao, YL, Fan, L, Yang, L, Zhang, WB, Liu, H, Lin, HX, Zhang, J, Ye, ZJ, et al
World journal of gastroenterology. 2024;(1):79-90
Abstract
BACKGROUND Laparoscopic radical gastrectomy is widely used, and perioperative complications have become a highly concerned issue. AIM: To develop a predictive model for complications in laparoscopic radical gastrectomy for gastric cancer to better predict the likelihood of complications in gastric cancer patients within 30 days after surgery, guide perioperative treatment strategies for gastric cancer patients, and prevent serious complications. METHODS In total, 998 patients who underwent laparoscopic radical gastrectomy for gastric cancer at 16 Chinese medical centers were included in the training group for the complication model, and 398 patients were included in the validation group. The clinicopathological data and 30-d postoperative complications of gastric cancer patients were collected. Three machine learning methods, lasso regression, random forest, and artificial neural networks, were used to construct postoperative complication prediction models for laparoscopic distal gastrectomy and laparoscopic total gastrectomy, and their prediction efficacy and accuracy were evaluated. RESULTS The constructed complication model, particularly the random forest model, could better predict serious complications in gastric cancer patients undergoing laparoscopic radical gastrectomy. It exhibited stable performance in external validation and is worthy of further promotion in more centers. CONCLUSION Using the risk factors identified in multicenter datasets, highly sensitive risk prediction models for complications following laparoscopic radical gastrectomy were established. We hope to facilitate the diagnosis and treatment of preoperative and postoperative decision-making by using these models.
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Bone Biomarkers and Subsequent Survival in Men with Hormone-sensitive Prostate Cancer: Results from the SWOG S1216 Phase 3 Trial of Androgen Deprivation Therapy with or Without Orteronel.
Lara, PN, Mayerson, E, Gertz, E, Tangen, C, Goldkorn, A, van Loan, M, Hussain, M, Gupta, S, Zhang, J, Parikh, M, et al
European urology. 2024;(2):171-176
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BACKGROUND Bone biomarkers are strongly prognostic for overall survival (OS) in men with castration-resistant prostate cancer but not fully established for hormone-sensitive prostate cancer (HSPC). OBJECTIVE Bone biomarkers in HSPC were prospectively evaluated as part of a phase 3 study of androgen deprivation therapy ± the CYP17 inhibitor orteronel. DESIGN, SETTING, AND PARTICIPANTS Patients were randomly divided into training (n = 316) and validation (n = 633) sets. Recursive partitioning and Cox proportional hazard models were employed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Bone resorption (C-telopeptide and pyridinoline) and bone formation markers (C-terminal collagen propeptide and bone alkaline phosphatase) were assessed from patient sera. RESULTS AND LIMITATIONS Of 1279 men, 949 had evaluable baseline bone biomarkers. Optimal cutoffs were identified to define elevated levels of each of the four biomarkers (all p < 0.05) that were associated with worse OS. After adjusting for clinical risk factors in the validation set, elevated bone biomarkers were statistically significantly associated with an increased risk of death (hazard ratios ranging from 1.37 to 1.92). Recursive partitioning algorithms applied to the training set identified three risk groups (low, intermediate, and poor) with differential OS outcomes (median OS: 8.2, 5.1, and 2.1 yr, respectively) based on combinations of bone biomarkers. These results were confirmed in the validation set. CONCLUSIONS In men with HSPC initiating androgen deprivation therapy, bone biomarkers are strongly and independently prognostic for OS. Bone biomarker levels alone or in combination with clinical covariates identify unique subsets of men with differential OS outcomes. These results validate the clinical value of bone biomarker assessment in the HSPC state, extending bone biomarker utility beyond the castration-resistant state. PATIENT SUMMARY In men with newly diagnosed metastatic prostate cancer, high levels of bone turnover biomarkers are associated with a shorter lifespan.
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Activity of Anlotinib in the Second-Line Therapy of Metastatic Gastrointestinal Stromal Tumors: A Prospective, Multicenter, In Vitro Study.
Zhou, Y, Zeng, C, Sun, X, Zhang, J, Qu, H, Zhang, X, Zhou, Y, Liu, Z, Wu, X, Wu, X, et al
The oncologist. 2023;(4):e191-e197
Abstract
BACKGROUND Anlotinib is a multi-target tyrosine kinase inhibitor that can effectively inhibit tumor cell proliferation after receptor kinase activation caused by KIT gene mutation. METHODS We tested the inhibitory effect of anlotinib in GIST cell lines with different gene mutations and evaluated the efficacy of anlotinib for patients with metastatic GIST after imatinib failure in a multicenter, single-arm, phase II study. RESULTS In vitro, V654A mutation encoded by KIT exon 13 was intermediately sensitive to anlotinib. Moreover, anlotinib was able to partly suppress the activation loop mutation D820A from exon 17 while another activation loop mutation N822K, also from exon 17, was resistant to anlotinib. From September 2018 to October 2020, 64 patients from 9 Chinese medical centers were enrolled in this study. Seven patients had partial response and 39 patients had stable disease. The median PFS was 8.0 months. There was no statistical significance comparing with PFS of sunitinib second-line therapy at the same period. The most common adverse events related to anlotinib treatment were hypertension, neutropenia, and fatigue. CONCLUSION Anlotinib showed moderate antitumor activity in drug-resistant GIST cell lines in vitro, and good PFS and better tolerance in second-line therapy study.
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Multi-omics analysis uncovers tumor ecosystem dynamics during neoadjuvant toripalimab plus nab-paclitaxel and S-1 for esophageal squamous cell carcinoma: a single-center, open-label, single-arm phase 2 trial.
Zhang, G, Yuan, J, Pan, C, Xu, Q, Cui, X, Zhang, J, Liu, M, Song, Z, Wu, L, Wu, D, et al
EBioMedicine. 2023;:104515
Abstract
BACKGROUND Immune checkpoint inhibitors combined with chemotherapy as a neoadjuvant therapy have been applied to the treatment of esophageal squamous cell carcinoma (ESCC). However, the optimal regimen needs to be further explored, particularly for older patients, and the mechanisms by which the immune checkpoint inhibitor combined with chemotherapy modulates the evolution of ESCC are unknown. METHODS In this single-arm phase 2 trial, patients with resectable (stage II/III/IV without metastasis) ESCC were enrolled and received nanoparticle albumin-bound (nab) paclitaxel for two cycles and oral S-1 for 2 weeks, combined with intravenous toripalimab for two cycles before surgery. Combination postoperative adjuvant therapy was administered. The primary outcome was the major pathological response (MPR). Secondary outcomes included pathological complete response (pCR), overall response rate (ORR), disease control rate (DCR), disease-free survival (DFS), overall survival (OS), improvement in Stooler's dysphagia score and degree of daily living ability (dADL). Biopsies and plasma pre- and post-neoadjuvant therapy were performed using whole-exome sequencing, transcriptome sequencing, immunohistochemistry (IHC) for PD-L1, multiplex immunofluorescence (mIF) and proximity extension assay technology (PEA) for 92 proteins. FINDINGS From November 2019 to July 2021, 60 patients were enrolled. After neoadjuvant therapy, R0 resection was achieved in 55 (98.21%) patients. MPR was identified in 27 patients (49.09%), and 16 patients (29.09%) achieved pCR. Patients with PR, SD and PD were 37 (61.67%), 21 (35.00%) and 2 (3.33%), respectively. The overall staging, Stooler dysphagia scores and dADL were significantly decreased after treatment. 11 patients (18.3%) experienced grade ≥3 AEs. Compared to PD-L1-Low patients, PD-L1-High patients had a significantly higher ratio of PR. During therapy, the tumor mutation burden (TMB) and tumor neoantigen burden (TNB) were significantly decreased in patients with PR. Differential clonal evolution within tumors was demonstrated by analysis of intratumoral heterogeneity. Transcriptome analyses revealed that the infiltration of CD4+ T lymphocytes at baseline was associated with clinical outcome. During therapy, CD8+ T cells and CD4+ T cells were increased in all patients; however, exhausted cells, nTregs and iTregs were significantly increased in patients with non-MPR. Protein analyses revealed that the levels of IFN-γ, Gal.1 and LAMP3 can predict the clinical benefit. In addition, the expression of CD83, TNFRSF4, TNFSF14, VEGFR2, ADA, ARG1, and HO-1 was associated with serious AEs. More importantly, the integration of CD4+ T cells with plasma protein of IFN-γ, Gal.1 or LAMP3 could further distinguish responders from non-responders. INTERPRETATION In this study, neoadjuvant therapy with toripalimab, nab-paclitaxel and S-1 was less toxic and showed promising antitumor activity in patients with resectable ESCC. Changes in the genome, transcriptome, PD-L1 expression and serum proteins were comprehensively analyzed and correlated with clinical outcomes, which provides insight into the mechanism of action of toripalimab combined with nab-paclitaxel and S-1 in patients with ESCC. FUNDING This study was funded by Major projects of the ministry of science and technology of the 13th five-year plan of China [grant number: 2018ZX09201013].
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Safety, Tolerability and Pharmacokinetics of Single and Multiple Doses of Mirogabalin in Healthy Chinese Participants: A Randomized, Double-Blind, Placebo-Controlled Study.
Li, Y, Toyama, K, Nakatsu, T, Ishizuka, H, Wu, H, Cao, G, Yu, J, Wang, Y, Liu, X, Guo, B, et al
Advances in therapy. 2023;(4):1628-1643
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INTRODUCTION Mirogabalin is a treatment option for patients with neuropathic pain; however, safety, tolerability, and pharmacokinetics (PK) data specifically for Chinese individuals are limited to a single-dose study. We aimed to assess these for both single- and multiple-dose mirogabalin in healthy Chinese participants. METHODS In this randomized, double-blind, placebo-controlled, phase I study, 54 healthy Chinese men and women aged 18-45 years were randomly allocated to receive single- (5, 10, or 15 mg, daily) or multiple-dose (5 mg titrated to 15 mg, twice-daily, over 22 days) oral mirogabalin or placebo. In each of three single-dose groups, 10 participants received mirogabalin and 2 received placebo; in the multiple-dose group, 14 participants received mirogabalin and 4 received placebo. The primary endpoints were PK, safety, and tolerability variables, including treatment-emergent adverse events (TEAEs), laboratory tests, and vital signs. PK data were collected for both single- and multiple-dose cohorts and evaluated by non-compartmental analysis. RESULTS Single- and multiple-dose mirogabalin was generally well tolerated with no deaths, serious TEAEs, or TEAEs leading to treatment discontinuation. Frequently reported TEAEs included dizziness, nystagmus, increased blood triglycerides, headache, and increased blood uric acid and creatine phosphokinase. Single-dose mirogabalin was rapidly absorbed (median time to maximum plasma concentration, 1.00 h) and eliminated (mean terminal elimination half-life, 2.57-3.08 h). The exposure was approximately dose-proportional. In the multiple-dose cohort, the trough plasma concentration increased dose-proportionally, and exposure and clearance were comparable to that following a single 15-mg dose. The mean cumulative amount excreted into urine up to 48 h post-dose increased in a dose-proportional manner, the mean cumulative percentage excreted into urine was 61.9%-74.3%, and renal clearance remained relatively constant. CONCLUSION Consistent with previous phase I studies in other populations, mirogabalin was safe and well tolerated in healthy Chinese participants at single and multiple doses of up to 15 mg twice-daily.
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Fibroblast Activation Protein-Targeted Radioligand Therapy with 177Lu-EB-FAPI for Metastatic Radioiodine-Refractory Thyroid Cancer: First-in-Human, Dose-Escalation Study.
Fu, H, Huang, J, Zhao, T, Wang, H, Chen, Y, Xu, W, Pang, Y, Guo, W, Sun, L, Wu, H, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023;(23):4740-4750
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PURPOSE Fibroblast activation protein (FAP) is a promising target for tumor treatment. In this study, we aimed to investigate the safety and efficacy of the albumin binder-conjugated FAP-targeted radiopharmaceutical, 177Lu-EB-FAPI (177Lu-LNC1004), in patients with metastatic radioiodine-refractory thyroid cancer (mRAIR-TC). PATIENTS AND METHODS This open-label, non-randomized, first-in-human, dose-escalation, investigator-initiated trial had a 3+3 design and involved a 6-week 177Lu-LNC1004 treatment cycle in patients with mRAIR-TC at 2.22 GBq initially, with subsequent cohorts receiving an incremental 50% dose increase until dose-limiting toxicity (DLT) was observed. RESULTS 177Lu-LNC1004 administration was well tolerated, with no life-threatening adverse events observed. No patients experienced DLT in Group A (2.22 GBq/cycle). One patient experienced grade 4 thrombocytopenia in Group B (3.33 GBq/cycle); hence, another three patients were enrolled, none of whom experienced DLT. Two patients experienced grade 3 and 4 hematotoxicity in Group C (4.99 GBq/cycle). The mean whole-body effective dose was 0.17 ± 0.04 mSv/MBq. Intense 177Lu-LNC1004 uptake and prolonged tumor retention resulted in high mean absorbed tumor doses (8.50 ± 12.36 Gy/GBq). The mean effective half-lives for the whole-body and tumor lesions were 90.20 ± 7.68 and 92.46 ± 9.66 hours, respectively. According to RECIST, partial response, stable disease, and progressive disease were observed in 3 (25%), 7 (58%), and 2 (17%) patients, respectively. The objective response and disease control rates were 25% and 83%, respectively. CONCLUSIONS FAP-targeted radioligand therapy with 177Lu-LNC1004 at 3.33 GBq/cycle was well tolerated in patients with advanced mRAIR-TC, with high radiation dose delivery to the tumor lesions, encouraging therapeutic efficacy, and acceptable side effects.
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Auxora vs. placebo for the treatment of patients with severe COVID-19 pneumonia: a randomized-controlled clinical trial.
Bruen, C, Al-Saadi, M, Michelson, EA, Tanios, M, Mendoza-Ayala, R, Miller, J, Zhang, J, Stauderman, K, Hebbar, S, Hou, PC
Critical care (London, England). 2022;(1):101
Abstract
BACKGROUND Calcium release-activated calcium (CRAC) channel inhibitors block proinflammatory cytokine release, preserve endothelial integrity and may effectively treat patients with severe COVID-19 pneumonia. METHODS CARDEA was a phase 2, randomized, double-blind, placebo-controlled trial evaluating the addition of Auxora, a CRAC channel inhibitor, to corticosteroids and standard of care in adults with severe COVID-19 pneumonia. Eligible patients were adults with ≥ 1 symptom consistent with COVID-19 infection, a diagnosis of COVID-19 confirmed by laboratory testing using polymerase chain reaction or other assay, and pneumonia documented by chest imaging. Patients were also required to be receiving oxygen therapy using either a high flow or low flow nasal cannula at the time of enrolment and have at the time of enrollment a baseline imputed PaO2/FiO2 ratio > 75 and ≤ 300. The PaO2/FiO2 was imputed from a SpO2/FiO2 determine by pulse oximetry using a non-linear equation. Patients could not be receiving either non-invasive or invasive mechanical ventilation at the time of enrolment. The primary endpoint was time to recovery through Day 60, with secondary endpoints of all-cause mortality at Day 60 and Day 30. Due to declining rates of COVID-19 hospitalizations and utilization of standard of care medications prohibited by regulatory guidance, the trial was stopped early. RESULTS The pre-specified efficacy set consisted of the 261 patients with a baseline imputed PaO2/FiO2≤ 200 with 130 and 131 in the Auxora and placebo groups, respectively. Time to recovery was 7 vs. 10 days (P = 0.0979) for patients who received Auxora vs. placebo, respectively. The all-cause mortality rate at Day 60 was 13.8% with Auxora vs. 20.6% with placebo (P = 0.1449); Day 30 all-cause mortality was 7.7% and 17.6%, respectively (P = 0.0165). Similar trends were noted in all randomized patients, patients on high flow nasal cannula at baseline or those with a baseline imputed PaO2/FiO2 ≤ 100. Serious adverse events (SAEs) were less frequent in patients treated with Auxora vs. placebo and occurred in 34 patients (24.1%) receiving Auxora and 49 (35.0%) receiving placebo (P = 0.0616). The most common SAEs were respiratory failure, acute respiratory distress syndrome, and pneumonia. CONCLUSIONS Auxora was safe and well tolerated with strong signals in both time to recovery and all-cause mortality through Day 60 in patients with severe COVID-19 pneumonia. Further studies of Auxora in patients with severe COVID-19 pneumonia are warranted. Trial registration NCT04345614.
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Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial.
Motzer, RJ, Powles, T, Burotto, M, Escudier, B, Bourlon, MT, Shah, AY, Suárez, C, Hamzaj, A, Porta, C, Hocking, CM, et al
The Lancet. Oncology. 2022;(7):888-898
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BACKGROUND In the primary analysis of CheckMate 9ER, nivolumab plus cabozantinib showed superior progression-free survival, overall survival, and objective response over sunitinib in patients with previously untreated advanced renal cell carcinoma (median follow-up of 18·1 months). Here, we report extended follow-up of overall survival and updated efficacy and safety. METHODS This open-label, randomised, phase 3 trial was done in 125 hospitals and cancer centres across 18 countries. We included patients aged 18 years or older with previously untreated advanced or metastatic clear-cell renal cell carcinoma, a Karnofsky performance status of 70% or higher, measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by the investigator, any International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk category, and available tumour tissue for PD-L1 testing. Patients were randomly assigned (1:1) to nivolumab (240 mg) intravenously every 2 weeks plus cabozantinib (40 mg) orally once daily or sunitinib (50 mg orally) once daily (4 weeks per 6-week cycle). Randomisation, stratified by IMDC risk status, tumour PD-L1 expression, and geographical region, was done by permuted block within each stratum using a block size of four, via an interactive response system. The primary endpoint was progression-free survival by blinded independent central review. Overall survival was a secondary endpoint (reported here as the preplanned final analysis according to the protocol). Efficacy was assessed in all randomly assigned patients; safety was assessed in all patients who received at least one dose of any study drug. This ongoing study, closed to recruitment, is registered with ClinicalTrials.gov, NCT03141177. FINDINGS Between Sept 11, 2017, and May 14, 2019, 323 patients were randomly assigned to the nivolumab plus cabozantinib group and 328 to the sunitinib group. With an extended follow-up (data cutoff of June 24, 2021; median 32·9 months [IQR 30·4-35·9]), median overall survival was 37·7 months (95% CI 35·5-not estimable) in the nivolumab plus cabozantinib group and 34·3 months (29·0-not estimable) in the sunitinib group (hazard ratio [HR] 0·70 [95% CI 0·55-0·90], p=0·0043) and updated median progression-free survival was 16·6 months (12·8-19·8) versus 8·3 months (7·0-9·7; HR 0·56 [95% CI 0·46-0·68], p<0·0001). Grade 3-4 treatment-related adverse events occurred in 208 (65%) of 320 patients with nivolumab plus cabozantinib versus 172 (54%) of 320 with sunitinib. The most common grade 3-4 treatment-related adverse events were hypertension (40 [13%] of 320 patients in the nivolumab plus cabozantinib group vs 39 [12%] of 320 in the sunitinib group), palmar-plantar erythrodysaesthesia (25 [8%] vs 26 [8%]), and diarrhoea (22 [7%] vs 15 [5%]). Grade 3-4 treatment-related serious adverse events occurred in 70 (22%) of 320 patients in the nivolumab plus cabozantinib group and 31 (10%) of 320 in the cabozantinib group. One additional treatment-related death occurred with sunitinib (sudden death). INTERPRETATION With extended follow-up and preplanned final overall survival analysis per protocol, nivolumab plus cabozantinib demonstrated improved efficacy versus sunitinib, further supporting the combination in the first-line treatment of advanced renal cell carcinoma. FUNDING Bristol Myers Squibb and Ono Pharmaceutical.
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Paroxysmal slow wave events are associated with cognitive impairment in patients with obstructive sleep apnea.
Li, M, Sun, Z, Sun, H, Zhao, G, Leng, B, Shen, T, Xue, S, Hou, H, Li, Z, Zhang, J
Alzheimer's research & therapy. 2022;14(1):200
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Obstructive sleep apnoea (OSA) is a disorder which results in an individual’s breathing being cut off momentarily whilst asleep. OSA has been associated with the development of cognitive impairment, which is characterised by declining memory. The reason for the link is thought to involve a dysfunction in the blood brain barrier, which can be measured by paroxysmal slow wave events (PSWEs). This study of 339 individuals with complaints of snoring aimed to determine the correlation between PSWEs and cognitive impairment. The results showed that cognitive impairment in individuals with OSA due to a lack of oxygen could be due to a dysfunction in the blood brain barrier and that PSWEs are a reliable measure of this. It was concluded that PSWEs can be used as a measure of cognitive impairment in patients with OSA and that brain barrier dysfunction may be involved in its development in this subset of individuals. This study could be used by healthcare professionals to understand that sleep apnoea is more than just snoring, it can be involved in the development of certain chronic diseases.
Abstract
BACKGROUND Increasing evidence has supported a link between obstructive sleep apnea (OSA) and cognition, and blood-brain barrier (BBB) dysfunction which can be reflected by paroxysmal slow wave events (PSWEs) may be a potential mechanism. The purpose of our study was to investigate the correlation between the PSWEs and cognitive impairment in patients with OSA, with a focus on the possible mechanism. METHODS In total, 339 subjects with subjective snoring complaints from the Sleep Medicine Center underwent magnetic resonance imaging and whole-night polysomnography. OSA was defined as apnea-hypopnea index (AHI) ≥ 5 events/h. MCI was defined as the MoCA < 26 and met the criteria: (1) subjective cognitive impairment; (2) objective impairment in one or more cognitive domains; (3) slightly impaired complex instrumental daily abilities, but independent daily living abilities; and (4) no dementia. The PSWEs calculated by self-developed Python scripts were defined for EEG recordings as a median power frequency of < 6 Hz for more than five consecutive seconds. Serum cyclophilin A (CyPA) and matrix metalloproteinase-9 (MMP-9) levels and amyloid-β 42 levels in neuron-derived exosomes were determined. The participants who received continuous positive airway pressure (CPAP) were followed up and their PSWEs were recalculated after 1 year of treatment. RESULTS A total of 339 participants were divided into the OSA+MCI group (n = 157), OSA-MCI group (n = 118), and controls (normal cognitive state without OSA) (n = 64). The total PSWEs and the occurrence per minute of PSWEs at stage REM in the OSA+MCI group were higher than those in the OSA-MCI and control groups. The duration ratio of PSWEs at stage REM in the OSA+MCI group significantly increased. The total PSWEs and PSWEs at the F4-M1, O1-M2, and O2-M1 channels in stage REM were independently associated with cognitive impairment in OSA patients. There were positive correlations between the PSWEs and serum CyPA and MMP-9 levels in patients with OSA. The mediation analysis showed that the relationship between mean SaO2 and percentage of sleep time spent with oxygen saturation <90% with MoCA scores was mediated by the total PSWEs (proportion of mediation 77.89% and 82.89%). The PSWEs were negatively correlated with global cognitive performance and cognitive subdomains. After 1 year of CPAP treatment, the total PSWEs, PSWEs in stage REM, and serum CyPA and MMP-9 levels decreased significantly, and MoCA scores were improved compared with baseline. CONCLUSIONS The PSWEs were implicated in cognitive impairment in patients with OSA, and the mechanisms of cognitive impairment due to hypoxia in OSA patients could be BBB dysfunction. The PSWEs can be used as a marker of cognitive impairment in patients with OSA. TRIAL REGISTRATION This trial is registered on the Chinese Clinical Trial Registry, number ChiCTR1900021544. The trial was registered on February 27, 2019.
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Pharmacological ascorbate improves the response to platinum-based chemotherapy in advanced stage non-small cell lung cancer.
Furqan, M, Abu-Hejleh, T, Stephens, LM, Hartwig, SM, Mott, SL, Pulliam, CF, Petronek, M, Henrich, JB, Fath, MA, Houtman, JC, et al
Redox biology. 2022;:102318
Abstract
PURPOSE Platinum-based chemotherapy with or without immunotherapy is the mainstay of treatment for advanced stage non-small cell lung cancer (NSCLC) lacking a molecular driver alteration. Pre-clinical studies have reported that pharmacological ascorbate (P-AscH-) enhances NSCLC response to platinum-based therapy. We conducted a phase II clinical trial combining P-AscH- with carboplatin-paclitaxel chemotherapy. EXPERIMENTAL DESIGN Chemotherapy naïve advanced stage NSCLC patients received 75 g ascorbate twice per week intravenously with carboplatin and paclitaxel every three weeks for four cycles. The primary endpoint was to improve tumor response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 compared to the historical control of 20%. The trial was conducted as an optimal Simon's two-stage design. Blood samples were collected for exploratory analyses. RESULTS The study enrolled 38 patients and met its primary endpoint with an objective response rate of 34.2% (p = 0.03). All were confirmed partial responses (cPR). The disease control rate was 84.2% (stable disease + cPR). Median progression-free and overall survival were 5.7 months and 12.8 months, respectively. Treatment-related adverse events (TRAE) included one grade 5 (neutropenic fever) and five grade 4 events (cytopenias). Cytokine and chemokine data suggest that the combination elicits an immune response. Immunophenotyping of peripheral blood mononuclear cells demonstrated an increase in effector CD8 T-cells in patients with a progression-free survival (PFS) ≥ 6 months. CONCLUSIONS The addition of P-AscH- to platinum-based chemotherapy improved tumor response in advanced stage NSCLC. P-AscH- appears to alter the host immune response and needs further investigation as a potential adjuvant to immunotherapy.