Anlotinib plus icotinib as a potential treatment option for EGFR-mutated advanced non-squamous non-small cell lung cancer with concurrent mutations: final analysis of the prospective phase 2, multicenter ALTER-L004 study.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation and concurrent mutations have a poor prognosis. This study aimed to examine anlotinib plus icotinib as a first-line treatment option for advanced NSCLC carrying EGFR mutation with or without concurrent mutations. METHODS: This phase 2, single-arm, multicenter trial (ClinicalTrials.gov NCT03736837) was performed at five hospitals in China from December 2018 to November 2020. Non-squamous NSCLC cases with EGFR-sensitizing mutations were treated with anlotinib and icotinib. The primary endpoint was progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. RESULTS: Sixty participants were enrolled, including 31 (52%) and 29 (48%) with concurrent mutations and pathogenic concurrent mutations, respectively. The median follow-up was 26.9 (range, 15.0-38.9) months. ORR and DCR were 68.5% and 98.2%, respectively. Median PFS was 15.1 (95%CI: 12.6-17.6) months which met the primary endpoint, median DoR was 13.5 (95%CI: 10.0-17.1) months, and median OS was 30.0 (95%CI: 25.5-34.5) months. Median PFS and OS in patients with pathogenic concurrent mutations were 15.6 (95%CI: 12.5-18.7) months and not reached (95%CI: 17.46 months to not reached), respectively. All patients experienced TRAEs, including 26 (43%) and 1 (1.7%) who had grade ≥ 3 and serious treatment-related adverse events (TRAEs). CONCLUSIONS: Anlotinib combined with icotinib was effective and well-tolerated as a first-line treatment option for EGFR mutation-positive advanced NSCLC with or without concurrent mutations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03736837.

[18F]FDG PET/MRI combined with chest HRCT in early cancer detection: a retrospective study of 3020 asymptomatic subjects.

PURPOSE: PET/MRI has become an important medical imaging approach in clinical practice. In this study, we retrospectively investigated the detectability of fluorine-18 (18F)-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging ([18F]FDG PET/MRI) combined with chest computerized tomography (CT) for early cancer in a large cohort of asymptomatic subjects. METHODS: This study included a total of 3020 asymptomatic subjects who underwent whole-body [18F]FDG PET/MRI and chest HRCT examinations. All subjects received a 2-4-year follow-up for cancer development. Cancer detection rate, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the [18F]FDG PET/MRI with or without chest HRCT were calculated and analyzed. RESULTS: Sixty-one subjects were pathologically diagnosed with cancers, among which 59 were correctly detected by [18F]FDG PET/MRI combined with chest HRCT. Of the 59 patients (32 with lung cancer, 9 with breast cancer, 6 with thyroid cancer, 5 with colon cancer, 3 with renal cancer, 1 with prostate cancer, 1 with gastric cancer, 1 with endometrial cancer, and 1 with lymphoma), 54 (91.5%) were at stage 0 or stage I (according to the 8th edition of the tumor-node-metastasis [TNM] staging system), 33 (55.9%) were detected by PET/MRI alone (27 with non-lung cancers and 6 with lung cancer). Cancer detection rate, sensitivity, specificity, PPV, and NPV for PET/MRI combined with chest CT were 2.0%, 96.7%, 99.6%, 83.1%, and 99.9%, respectively. For PET/MRI alone, the metrics were 1.1%, 54.1%, 99.6%, 73.3%, and 99.1%, respectively, and for PET/MRI in non-lung cancers, the metrics were 0.9%, 93.1%, 99.6%, 69.2%, and 99.9%, respectively. CONCLUSIONS: [18F]FDG PET/MRI holds great promise for the early detection of non-lung cancers, while it seems insufficient for detecting early-stage lung cancers. Chest HRCT can be complementary to whole-body PET/MRI for early cancer detection. TRIAL REGISTRATION: ChiCTR2200060041. Registered 16 May 2022. Public site: https://www.chictr.org.cn/index.html.

Effect of intraoperative remimazolam on postoperative sleep quality in elderly patients after total joint arthroplasty: a randomized control trial.

PURPOSE: To investigate the effect of intraoperative remimazolam sedation on postoperative sleep quality in elderly patients after total joint arthroplasty. METHODS: Between May 15, 2021 and March 26, 2022, 108 elderly patients (age ≥ 65 years) who received total joint arthroplasty under neuraxial anesthesia were randomized into remimazolam group (a loading dose of 0.025-0.1 mg/kg and followed by an infusion rate of 0.1-1.0 mg/kg/h till end of surgery) or routine group (sedation was given on patient's requirement by dexmedetomidine 0.2-0.7 µg/kg/h). Primary outcome was the subjective sleep quality at surgery night which was evaluated by Richards Campbell Sleep Questionnaire (RCSQ). Secondary outcomes included RCSQ scores at postoperative first and second nights and numeric rating scale pain intensity within first 3 days after surgery. RESULTS: RCSQ score at surgery night was 59 (28, 75) in remimazolam group which was comparable with 53 (28, 67) in routine group (median difference 6, 95% CI - 6 to 16, P = 0.315). After adjustment of confounders, preoperative high Pittsburg sleep quality index was associated worse RCSQ score (P = 0.032), but not remimazolam (P = 0.754). RCSQ score at postoperative first night [69 (56, 85) vs. 70 (54, 80), P = 0.472] and second night [80 (68, 87) vs. 76 (64, 84), P = 0.066] were equivalent between two groups. Safety outcomes were comparable between the two groups. CONCLUSIONS: Intraoperative remimazolam did not significantly improve postoperative sleep quality in elderly patients undergoing total joint arthroplasty. But it is proved to be effective and safe for moderate sedation in these patients. CLINICAL TRIAL NUMBER AND REGISTRY URL: ChiCTR2000041286 ( www.chictr.org.cn ).

Poor response to selpercatinib plus crizotinib in a rearranged during transfection fusion-positive patient with acquired selpercatinib-resistant MNNG HOS transforming amplification: a case report.

Selpercatinib has been approved by most major regulatory bodies in 2020 and become the standard therapy for rearranged during transfection ( RET )-rearranged nonsmall-cell lung cancer (NSCLC). Knowledge is limited regarding mechanisms of resistance to selpercatinib and effective treatment. One study identified MNNG HOS transforming ( MET ) amplification as intrinsic or secondary resistance mechanism from four patients, and three of them showed ~40% tumor reduction when treated with selpercatinib plus crizotinib. We report a 30-year-old female nonsmoker diagnosed in 2019 with stage IV lung adenocarcinoma harboring KIF5B-RET and a novel FOXD1-RET fusion. Frontline therapy consisted of bevacizumab combined with pemetrexed and carboplatin and achieved a progression-free survival (PFS) of 14 months with best response of stable disease. The patient then enrolled in the LIBRETTO-321 trial (NCT03157129) and started selpercatinib, which elicited a PFS of 9 months with best response of partial response. MNNG HOS transforming ( MET ) amplification was subsequently detected upon progression on selpercatinib, and the patient was placed on third-line treatment with selpercatinib plus crizotinib. However, her health deteriorated rapidly and died of cancer 4 months later. We provided additional evidence supporting MET amplification as an acquired mechanism of resistance to selective RET inhibition. In addition, the apparent lack of response to selpercatinib plus crizotinib in this case highlights the need for future cohort studies for examining the value of combining RET and MET inhibitors in treating RET -rearranged, MET -amplified NSCLC.

Quantitative parameters derived from 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging can accurately estimate the histologic grade of hypopharyngeal squamous cell carcinoma preoperatively.

PURPOSE: Among head and neck cancers, hypopharyngeal squamous cell carcinoma (HSCC) shows the highest malignancy, which is associated with histologic grading. This study was designed to investigate whether quantitative parameters derived from 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) can preoperatively estimate the histologic grade of HSCC. METHODS: 18F-FDG PET/MRI of neck was successfully performed in 21 patients with histologically proven HSCC including poorly differentiated group (ten patients) and well-moderately differentiated group (eleven patients). Quantitative parameters derived from FDG-PET, diffusion-weighted imaging (DWI), and dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) were calculated based on volume of interest drawn on the tumor and compared between two groups. The efficacy of quantitative parameters for the estimation of histologic grades of HSCC was evaluated. RESULTS: There were statistically significant differences in mean value of standard uptake value (SUV), apparent diffusion coefficient (ADC), and Ktrans derived from 18F-FDG PET/MRI of HSCC between two groups (p < 0.05). There was no statistically significant difference in other quantitative parameters derived from 18F-FDG PET/MRI of HSCC between two groups. The area under the curve (AUC) of the combination of SUVmean, ADCmean, and Ktrans in the estimation of histologic grade of HSCC was 0.936 with sensitivity of 90.0% and specificity of 81.8%. CONCLUSION: The combination of SUVmean, ADCmean, and Ktrans derived from 18F-FDG PET/MRI can accurately predict the histologic grade of HSCC preoperatively.

Prognostic Value of 18F-Fluorodeoxyglucose-Positron Emission Tomography/Magnetic Resonance Imaging in Patients With Hypopharyngeal Squamous Cell Carcinoma.

OBJECTIVE: The aim of the study is to investigate the value of pretreatment integrated positron emission tomography/magnetic resonance imaging (PET/MRI) in predicting the prognosis of patients with hypopharyngeal squamous cell carcinoma (HSCC). METHODS: Twenty-one untreated patients with HSCC who underwent PET/MRI before treatment were enrolled. We analyzed the value of PET/MRI parameters in predicting the progression-free survival (PFS) and overall survival (OS) of HSCC patients. Kaplan-Meier method and log rank test were used to perform univariate survival analysis, whereas Cox proportional hazard regression models were used to perform multivariate analysis. RESULTS: Of the 21 patients with a median follow-up time of 20.3 months (range, 4.2-37.6 months), 2 (9.5%) had local recurrence, 2 (9.5%) had distant metastases, and 8 (38.1%) died because of cancer. Univariate analysis showed that T stage, clinical stage, total lesion glycolysis (TLG), and metabolic tumor volume (MTV) were significant prognostic factors for PFS (P < 0.05). T stage, clinical stage, TLG, MTV, the mean apparent diffusion coefficient (ADCmean), and the minimal apparent diffusion coefficient (ADCmin) were significant prognostic factors for OS (P < 0.05). The Cox proportional hazard regression model revealed that MTV was an independent prognostic factor for PFS, and TLG was an independent prognostic factor for OS (P < 0.05). CONCLUSIONS: Metabolic tumor volume was an independent predictor of PFS in patients with HSCC, while TLG was an independent predictor of OS. T stage, clinical stage, ADCmean, and ADCmin are potential prognostic indicators for HSCC. Positron emission tomography/magnetic resonance imaging can provide effective information for predicting the prognosis for HSCC patients.

Impact of Dexmedetomidine on Long-term Outcomes After Noncardiac Surgery in Elderly: 3-Year Follow-up of a Randomized Controlled Trial.

OBJECTIVES: The aim was to compare the long-term outcomes of low-dose dexmedetomidine versus placebo in a randomized controlled trial (ChiCTR-TRC-10000802). BACKGROUND: Low-dose dexmedetomidine infusion decreased delirium occurrence within 1 week after surgery in elderly admitted to the intensive care unit (ICU) after noncardiac surgery, but the long-term outcome of this intervention is unknown. METHODS: Patients or their family members were telephone-interviewed for a 3-year follow-up data collection of survival, cognitive function assessed with the modified Telephone Interview for Cognitive Status, and quality of life evaluated with the World Health Organization Quality of Life. RESULTS: Of the 700 patients, 23 (3.3%) were lost at 3-year follow-up. The 3-year overall survival was not statistically different between the dexmedetomidine and placebo groups [114 deaths vs 122/350; hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.68-1.13, P = 0.303]. The survival rates at 6 months, 1 year, and 2 years were significantly higher in the dexmedetomidine than in the placebo group (rate difference of 5.2%, 5.3%, and 6.7% respectively; all P < 0.05). The remaining 98.4% (434/441) 3-year survivors, the dexmedetomidine group, had significantly better cognitive function (mean difference 4.7, 95% CI 3.8-5.6, P < 0.0001) and quality of life (physical domain: 13.6 [10.6-16.6]; psychological domain: 15.2 [12.5-18.0]; social relationship domain: 8.1 [5.5-10.7]; environment domain: 13.3 [10.9-15.7]; all P < 0.0001) than in the placebo group. CONCLUSIONS: For elderly admitted to ICU after noncardiac surgery, low-dose dexmedetomidine infusion did not significantly change 3-year overall survival, but increased survival up to 2 years, and improved cognitive function and quality of life in 3-year survivors.

Handover of anesthesia care is associated with an increased risk of delirium in elderly after major noncardiac surgery: results of a secondary analysis.

In patients undergoing major surgery, complete handover of intraoperative anesthesia care is associated with adverse postoperative outcomes including high mortality and more major complications. The purpose of this study was to explore the association between the intraoperative complete handover between anesthesiologists and the occurrence of postoperative delirium. This was a secondary analysis of the database of a previously published clinical trial. Seven hundred patients aged 65 years or older, who were admitted to the intensive care unit after noncardiac surgery, were included. Delirium was assessed with the Confusion Assessment Method for the Intensive Care Unit twice daily during the first 7 postoperative days. Other postoperative outcomes were also monitored. The association between the intraoperative complete handover of anesthesia care and the development of postoperative delirium was analyzed with a logistic regression model. Of the 700 enrolled patients, 111 (15.9%) developed postoperative delirium within 7 days. After correction for confounding factors, intraoperative complete handover between anesthesiologists was associated with an increased risk of postoperative delirium (OR 1.787, 95% CI 1.012-3.155, P = 0.046). Patients with intraoperative complete handover also had higher incidence of non-delirium complications (P = 0.003) and stayed longer in hospital after surgery (P = 0.002). For elderly patients admitted to the intensive care unit after noncardiac surgery, intraoperative complete handover of anesthesia care was associated with an increased risk of postoperative delirium. Chinese Clinical Trial Registry ( http://www.chictr.org.cn ): ChiCTR-TRC-10000802.

Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Delirium is a postoperative complication that occurs frequently in patients older than 65 years, and presages adverse outcomes. We investigated whether prophylactic low-dose dexmedetomidine, a highly selective α2 adrenoceptor agonist, could safely decrease the incidence of delirium in elderly patients after non-cardiac surgery. METHODS: We did this randomised, double-blind, placebo-controlled trial in two tertiary-care hospitals in Beijing, China. We enrolled patients aged 65 years or older, who were admitted to intensive care units after non-cardiac surgery, with informed consent. We used a computer-generated randomisation sequence (in a 1:1 ratio) to randomly assign patients to receive either intravenous dexmedetomidine (0·1 µg/kg per h, from intensive care unit admission on the day of surgery until 0800 h on postoperative day 1), or placebo (intravenous normal saline). Participants, care providers, and investigators were all masked to group assignment. The primary endpoint was the incidence of delirium, assessed twice daily with the Confusion Assessment Method for intensive care units during the first 7 postoperative days. Analyses were done by intention-to-treat and safety populations. This study is registered with Chinese Clinical Trial Registry, www.chictr.org.cn, number ChiCTR-TRC-10000802. FINDINGS: Between Aug 17, 2011, and Nov 20, 2013, of 2016 patients assessed, 700 were randomly assigned to receive either placebo (n=350) or dexmedetomidine (n=350). The incidence of postoperative delirium was significantly lower in the dexmedetomidine group (32 [9%] of 350 patients) than in the placebo group (79 [23%] of 350 patients; odds ratio [OR] 0·35, 95% CI 0·22-0·54; p<0·0001). Regarding safety, the incidence of hypertension was higher with placebo (62 [18%] of 350 patients) than with dexmedetomidine (34 [10%] of 350 patients; 0·50, 0·32-0·78; p=0·002). Tachycardia was also higher in patients given placebo (48 [14%] of 350 patients) than in patients given dexmedetomidine (23 [7%] of 350 patients; 0·44, 0·26-0·75; p=0·002). Occurrence of hypotension and bradycardia did not differ between groups. INTERPRETATION: For patients aged over 65 years who are admitted to the intensive care unit after non-cardiac surgery, prophylactic low-dose dexmedetomidine significantly decreases the occurrence of delirium during the first 7 days after surgery. The therapy is safe. FUNDING: Braun Anaesthesia Scientific Research Fund and Wu Jieping Medical Foundation, Beijing, China. Study drugs were manufactured and supplied by Jiangsu Hengrui Medicine Co, Ltd, Jiangsu, China.

Parecoxib Supplementation to Morphine Analgesia Decreases Incidence of Delirium in Elderly Patients After Hip or Knee Replacement Surgery: A Randomized Controlled Trial.

BACKGROUND: Severe pain and high-dose opioids are both associated with increased risk of postoperative delirium. The authors investigated whether parecoxib-supplemented IV morphine analgesia could decrease the incidence of delirium in elderly patients after total hip or knee replacement surgery. METHODS: In a randomized, double-blind, 2-center trial, patients of 60 years or older who underwent elective total hip or knee replacement surgery were assigned in a 1:1 ratio to receive either parecoxib (40 mg at the end of surgery and then every 12 hours for 3 days) or placebo (normal saline). All patients received combined spinal-epidural anesthesia during surgery and IV morphine for postoperative analgesia. The primary outcome was the incidence of delirium within 5 days after surgery. RESULTS: Between January 2011 and May 2013, 620 patients were enrolled and were included in the intention-to-treat and safety analyses. The incidence of delirium was significantly reduced from 11.0% (34/310) with placebo to 6.2% (19/310) with parecoxib (relative risk 0.56, 95% confidence interval 0.33-0.96, P = .031). The severity of pain and the cumulative consumptions of morphine at 24, 48, and 72 hours after surgery were significantly lower with parecoxib than with placebo (all P < .001), although the differences were small. There was no difference in the incidence of postoperative complications between the 2 groups (12.3% [38/310] with placebo versus 11.6% [36/310] with parecoxib; P = .80). CONCLUSIONS: For low-risk elderly patients undergoing elective total hip or knee replacement surgery, multidose parecoxib supplemented to IV morphine decreased the incidence of postoperative delirium without increasing adverse events.

Low-dose Dexmedetomidine Improves Sleep Quality Pattern in Elderly Patients after Noncardiac Surgery in the Intensive Care Unit: A Pilot Randomized Controlled Trial.

BACKGROUND: Patients admitted to the intensive care unit (ICU) after surgery often develop sleep disturbances. The authors tested the hypothesis that low-dose dexmedetomidine infusion could improve sleep architecture in nonmechanically ventilated elderly patients in the ICU after surgery. METHODS: This was a pilot, randomized controlled trial. Seventy-six patients age 65 yr or older who were admitted to the ICU after noncardiac surgery and did not require mechanical ventilation were randomized to receive dexmedetomidine (continuous infusion at a rate of 0.1 µg kg h; n = 38) or placebo (n = 38) for 15 h, i.e., from 5:00 PM on the day of surgery until 8:00 AM on the first day after surgery. Polysomnogram was monitored during the period of study-drug infusion. The primary endpoint was the percentage of stage 2 non-rapid eye movement (stage N2) sleep. RESULTS: Complete polysomnogram recordings were obtained in 61 patients (30 in the placebo group and 31 in the dexmedetomidine group). Dexmedetomidine infusion increased the percentage of stage N2 sleep from median 15.8% (interquartile range, 1.3 to 62.8) with placebo to 43.5% (16.6 to 80.2) with dexmedetomidine (difference, 14.7%; 95% CI, 0.0 to 31.9; P = 0.048); it also prolonged the total sleep time, decreased the percentage of stage N1 sleep, increased the sleep efficiency, and improved the subjective sleep quality. Dexmedetomidine increased the incidence of hypotension without significant intervention. CONCLUSIONS: In nonmechanically ventilated elderly patients who were admitted to the ICU after noncardiac surgery, the prophylactic low-dose dexmedetomidine infusion may improve overall sleep quality.

Combined average standard uptake value and rate constant can predict expression of EGFR in hypopharyngeal squamous cell carcinoma: A pilot study with integrated PET/MRI.

PURPOSE: To investigate whether the quantitative multiparameters of 18F-FDG PET/MRI can predict expression of epidermal growth factor receptor (EGFR) of hypopharyngeal squamous cell carcinoma (HSCC). METHODS: Twenty-one patients with HSCC confirmed by biopsy underwent neck integrated 18F-FDG PET/MRI and EGFR expression detection. Quantitative parameters derived from 18F-FDG PET, difusion-weighted imaging (DWI), and dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) were measured. The efficacies of quantitative multiparameters derived from 18F-FDG PET/MRI for predicting the expression of EGFR of HSCC were evaluated. RESULTS: The patients were divided into positive expression group (PEG, n = 14) and negative expression group (NEG, n = 7). Mann-Whitney U nonparametric test showed that SUVmean and Kep had statistical difference between PEG and NPG, while other parameters had no statistical difference. Using 14.50 and 2.10 min-1 as the threshold values, areas under the curve (AUCs) for SUVmean and Kep were 0.786 with specificity of 92.9 % and sensitivity of 57.1 %. The combined use of SUVmean and Kep had better efficacy to evaluate the expression of EGFR with AUC of 0.980, sensitivity of 92.9 %, and specificity of 100.0 %. CONCLUSION: Combined use of SUVmean and Kep showed good performance in predicting the expression of EGFR in HSCC. Integrated 18F-FDG PET/MRI enables simultaneous acquisition of SUVmean and Kep, so it represents as a powerful tool to noninvasively and repeatably evaluate the expression of EGFR during the management of HSCC.

The efficacy of lorlatinib in a lung adenocarcinoma patient with a novel ALK G1202L mutation: a case report.

Acquired mutations in anaplastic lymphoma kinase (ALK) gene have been implicated as the major resistance mechanism to ALK inhibitors; however, information on the treatment options after acquiring novel ALK secondary mutations is limited. Herein, we report the efficacy of lorlatinib upon the detection of a novel ALK G1202L after progression on brigatinib. Our patient was a 30-year-old man with ALK-rearranged advanced lung adenocarcinoma. He had a partial clinical response to crizotinib lasting 11 months. Brigatinib was then administered for 12.8 months with stable disease as the best response. Sequencing at progression revealed the retention of EML4-ALK fusion and the emergence of a novel ALK G1202L mutation. With no standard treatment available, lorlatinib was administered, which achieved disease control for 9 months. Our report reveals the efficacy of lorlatinib in targeting ALK G1202L and can serve as an option for the clinical management of patients with ALK-rearranged lung adenocarcinoma after acquiring G1202L-mediated resistance from prior ALK inhibitor therapy. Furthermore, we also demonstrate the sequential use of crizotinib, brigatinib, and lorlatinib in a patient with advanced ALK-rearranged lung adenocarcinoma with an overall progression-free survival of 33.3 months for the sequential ALK inhibitor regimens. His overall survival was 41.5 months inclusive of all regimens.

Peripheral blood indices to predict PFS/OS with anlotinib as a subsequent treatment in advanced small-cell lung cancer.

OBJECTIVE: In the phase II ALTER-1202 (NCT03059797) trial, anlotinib significantly improved progression-free survival (PFS) and overall survival (OS) in patients with advanced small-cell lung cancer (SCLC) who underwent at least 2 previous chemotherapy cycles, when compared with a placebo group. To identify potential factors for predicting efficacy and prognosis with anlotinib treatment, we analyzed hematological indices at baseline and adverse events (AEs) over the course of anlotinib treatment. METHODS: Data were collected from March 2017 to April 2019 from a randomized, double-blind, placebo-controlled, multicenter, phase II trial of anlotinib. Eligible patients were randomly assigned 2:1 to receive anlotinib or placebo until disease progression, intolerable toxicity, or withdrawal of consent. The patients received anlotinib (12 mg) or an analogue capsule (placebo) orally once daily for 14 days every 3 weeks. The hematological indices at baseline and AEs that occurred in the initial 2 treatment cycles were recorded. The Kaplan-Meier test and Cox regression model were used to assess survival differences. RESULTS: A total of 82 patients (81 patients with complete data) were randomly assigned to receive anlotinib, with 38 receiving a placebo as a control. Multivariate analysis indicated that an elevated neutrophil to lymphocyte ratio > 7.75 and lactate dehydrogenase > 254.65 U/L at baseline were independent risk factors for PFS; basal elevated aspartate aminotransferase > 26.75 U/L, neuron specific enolase > 18.64 ng/mL, and fibrinogen > 4.645 g/L were independent risk factors for OS. During treatment, elevated γ glutamyltransferase and hypophosphatemia were independent predictors for a poor PFS, and elevated γ-glutamyl transferase and hypercholesterolemia were independent factors for OS. CONCLUSIONS: Our study preliminarily defined potential factors that affected the PFS and OS at baseline and during anlotinib treatment in patients with advanced SCLC. Our findings provide a basis for screening the dominant population and for dynamic efficacy monitoring with anlotinib therapy.

XPO1 inhibition synergizes with PARP1 inhibition in small cell lung cancer by targeting nuclear transport of FOXO3a.

Patient mortality rates have remained stubbornly high for the past decades in small cell lung cancer (SCLC) because of having no standard targeted therapies with confirmed advantages at present. Poly [ADP-ribose] polymerase (PARP) inhibitors have shown promise in preclinical models but have had unsatisfactory clinical results in SCLC. By RNA-seq and isobaric tags for relative and absolute quantification (ITRAQ), we revealed that PARP1 inhibition led to the relocalization of forkhead box-O3a (FOXO3a) from nuclear to cytoplasm. By performing co-Immunoprecipitation (co-IP) and CRISPR-Cas9-mediated knockout plasmid we showed that FOXO3a was subject to exportin 1 (XPO1)-dependent nuclear export. We demonstrated the effects of the PARP inhibitor BMN673 on apoptosis and DNA damage were markedly enhanced by simultaneous inhibition of XPO1 in vitro. The combination of BMN673 and the XPO1 inhibitor selinexor inhibited primary SCLC cell proliferation in mini-patient-derived xenotransplants (miniPDXs) and markedly inhibited tumor growth without significant toxicity in xenograft models. The efficacy was enhanced for more than 2.5 times, compared to the single agent. Based on these findings, we further designed a novel dual PARP-XPO1 inhibitor and showed its effectiveness in SCLC. In this work, we illustrated that combining a PARP inhibitor with an XPO1 inhibitor is associated with significantly improved efficacy and tolerability. Dual PARP-XPO1 inhibition restored the FOXO3a balance and activity in SCLC. Collectively, targeting PARP1 and XPO1 opens new avenues for therapeutic intervention against SCLC, warranting further investigation in potential clinical trials.

Correlation between apparent diffusion coefficients and metabolic parameters in hypopharyngeal squamous cell carcinoma: A prospective study with integrated PET/MRI.

PURPOSE: Apparent diffusion coefficients (ADCs) derived from diffusion-weighted magnetic resonance imaging (DW-MRI) and metabolic parameters derived from 18F-FDG positron emission tomography (PET) are promising prognostic indicators for head and neck squamous cell carcinoma (SCC). However, the relationship between them remains unclear. This study aimed to investigate the relationship between ADCs and metabolic parameters in hypopharyngeal SCC (HSCC) using integrated PET/MRI. MATERIALS AND METHODS: Twenty-seven patients with biopsy-proven HSCC underwent integrated 18F-FDG neck PET/MRI. ADCs of HSCC, including the mean and minimum ADC values (ADCmean and ADCmin), were measured manually on ADC maps. Metabolic parameters of HSCC, including maximum and mean standardized uptake values (SUVmax and SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG), were calculated automatically on PET images. Spearman correlation coefficients were used to assess the relationships between ADCs and metabolic parameters in HSCC tumors as well as in tumor groups with different histological grading, clinical staging, and anatomical subsites. P values < 0.05 were considered statistically significant. RESULTS: No significant correlation was observed between ADCs and 18F-FDG PET metabolic parameters in the entire cohort, except for a significant inverse correlation between ADCmean and MTV (r = -0.556, P = 0.003). Furthermore, a significant inverse correlation was observed between ADCmean and MTV of HSCC in the moderately to well differentiated group (rADCmean/MTV = -0.692, P = 0.006), stage III group (rADCmean/MTV = -0.758, P = 0.003), and pyriform sinus group (rADCmean/MTV = -0.665, P = 0.007), whereas no significant correlation was observed in the poorly differentiated group, stage IV group, or non-pyriform sinus group. CONCLUSIONS: Inverse correlation between ADCmean and MTV in the HSCC population was observed and the correlativity depended on histological grading, clinical staging, and anatomical subsites of HSCC.

Durable efficacy of anlotinib in a patient with advanced thymic squamous cell carcinoma after multiline chemotherapy and apatinib: A case report and literature review.

Thymic carcinoma is a rare and highly aggressive mediastinal tumor. Most patients are diagnosed at surgically unresectable stages. Current prospective and retrospective studies have indicated that platinum and anthracycline-based chemotherapy are the first choice drugs of first-line therapy for advanced thymic carcinoma. However, there is no optimal treatment after progression for patients who have undergone first-line and subsequent chemotherapy. Anlotinib, a novel small molecule tyrosine kinase multitarget inhibitor, was approved by the China Food and Drug Administration as a third-line treatment for advanced non-small cell lung cancer (NSCLC) in May 2018. Herein we report a case of an advanced thymic squamous cell carcinoma patient harboring EGFR exon 20 insertion who had previously received multiline therapy, including chemotherapy, radiotherapy as well as antiangiogenic therapy. Also as an angiogenesis inhibitor, anotinib had controlled his mediastinal mass after failure of the apatinib treatment. To date, over 23 months of progression-free survival (PFS) and six years of overall survival (OS) have been achieved. Compared with apatinib, the adverse reactions have been mild and tolerable and the patient's quality of life has improved. To our knowledge, this is the first report where anlotinib has been effective in controlling the progression of thymic carcinoma. In the multiline treatment of advanced thymic carcinoma, anlotinib appears to show great potential when utilized as a salvage treatment.

Epidural morphine improves postoperative analgesia in patients after total knee arthroplasty: A randomized controlled trial.

BACKGROUND: Patients after total knee arthroplasty (TKA) often develop moderate to severe pain. This study compared the analgesic effect of low-dose epidural morphine vs. a comparable saline injection in patients following TKA surgery. METHODS: This randomized, double-blinded, and placebo-controlled trial was conducted in a tertiary hospital in Beijing between July 1, 2017 and May 30, 2018. One hundred and ten patients following TKA under combined spinal-epidural anesthesia were randomized to receive either epidural morphine (2 mg diluted to 5 ml normal saline, the epidural morphine group) or placebo (5 ml normal saline, the placebo group). For all patients, single-injection femoral nerve block was performed, and a supplementary patient-controlled intravenous analgesia pump was provided. The severity of pain was assessed with the numerical rating scale (NRS, an 11-point scale where 0 = no pain and 10 = the worst pain) at 6, 12, 24, 36, and 48 hours after surgery. The primary endpoint was moderate to severe pain (NRS pain score ≥4) within 48 hours after surgery. RESULTS: The percentage with moderate to severe pain within 48 hours was lower in the epidural morphine group than in the placebo group (58.2% [32/55] with epidural morphine vs. 76.4% [42/55] with placebo; OR 0.43, 95% CI 0.19-0.98; p = 0.042). Furthermore, the cumulative morphine consumption within 48 hours was lower (18.4±6.1 mg vs. 22.4±7.3 mg; p = 0.002) whereas the mental component summary score of 30-day quality of life was higher (63.8±2.9 vs. 61.9±4.2; p = 0.008) in the epidural morphine group than in the placebo group. CONCLUSIONS: For patients following TKA, the addition of epidural morphine to single-injection femoral nerve block improves the quality of analgesia within 48 hours, without increasing adverse events. TRIAL REGISTRATION: ClinicalTrials.gov NCT03203967.

Preoperative severe hypoalbuminemia is associated with an increased risk of postoperative delirium in elderly patients: Results of a secondary analysis.

PURPOSE: To explore the association between the severity of preoperative hypoalbuminemia and the occurrence of postoperative delirium. MATERIALS AND METHODS: This was a secondary analysis of the database from a previously conducted clinical trial. 700 elderly patients (age ≥65years) who were admitted to intensive care unit (ICU) after noncardiac surgery were included. Delirium was assessed with the Confusion Assessment Method for the ICU twice daily during the first 7days postoperatively. Other outcomes were also monitored. The relationship between preoperative albumin level and postoperative delirium were analyzed using a logistic regression model. RESULTS: 111 of 700 patients (15.9%) developed postoperative delirium. When compared with normal albumin level (>40.0g/L), severe (≤30.0g/L: OR 2.727, 95% CI 1.283-5.797, P=0.009), but not mild (35.1-40.0g/L: OR 1.175, 95% CI 0.679-2.032, P=0.565) or moderate (30.1-35.0g/L: OR 1.674, 95% CI 0.897-3.122, P=0.105) hypoalbuminemia was associated with an increased risk of postoperative delirium. Preoperative severe hypoalbuminemia was also associated with prolonged mechanical ventilation, increased non-delirium complications, and prolonged ICU and hospital stay after surgery. CONCLUSIONS: Preoperative severe hypoalbuminemia (≤30.0g/L) was associated with an increased risk of postoperative delirium and worse outcomes. TRIAL REGISTRATION: Chinese Clinical Trial Registry, www.chictr.org.cn, ChiCTR-TRC-10000802.