Chronic Mild Sleep Restriction Does Not Lead to Marked Neuronal Alterations Compared With Maintained Adequate Sleep in Adults.

BACKGROUND: Sleep restriction (SR) has been shown to upregulate neuronal reward networks in response to food stimuli, but prior studies were short-term and employed severe SR paradigms. OBJECTIVE: Our goal was to determine whether mild SR, achieved by delaying bedtimes by 1.5 h, influences neuronal networks responsive to food stimuli compared with maintained adequate sleep (AS) >7 h/night. METHODS: A randomized controlled crossover study with 2 6-wk phases, AS (≥7 h sleep/night) and SR (-1.5 h/night relative to screening), was conducted. Adults with AS duration, measured using wrist actigraphy over a 2-wk screening period, and self-reported good sleep quality were enrolled. Resting-state and food-stimulated functional neuroimaging (fMRI) was performed at the endpoint of each phase. Resting-state fMRI data analyses included a priori region-of-interest seed-based functional connectivity, whole-brain voxel-wise analyses, and network analyses. Food task-fMRI analyses compared brain activity patterns in response to food cues between conditions. Paired-sample t tests tested differences between conditions. RESULTS: Twenty-six participants (16 males; age 29.6 ± 5.3 y, body mass index 26.9 ± 4.0 kg/m2) contributed complete data. Total sleep time was 7 h 30 ± 28 min/night during AS compared with 6 h 12 ± 26 min/night during SR. We employed different statistical approaches to replicate prior studies in the field and to apply more robust approaches that are currently advocated in the field. Using uncorrected P value of <0.01, cluster ≥10-voxel thresholds, we replicated prior findings of increased activation in response to foods in reward networks after SR compared with AS (right insula, right inferior frontal gyrus, and right supramarginal gyrus). These findings did not survive more rigorous analytical approaches (Gaussian Random Field theory correction at 2-tailed voxel P < 0.001, cluster P < 0.05). CONCLUSIONS: The results suggest that mild SR leads to increased reward responsivity to foods but with low confidence given the failure to meet significance from rigorous statistical analyses. Further research is necessary to inform the mechanisms underlying the role of sleep on food intake regulation. This trial was registered at clinicaltrials.gov as NCT02960776.

Neural representations of self-generated thought during think-aloud fMRI.

Is the brain at rest during the so-called resting state? Ongoing experiences in the resting state vary in unobserved and uncontrolled ways across time, individuals, and populations. However, the role of self-generated thoughts in resting-state fMRI remains largely unexplored. In this study, we collected real-time self-generated thoughts during "resting-state" fMRI scans via the think-aloud method (i.e., think-aloud fMRI), which required participants to report whatever they were currently thinking. We first investigated brain activation patterns during a think-aloud condition and found that significantly activated brain areas included all brain regions required for speech. We then calculated the relationship between divergence in thought content and brain activation during think-aloud and found that divergence in thought content was associated with many brain regions. Finally, we explored the neural representation of self-generated thoughts by performing representational similarity analysis (RSA) at three neural scales: a voxel-wise whole-brain searchlight level, a region-level whole-brain analysis using the Schaefer 400-parcels, and at the systems level using the Yeo seven-networks. We found that "resting-state" self-generated thoughts were distributed across a wide range of brain regions involving all seven Yeo networks. This study highlights the value of considering ongoing experiences during resting-state fMRI and providing preliminary methodological support for think-aloud fMRI.

Aberrant degree centrality profiles during rumination in major depressive disorder.

Rumination is closely linked to the onset and maintenance of major depressive disorder (MDD). Prior neuroimaging studies have identified the association between self-reported rumination trait and the functional coupling among a network of brain regions using resting-state functional magnetic resonance imaging (MRI). However, little is known about the underlying neural circuitry mechanism during active rumination in MDD. Degree centrality (DC) is a simple metric to denote network integration, which is critical for higher-order psychological processes such as rumination. During an MRI scan, individuals with MDD (N = 45) and healthy controls (HC, N = 46) completed a rumination state task. We examined the interaction effect between the group (MDD vs. HC) and condition (rumination vs. distraction) on vertex-wise DC. We further characterized the identified brain region's functional involvement with Neurosynth and BrainMap. Network-wise seed-based functional connectivity (FC) analysis was also conducted for the identified region of interest. Finally, exploratory correlation analysis was conducted between the identified region of interest's network FCs and self-reported in-scanner affect levels. We found that a left superior frontal gyrus (SFG) region, generally overlapped with the frontal eye field, showed a significant interaction effect. Further analysis revealed its involvement with executive functions. FCs between this region, the frontoparietal, and the dorsal attention network (DAN) also showed significant interaction effects. Furthermore, its FC to DAN during distraction showed a marginally significant negative association with in-scanner affect level at the baseline. Our results implicated an essential role of the left SFG in the rumination's underlying neural circuitry mechanism in MDD and provided novel evidence for the conceptualization of rumination in terms of impaired executive control.

Delirium in older patients given propofol or sevoflurane anaesthesia for major cancer surgery: a multicentre randomised trial.

BACKGROUND: Delirium is a common and disturbing postoperative complication that might be ameliorated by propofol-based anaesthesia. We therefore tested the primary hypothesis that there is less delirium after propofol-based than after sevoflurane-based anaesthesia within 7 days of major cancer surgery. METHODS: This multicentre randomised trial was conducted in 14 tertiary care hospitals in China. Patients aged 65-90 yr undergoing major cancer surgery were randomised to either propofol-based anaesthesia or to sevoflurane-based anaesthesia. The primary endpoint was the incidence of delirium within 7 postoperative days. RESULTS: A total of 1228 subjects were enrolled and randomised, with 1195 subjects included in the modified intention-to-treat analysis (mean age 71 yr; 422 [35%] women); one subject died before delirium assessment. Delirium occurred in 8.4% (50/597) of subjects given propofol-based anaesthesia vs 12.4% (74/597) of subjects given sevoflurane-based anaesthesia (relative risk 0.68 [95% confidence interval {CI}: 0.48-0.95]; P=0.023; adjusted relative risk 0.59 [95% CI: 0.39-0.90]; P=0.014). Delirium reduction mainly occurred on the first day after surgery, with a prevalence of 5.4% (32/597) with propofol anaesthesia vs 10.7% (64/597) with sevoflurane anaesthesia (relative risk 0.50 [95% CI: 0.33-0.75]; P=0.001). Secondary endpoints, including ICU admission, postoperative duration of hospitalisation, major complications within 30 days, cognitive function at 30 days and 3 yr, and safety outcomes, did not differ significantly between groups. CONCLUSIONS: Delirium was a third less common after propofol than sevoflurane anaesthesia in older patients having major cancer surgery. Clinicians might therefore reasonably select propofol-based anaesthesia in patients at high risk of postoperative delirium. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR-IPR-15006209) and ClinicalTrials.gov (NCT02662257).

Long-term survival in older patients given propofol or sevoflurane anaesthesia for major cancer surgery: follow-up of a multicentre randomised trial.

BACKGROUND: Experimental evidence indicates that i.v. anaesthesia might reduce cancer recurrence compared with volatile anaesthesia, but clinical information is observational only. We therefore tested the primary hypothesis that propofol-based anaesthesia improves survival over 3 or more years after potentially curative major cancer surgery. METHODS: This was a long-term follow-up of a multicentre randomised trial in 14 tertiary hospitals in China. We enrolled 1228 patients aged 65-90 yr who were scheduled for major cancer surgery. They were randomised to either propofol-based i.v. anaesthesia or to sevoflurane-based inhalational anaesthesia. The primary endpoint was overall survival after surgery. Secondary endpoints included recurrence-free and event-free survival. RESULTS: Amongst subjects randomised, 1195 (mean age 72 yr; 773 [65%] male) were included in the modified intention-to-treat analysis. At the end of follow-up (median 43 months), there were 188 deaths amongst 598 patients (31%) assigned to propofol-based anaesthesia compared with 175 deaths amongst 597 patients (29%) assigned to sevoflurane-based anaesthesia; adjusted hazard ratio 1.02; 95% confidence interval (CI): 0.83-1.26; P=0.834. Recurrence-free survival was 223/598 (37%) in patients given propofol anaesthesia vs 206/597 (35%) given sevoflurane anaesthesia; adjusted hazard ratio 1.07; 95% CI: 0.89-1.30; P=0.465. Event-free survival was 294/598 (49%) in patients given propofol anaesthesia vs 274/597 (46%) given sevoflurane anaesthesia; adjusted hazard ratio 1.09; 95% CI 0.93 to 1.29; P=0.298. CONCLUSIONS: Long-term survival after major cancer surgery was similar with i.v. and volatile anaesthesia. Propofol-based iv. anaesthesia should not be used for cancer surgery with the expectation that it will improve overall or cancer-specific survival. CLINICAL TRIAL REGISTRATIONS: ChiCTR-IPR-15006209; NCT02660411.

Addition of preoperative transversus abdominis plane block to multimodal analgesia in open gynecological surgery: a randomized controlled trial.

BACKGROUND: Transversus abdominis plane (TAP) block can provide effective analgesia for abdominal surgery. However, it was questionable whether TAP had additional effect in the context of multimodal analgesia (MMA). Therefore, this study aimed to assess the additional analgesic effect of preoperative TAP block when added to MMA protocol in open gynecological surgery. METHODS: In this prospective, randomized-controlled trial, 64 patients scheduled for open gynecological surgery were randomized to receive preoperative TAP block (Study group, n = 32) or placebo (Control group, n = 32) in addition to MMA protocol comprising dexamethasone, acetaminophen, flurbiprofen and celecoxib, and rescued morphine analgesia. The primary outcome was rescued morphine within 24 h after surgery. Secondary outcomes included pain scores, adverse effects, quality of recovery measured by 40-item quality of recovery questionnaire score (QoR-40) at 24 h, and quality of life measured with short-form health survey (SF - 36) on postoperative day (POD) 30. RESULTS: The Study group had less rescued morphine than the control group within 24 h [5 (2-9) vs. 8.5 (5-12.8) mg, P = 0.013]. The Study group had lower pain scores at 1 h [3 (2-4) vs. 4 (3-5), P = 0.007], 2 h [3 (2-4) vs. 3.5 (3-5), P = 0.010] and 6 h [3 (2-3) vs. 3 (2.3-4), P = 0.028], lower incidence of nausea at 48 h (25.8% vs. 50%, P = 0.039), and higher satisfaction score [10 (10-10) vs. 10 (8-10), P = 0.041]. The SF-36 bodily pain score on POD 30 was higher in the Study group (59 ± 13 vs. 49 ± 16, P = 0.023). CONCLUSIONS: Preoperative TAP block had additional analgesic effect for open gynecological surgery when used as part of multimodal analgesia. Rescued morphine within 24 h was significantly reduced and the SF-36 bodily pain dimension at 30 days after surgery was significantly improved. TRIAL REGISTRATION: www.chictr.org.cn (ChiCTR2000040343, on Nov 28 2020).

Dignity in nursing: A bibliometric and visual analysis of scientific publications.

BACKGROUND: Dignity-conserved nursing has been widely studied by scholars all over the world; however, there is no clear direction in which this field is trending. AIM: To conduct a bibliometric analysis that systematically characterises publications on dignity research in the nursing field from 2011 to 2020. DESIGN: Bibliometric and visual analysis of retrieved articles. METHODS: The Web of Science Core Collection database was used to retrieve all articles which addressed dignity in nursing from 2011 to 2020. The WoSCC's own analysis tool, CiteSpace and VOSviewer, were used to obtain visual analysis results. Reporting follows the STROBE checklist. RESULTS: A total of 1429 papers on dignity care are included in this study. We found that the number of papers on this topic increased steadily, and the United States topped the list with 366 articles in total. The institute with the most publications was King's College London, and the most widely published journal was Nursing Ethics. We were able to identify four major research topics, namely dignity in: (a) palliative care, (b) dementia and the elderly, (c) health care and (d) nursing ethics. Terminally ill patient, home, value, rehabilitation and psychological distress were the five keywords with the highest burst strength. CONCLUSIONS: The interest in dignity care research has been steadily increasing from 2011 and is reflected in the number of published papers. The United States and Western Europe are leading in this field, both having a high number of cutting-edge researchers and high-level scientific research institutions. In the domain of dignity care, several stable and high-yield core author groups have been formed. While the existing research mainly focuses on four hot spots, psychological distress, advanced cancer, maternity care and content analysis may be the research frontiers.

Transcriptomic analysis reveals the regulatory mechanism underlying the indirubin-mediated amelioration of dextran sulfate sodium-induced colitis in mice.

CONTEXT: Aryl hydrocarbon receptor (AhR) agonists are potential therapeutic agents for ulcerative colitis (UC). Indirubin (IDR), which is a natural AhR ligand approved for leukemia treatment, ameliorates dextran sulfate sodium (DSS)-induced colitis in mice. However, the therapeutic mechanisms of IDR are unknown, limiting its application. OBJECTIVE: This study explores the therapeutic mechanisms of IDR in DSS-induced colitis using transcriptomic analysis. MATERIALS AND METHODS: Male BALB/c mice were categorized to six groups: normal, DSS model (2% DSS), IDR treatment (10, 20 and 40 mg/kg), and sulfasalazine (520 mg/kg) groups. The drugs were intragastrically administered for 7 consecutive days. The disease activity index (DAI) was recorded. After euthanasia, the colon length was measured, and histopathological examination, immunohistochemistry staining using F4/80, and colonic transcriptomic analysis were conducted. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting (WB) were conducted to verify our findings. RESULTS: Compared with DSS, IDR treatment decreased the DAI score by 64.9% and increased colon length by 26.2%. Moreover, it alleviated mucosal injury and reduced macrophage infiltration. Transcriptomic analysis identified several downregulated genes (Igkvs and Nlrp3), as well as Nlrp3/Il1ß and hemoglobin gene networks, after IDR treatment. The abundances of NF-κB p65, NLRP3, IL-1ß, and HBA decreased by 69.1, 59.4, 81.1, and 83.0% respectively, after IDR treatment. DISCUSSION AND CONCLUSION: Apart from the well-documented NF-κB signalling pathway, IL-17A, and NLRP3-IL-1ß, the suppression of haemoglobin-induced lipid peroxidation could be a previously unknown mechanism of IDR. Our study can help improve its application for UC treatment.

PBRM1 deficiency oncogenic addiction is associated with activated AKT-mTOR signalling and aerobic glycolysis in clear cell renal cell carcinoma cells.

The PBRM1 (PB1) gene which encodes the specific subunit BAF180 of the PBAF SWI/SNF complex, is highly mutated (~ 40%) in clear cell renal cell carcinoma (ccRCC). However, its functions and impact on cell signalling are still not fully understood. Aerobic glycolysis, also known as the 'Warburg Effect', is a hallmark of cancer, whether PB1 is involved in this metabolic shift in clear cell renal cell carcinoma remains unclear. Here, with established stable knockdown PB1 cell lines, we performed functional assays to access the effects on 786-O and SN12C cells. Based on the RNA-seq data, we selected some genes encoding key glycolytic enzymes, including PFKP, ENO1, PKM and LDHA, and examined the expression levels. The AKT-mTOR signalling pathway activity and expression of HIF1α were also analysed. Our data demonstrate that PB1 deficiency promotes the proliferation, migration, Xenograft growth of 786-O and SN12C cells. Notably, knockdown of PB1 activates AKT-mTOR signalling and increases the expression of key glycolytic enzymes at both mRNA and protein levels. Furthermore, we provide evidence that deficient PB1 and hypoxic conditions exert a synergistic effect on HIF 1α expression and lactate production. Thus, our study provides novel insights into the roles of tumour suppressor PB1 and suggests that the AKT-mTOR signalling pathway, as well as glycolysis, is a potential drug target for ccRCC patients with deficient PB1.

Disrupted intrinsic functional brain topology in patients with major depressive disorder.

Aberrant topological organization of whole-brain networks has been inconsistently reported in studies of patients with major depressive disorder (MDD), reflecting limited sample sizes. To address this issue, we utilized a big data sample of MDD patients from the REST-meta-MDD Project, including 821 MDD patients and 765 normal controls (NCs) from 16 sites. Using the Dosenbach 160 node atlas, we examined whole-brain functional networks and extracted topological features (e.g., global and local efficiency, nodal efficiency, and degree) using graph theory-based methods. Linear mixed-effect models were used for group comparisons to control for site variability; robustness of results was confirmed (e.g., multiple topological parameters, different node definitions, and several head motion control strategies were applied). We found decreased global and local efficiency in patients with MDD compared to NCs. At the nodal level, patients with MDD were characterized by decreased nodal degrees in the somatomotor network (SMN), dorsal attention network (DAN) and visual network (VN) and decreased nodal efficiency in the default mode network (DMN), SMN, DAN, and VN. These topological differences were mostly driven by recurrent MDD patients, rather than first-episode drug naive (FEDN) patients with MDD. In this highly powered multisite study, we observed disrupted topological architecture of functional brain networks in MDD, suggesting both locally and globally decreased efficiency in brain networks.

The composite risk index based on frailty predicts postoperative complications in older patients recovering from elective digestive tract surgery: a retrospective cohort study.

BACKGROUND: Limitations exist in available studies investigating effect of preoperative frailty on postoperative outcomes. This study was designed to analyze the association between composite risk index, an accumulation of preoperative frailty deficits, and the risk of postoperative complications in older patients recovering from elective digestive tract surgery. METHODS: This was a retrospective cohort study. Baseline and perioperative data of older patients (age ≥ 65 years) who underwent elective digestive tract surgery from January 1, 2017 to December 31, 2018 were collected. The severity of frailty was assessed with the composite risk index, a composite of frailty deficits including modified frailty index. The primary endpoint was the occurrence of postoperative complications during hospital stay. The association between the composite risk index and the risk of postoperative complications was assessed with a multivariable logistic regression model. RESULTS: A total of 923 patients were included. Of these, 27.8% (257) developed postoperative complications. Four frailty deficits, i.e., modified frailty index ≥0.27, malnutrition, hemoglobin < 90 g/L, and albumin ≤30 g/L, were combined to generate a composite risk index. Multivariable analysis showed that, when compared with patients with composite risk index of 0, the odds ratios (95% confidence intervals) were 2.408 (1.714-3.383, P <  0.001) for those with a composite risk index of 1, 3.235 (1.985-5.272, P <  0.001) for those with a composite risk index of 2, and 9.227 (3.568-23.86, P <  0.001) for those with composite risk index of 3 or above. The area under receiver-operator characteristic curve to predict postoperative complications was 0.653 (95% confidence interval 0.613-0.694, P <  0.001) for composite risk index compared with 0.622 (0.581-0.663, P <  0.001) for modified frailty index. CONCLUSION: For older patients following elective digestive tract surgery, high preoperative composite risk index, a combination of frailty deficits, was independently associated with an increased risk of postoperative complications.

Long-circulating doxorubicin and schizandrin A liposome with drug-resistant liver cancer activity: preparation, characterization, and pharmacokinetic.

The selectivity of chemotherapeutic agents for liver cancer is poor. When they kill tumour cells, they produce serious adverse reactions in the whole body and multidrug resistance (MDR) is also a major hurdle in liver cancer chemotherapy. Combination therapy is a useful method for overcoming MDR and reducing toxic and side effects. In this study, we developed a long-circulating codelivery system, in which doxorubicin (DOX) and schizandrin A (SchA) are combined against MCF-7/ADR cells. The DOX-SchA long-circulating liposome (DOX-SchA-Lip) was prepared using ammonium sulphate gradient method. The two drugs were co-encapsulated into the distearoyl phosphatidylethanolamine-polyethylene glycol (DSPE-mPEG2000) liposome and the liposome had an average particle size of (100 ± 3.5) nm and zeta electrical potential of (-31.3 ± 0.5) mV. The average encapsulation rate of DOX was 97.98% and that of SchA was 86.94%. DOX in liposome had good sustained-release effect. The results showed that DOX-SchA-Lip could significantly prolong the half-life (t1/2z) of the DOX and SchA, increase their circulation time in vivo, improve its bioavailability and reduce their side effects. Liposome can effectively induce early apoptosis of HepG2/ADR cells and the cell cycle was blocked in S-phase by DOX-SchA-Lip in a dose-dependent manner. The IC50 of compound liposome to HepG2 and HepG2/ADR were 0.55 µmol/L and 1.38 µmol/L, respectively, which could significantly reverse the resistance of HepG2/ADR and the reversion multiple was 30.28. It was verified that DOX-SchA-Lip can effectively kill tumour cells and reverse MDR.

Severe functional impairment increases the risk of major morbidity and mortality in older patients after digestive tract surgery: a retrospective cohort study.

PURPOSE: The relationship between the severity of impairment in basic activities of daily living (ADLs) function and postoperative outcomes in older surgical patients remains unclear. This study aimed to clarify the association between the severity of preoperative functional impairment and the composite postoperative outcome of major morbidity and mortality in older patients undergoing digestive tract surgery. METHODS: This was a retrospective cohort study. We collected perioperative data of older patients (age ≥ 65 years) who underwent digestive tract surgery in our institution. The severity of functional impairment was assessed using the Barthel Index scale before surgery. The major morbidity and mortality were defined as Clavien-Dindo grade III or greater postoperative complications during hospital stay. The association between the severity of functional impairment and the major morbidity and mortality was assessed using a multivariable logistic regression model. RESULTS: 131 of 1076 patients (12.2%) developed major morbidity and mortality. After controlling for confounding factors, high Barthel Index scores were correlated with decreased risk of major morbidity and mortality (OR 0.986, 95% CI 0.976-0.997, P = 0.011); preoperative severe (OR 2.862, 95% CI 1.172-6.989, P = 0.021), but not mild or moderate (OR 1.019, 95% CI 0.602-1.726, P = 0.943) functional impairment was independently associated with an increased risk of major morbidity and mortality, when compared with independent functional status. CONCLUSIONS: Preoperative severe functional impairment in basic ADLs was independently associated with a higher risk of major postoperative morbidity and mortality in older patients undergoing digestive tract surgery.

Preoperative dipstick albuminuria is associated with acute kidney injury in high-risk patients following non-cardiac surgery: a single-center prospective cohort study.

PURPOSE: This study aimed to investigate the association between preoperative dipstick albuminuria (DA) and acute kidney injury (AKI) in high-risk patients following non-cardiac surgery. METHODS: This was a single-center prospective cohort study. Adult patients with high risk of AKI undergoing non-cardiac surgery were enrolled. The primary outcome was AKI, defined according to KDIGO criteria within 7 days following non-cardiac surgery. DA status was determined by urinalysis performed within 24 h of hospital admission. Multivariate logistic regression model was used to analyze the association between preoperative DA and postoperative AKI. RESULTS: During the study period, 552 patients were enrolled and 8.5% of them developed postoperative AKI. The overall rate of preoperative positive DA was 26.4% with 30 and ≥ 100 mg/dL DA accounting for 19.2% and 7.2%, respectively. Patients with more severe preoperative DA had much higher rate of postoperative AKI (5.2% in patients with negative or trace DA, 13.2% in patients with 30 mg/dL DA and 30.0% in patients with ≥ 100 mg/dL DA, P < 0.001). After adjusting for several perioperative variables, preoperative 30 mg/dL DA (OR 2.575; 95% CI 1.049-6.322; P = 0.039) and ≥ 100 mg/dL DA (OR 3.868; 95% CI 1.246-12.010; P = 0.019) showed an independent association with postoperative AKI. In addition, patients with higher DA status demonstrated significantly increased level of postoperative urine biomarkers and their ratio to urine creatinine. CONCLUSIONS: Preoperative DA was independently associated with AKI in high-risk patients following non-cardiac surgery. Preoperative routine urinalysis for determination of DA status was suggested in early risk stratification.

Exploring self-generated thoughts in a resting state with natural language processing.

The present study seeks to examine individuals' stream of thought in real time. Specifically, we asked participants to speak their thoughts freely out loud during a typical resting-state condition. We first examined the feasibility and reliability of the method and found that the oral reporting method did not significantly change the frequency or content characteristics of self-generated thoughts; moreover, its test-retest reliability was high. Based on methodological feasibility, we combined natural language processing (NLP) with the Bidirectional Encoder Representation from Transformers (BERT) model to directly quantify thought content. We analyzed the divergence of self-generated thought content and expressions of sadness and empirically verified the validity and behavioral significance of the metrics calculated by BERT. Furthermore, we found that reflection and brooding could be differentiated by detecting the divergence of self-generated thought content and expressions of sadness, thus deepening our understanding of rumination and depression and providing a way to distinguish adaptive from maladaptive rumination. Finally, this study provides a new framework to examine self-generated thoughts in a resting state with NLP, extending research on the continuous content of instant self-generated thoughts with applicability to resting-state functional brain imaging.

Epidural Anesthesia-Analgesia and Recurrence-free Survival after Lung Cancer Surgery: A Randomized Trial.

BACKGROUND: Regional anesthesia and analgesia reduce the stress response to surgery and decrease the need for volatile anesthesia and opioids, thereby preserving cancer-specific immune defenses. This study therefore tested the primary hypothesis that combining epidural anesthesia-analgesia with general anesthesia improves recurrence-free survival after lung cancer surgery. METHODS: Adults scheduled for video-assisted thoracoscopic lung cancer resections were randomized 1:1 to general anesthesia and intravenous opioid analgesia or combined epidural-general anesthesia and epidural analgesia. The primary outcome was recurrence-free survival (time from surgery to the earliest date of recurrence/metastasis or all-cause death). Secondary outcomes included overall survival (time from surgery to all-cause death) and cancer-specific survival (time from surgery to cancer-specific death). Long-term outcome assessors were blinded to treatment. RESULTS: Between May 2015 and November 2017, 400 patients were enrolled and randomized to general anesthesia alone (n = 200) or combined epidural-general anesthesia (n = 200). All were included in the analysis. The median follow-up duration was 32 months (interquartile range, 24 to 48). Recurrence-free survival was similar in each group, with 54 events (27%) with general anesthesia alone versus 48 events (24%) with combined epidural-general anesthesia (adjusted hazard ratio, 0.90; 95% CI, 0.60 to 1.35; P = 0.608). Overall survival was also similar with 25 events (13%) versus 31 (16%; adjusted hazard ratio, 1.12; 95% CI, 0.64 to 1.96; P = 0.697). There was also no significant difference in cancer-specific survival with 24 events (12%) versus 29 (15%; adjusted hazard ratio, 1.08; 95% CI, 0.61 to 1.91; P = 0.802). Patients assigned to combined epidural-general had more intraoperative hypotension: 94 patients (47%) versus 121 (61%; relative risk, 1.29; 95% CI, 1.07 to 1.55; P = 0.007). CONCLUSIONS: Epidural anesthesia-analgesia for major lung cancer surgery did not improve recurrence-free, overall, or cancer-specific survival compared with general anesthesia alone, although the CI included both substantial benefit and harm.

Long-term Survival after Combined Epidural-General Anesthesia or General Anesthesia Alone: Follow-up of a Randomized Trial.

BACKGROUND: Experimental and observational research suggests that combined epidural-general anesthesia may improve long-term survival after cancer surgery by reducing anesthetic and opioid consumption and by blunting surgery-related inflammation. This study therefore tested the primary hypothesis that combined epidural-general anesthesia improves long-term survival in elderly patients. METHODS: This article presents a long-term follow-up of patients enrolled in a previous trial conducted at five hospitals. Patients aged 60 to 90 yr and scheduled for major noncardiac thoracic and abdominal surgeries were randomly assigned to either combined epidural-general anesthesia with postoperative epidural analgesia or general anesthesia alone with postoperative intravenous analgesia. The primary outcome was overall postoperative survival. Secondary outcomes included cancer-specific, recurrence-free, and event-free survival. RESULTS: Among 1,802 patients who were enrolled and randomized in the underlying trial, 1,712 were included in the long-term analysis; 92% had surgery for cancer. The median follow-up duration was 66 months (interquartile range, 61 to 80). Among patients assigned to combined epidural-general anesthesia, 355 of 853 (42%) died compared with 326 of 859 (38%) deaths in patients assigned to general anesthesia alone: adjusted hazard ratio, 1.07; 95% CI, 0.92 to 1.24; P = 0.408. Cancer-specific survival was similar with combined epidural-general anesthesia (327 of 853 [38%]) and general anesthesia alone (292 of 859 [34%]): adjusted hazard ratio, 1.09; 95% CI, 0.93 to 1.28; P = 0.290. Recurrence-free survival was 401 of 853 [47%] for patients who had combined epidural-general anesthesia versus 389 of 859 [45%] with general anesthesia alone: adjusted hazard ratio, 0.97; 95% CI, 0.84 to 1.12; P = 0.692. Event-free survival was 466 of 853 [55%] in patients who had combined epidural-general anesthesia versus 450 of 859 [52%] for general anesthesia alone: adjusted hazard ratio, 0.99; 95% CI, 0.86 to 1.12; P = 0.815. CONCLUSIONS: In elderly patients having major thoracic and abdominal surgery, combined epidural-general anesthesia with epidural analgesia did not improve overall or cancer-specific long-term mortality. Nor did epidural analgesia improve recurrence-free survival. Either approach can therefore reasonably be selected based on patient and clinician preference.

Radiotherapy plus chemotherapy versus chemotherapy alone in penile cancer patients with extracapsular nodal extension after inguinal lymph node surgery: a multi-institutional study.

PURPOSE: Because there is a lack of evidence, it is not generally recommended to use adjuvant radiotherapy plus chemotherapy to treat lymph node disease in penile cancer. The aim of this study was to determine the benefit of using adjuvant radiotherapy after inguinal surgery for penile cancer. METHODS: Multi-institutional data were obtained from a total of nine centers from April 2003 to April 2015 and retrospectively analyzed. pN3 patients with an extracapsular nodal extension who received adjuvant therapy after inguinal surgery were included. Cancer-specific survival (CSS) was estimated using the Kaplan-Meier method. The multivariate analysis was performed using a Cox proportional hazards model. RESULTS: A total of 93 pN3 patients met the inclusion criteria. During the study period, 32 (34.4%) and 61 (65.6%) of these patients received adjuvant radiotherapy plus chemotherapy (AR + AC) or adjuvant chemotherapy alone (AC). The median CSS in all patients was 12.0 months (interquartile range [IQR] 7.5-16.5). The Kaplan-Meier estimated 3-year CSS rate was significantly longer in the AR + AC group (28.5%) than the AC group (16.2%) (p = 0.036). AC + AR was associated with an improvement in CSS by 7.7 months (17.7 [IQR 3.8-31.6] vs. 10.0 [IQR 6.6-13.4] months). In the Cox regression analysis, AR + AC was an independent predictor of CSS [model a: HR 0.486 (95% CI 0.258-0.916), model b: HR 0.527 (95% CI 0.286-0.972)]. CONCLUSION: In conclusions, AR + AC was associated with improved CCS in patients with penile cancer who displayed an extracapsular nodal extension after inguinal surgery. This hypothesis requires further confirmation.

CDKN2A deletions are associated with poor outcomes in 101 adults with T-cell acute lymphoblastic leukemia.

The identification of genetic risk subgroups of T-cell acute lymphoblastic leukemia (T-ALL) may provide evidence for risk stratification and individualized treatment. We investigated the characteristics and prognostic value of tumor suppressor gene CDKN2A deletions in 101 patients with T-ALL. The CDKN2A deletion was present in 23% (23/101) of T-ALL by fluorescence in situ hybridization (FISH). The most common type of CDKN2A deletion was homozygous deletion (70%, 16/23). A lower frequency of CDKN2A deletion was found in patients with early T-cell precursor (ETP) ALL than in patients with non-ETP-ALL (10.4% vs 34.0%; P = .008). Deletion of CDKN2A was significantly associated with younger age (P = .001), higher white blood cell (WBC) count (P < .001) and higher lactate dehydrogenase (LDH) level (P = .002). Patients with CDKN2A deletion had lower 2-year overall survival (OS) and event-free survival (EFS) rates than patients without CDKN2A deletion (2-year OS: 18.6% ± 8.9% vs 47.4% ± 6.2%, P = .032; EFS: 16.4 ± 8.3 vs 38.6 ± 5.9%, P = .022). In multivariable analysis, CDKN2A deletion was an independent adverse prognostic factor for OS (P = .016). In conclusion, adult T-ALL patients with CDKN2A deletion had a poor prognosis, and these patients might benefit from intensive chemotherapy or allogeneic hematopoietic stem-cell transplantation.

Association Between Cerebral Desaturation and Postoperative Delirium in Thoracotomy With One-Lung Ventilation: A Prospective Cohort Study.

BACKGROUND: The association between cerebral desaturation and postoperative delirium in thoracotomy with one-lung ventilation (OLV) has not been specifically studied. METHODS: A prospective observational study performed in thoracic surgical patients. Cerebral tissue oxygen saturation (Scto2) was monitored on the left and right foreheads using a near-infrared spectroscopy oximeter. Baseline Scto2 was measured with patients awake and breathing room air. The minimum Scto2 was the lowest measurement at any time during surgery. Cerebral desaturation and hypersaturation were an episode of Scto2 below and above a given threshold for ≥15 seconds during surgery, respectively. The thresholds based on relative changes by referring to the baseline measurement were <80%, <85%, <90%, <95%, and <100% baseline for desaturation and >105%, >110%, >115%, and >120% baseline for hypersaturation. The thresholds based on absolute values were <50%, <55%, <60%, <65%, and <70% for desaturation and >75%, >80%, >85%, and >90% for hypersaturation. The given area under the threshold (AUT)/area above the threshold (AAT) was analyzed. Delirium was assessed until postoperative day 5. The primary analysis was the association between the minimum Scto2 and delirium using multivariable logistic regression controlled for confounders (age, OLV time, use of midazolam, occurrence of hypotension, and severity of pain). The secondary analysis was the association between cerebral desaturation/hypersaturation and delirium, and between the AUT/AAT and delirium using multivariable logistic regression controlled for the same confounders. Multiple testing was corrected using the Holm-Bonferroni method. We additionally monitored somatic tissue oxygen saturation on the forearm and upper thigh. RESULTS: Delirium occurred in 35 (20%) of 175 patients (65 ± 6 years old). The minimum left or right Scto2 was not associated with delirium. Cerebral desaturation defined by <90% baseline for left Scto2 (odds ratio [OR], 5.82; 95% confidence interval [CI], 2.12-19.2; corrected P =.008) and <85% baseline for right Scto2 (OR, 4.27; 95% CI, 1.77-11.0; corrected P =.01) was associated with an increased risk of delirium. Cerebral desaturation defined by other thresholds, cerebral hypersaturation, the AUT/AAT, and somatic desaturation and hypersaturation were all not associated with delirium. CONCLUSIONS: Cerebral desaturation defined by <90% baseline for left Scto2 and <85% baseline for right Scto2, but not the minimum Scto2, may be associated with an increased risk of postthoracotomy delirium. The validity of these thresholds needs to be tested by randomized controlled trials.