Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer.

BACKGROUND: The addition of pembrolizumab to neoadjuvant chemotherapy led to a significantly higher percentage of patients with early triple-negative breast cancer having a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery in an earlier analysis of this phase 3 trial of neoadjuvant and adjuvant therapy. The primary results regarding event-free survival in this trial have not been reported. METHODS: We randomly assigned, in a 2:1 ratio, patients with previously untreated stage II or III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab (pembrolizumab-chemotherapy group) or placebo (placebo-chemotherapy group) every 3 weeks for up to nine cycles. The primary end points were pathological complete response (the results for which have been reported previously) and event-free survival, defined as the time from randomization to the date of disease progression that precluded definitive surgery, local or distant recurrence, occurrence of a second primary cancer, or death from any cause. Safety was also assessed. RESULTS: Of the 1174 patients who underwent randomization, 784 were assigned to the pembrolizumab-chemotherapy group and 390 to the placebo-chemotherapy group. The median follow-up at this fourth planned interim analysis (data cutoff, March 23, 2021) was 39.1 months. The estimated event-free survival at 36 months was 84.5% (95% confidence interval [CI], 81.7 to 86.9) in the pembrolizumab-chemotherapy group, as compared with 76.8% (95% CI, 72.2 to 80.7) in the placebo-chemotherapy group (hazard ratio for event or death, 0.63; 95% CI, 0.48 to 0.82; P<0.001). Adverse events occurred predominantly during the neoadjuvant phase and were consistent with the established safety profiles of pembrolizumab and chemotherapy. CONCLUSIONS: In patients with early triple-negative breast cancer, neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab after surgery, resulted in significantly longer event-free survival than neoadjuvant chemotherapy alone. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.).

21-gene expression assay and clinical outcomes of premenopausal patients with hormone receptor-positive breast cancer.

The prognostic role of the recurrence score (RS) based on the 21-gene expression assay in premenopausal women is not well delineated, and we investigated the association of outcomes and the RS in premenopausal patients who had 21-gene expression assay at Asan Medical Center, Seoul, Korea, between June 2005 and July 2018. Invasive breast cancer-free survival (IBCFS) by STEEP version 2.0 was compared according to the RS and clinical risk factors. A total of 554 patients were included in our study and 116 patients (20.9%) had age <40 years, 238 patients (43.0%) had luminal B subtype (Ki67 ≥ 20%), and 83 patients (15.0%) had RS >25. All patients received adjuvant tamoxifen ± chemotherapy. Overall, patients with RS >25 showed trend toward worse IBCFS from multivariable analysis (adjusted HR 1.89 [95% CI: 0.95-3.73], P = .069). When comparing outcomes according to age and luminal subtypes, patients with luminal B subtype and age <40 years (n = 60) showed significantly worse outcomes compared to the others (luminal A or luminal B + age ≥40 years, n = 494; adjusted HR 2.95 [95% CI: 1.49-5.82], log-rank P < .001). Among patients with luminal B subtype and age <40 years, there was no significant association observed between IBCFS and the RS (log-rank P = .51). In conclusion, while RS >25 showed association with poor outcomes in premenopausal women, it may have less prognostic significance among those with luminal B subtype and age <40 years.

Phase 2 trial of avelumab in combination with gemcitabine in advanced leiomyosarcoma as a second-line treatment (EAGLES, Korean Cancer Study Group UN18-09).

BACKGROUND: In this single-arm, multicenter, phase 2 trial, the authors evaluated the efficacy and safety of avelumab plus gemcitabine in patients with leiomyosarcoma (LMS) who failed on first-line chemotherapy. METHODS: Patients with advanced LMS received avelumab 10 mg/kg on days 1 and 15 (for up to 24 months) plus gemcitabine 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle until they developed disease progression or intolerable toxicity. The primary end point was the objective response rate (ORR). RESULTS: In total, 38 patients were enrolled. Of these, 35 patients were evaluable, and the ORR was 20% (95% confidence interval; [CI], 8%-37%). The disease control rate was 71%, and the median duration of response was 21.8 months (range, 7.6 to ≥43.3 months). The median progression free-survival was 5.6 months (95% CI, 4.5-6.8 months), and the median overall survival was 27.5 months (95% CI, 20.4-34.6 months). Grade 3-4 adverse events occurred in 70% of patients, of which neutropenia was the most common (54%). Immune-mediated adverse events occurred in five patients (14%; hypothyroidism, n = 3; hepatitis, n = 2). Patients who had a higher density of tumor-infiltrating lymphocytes (greater than the median) exhibited better ORR (35% vs. 8%; p = .104), progression-free survival (median, 7.3 vs. 3.3 months; p = .024), and overall survival (median, not reached vs. 21.5 months; p = .027). CONCLUSIONS: The combination of avelumab and gemcitabine demonstrated promising efficacy and manageable safety in patients with advanced LMS who progressed on first-line therapy. Tumor-infiltrating lymphocyte density may be an important factor in predicting the response to combining immunotherapy with chemotherapy.

Favorable clinical efficacy of cytotoxic chemotherapy in patients with progressive desmoid tumors: a retrospective real-world study.

BACKGROUND: The real-world evidence about the efficacy of cytotoxic chemotherapy in desmoid tumors is still limited. We investigated the efficacy of chemotherapy in the treatment of recurrent or progressive desmoid tumors. METHODS: The patients with desmoid tumors who had received cytotoxic chemotherapy between November 2007 and June 2020 in two tertiary hospitals in Korea were reviewed. RESULTS: A total of 25 patients were included in the analysis. The most common primary tumor site was the intra-abdominal or pelvic cavity (56%), followed by the trunk and abdominal wall (24%), extremities (16%), and head and neck (4%). Sixty percent of the patients had familial adenomatous polyposis and 76% received doxorubicin plus dacarbazine. The objective response rate and disease control rate was 64% (95% confidence interval [CI]: 40.7-82.8) and 96% (95% CI: 77.2-99.9), respectively. With the median follow-up time of 55 months (95% CI: 41.0-68.2), the 3-year PFS rate was 65% (95% CI: 41.1-80.5), and the 3-year OS rate was 89% (95% CI: 63.8-97.3). Grade 3 or 4 hematologic adverse events were reported in 14 patients, all of which were manageable. CONCLUSION: Our real-world evidence suggests that doxorubicin-based cytotoxic chemotherapy can be an effective treatment option for recurrent and progressive desmoid tumors with respect to favorable clinical outcomes.

A comparative study using gastric ultrasound to evaluate the safety of shortening the fasting time before pediatric echocardiography: a randomized controlled non-inferiority study.

PURPOSE: The objective of this study was to demonstrate that the gastric cross-sectional area (CSA) in the right lateral decubitus position (RLDP) during a 2-h fasting period is not larger than that during a conventional 4-h fasting period prior to pediatric echocardiography. METHODS: 93 patients aged under 3 years scheduled for echocardiography under sedation were enrolled and randomly allocated into two groups; 2-h fasting vs 4-h fasting. For group 4 h (n = 46), the patients were asked to be fasted for all types of liquid for more than 4 h, while group 2 h (n = 47) were asked to be fasted for all types of liquid for 2 h before echocardiography. Gastric ultrasound was performed before echocardiography, and CSARLDP was measured. We compared CSARLDP, incidence of at-risk stomach, fasting duration, and the incidence of major (pulmonary aspiration, aspiration pneumonia) and minor complications (nausea, retching, and vomiting, apnea, and bradycardia) between two groups. RESULTS: The mean difference of CSARLDP (group 2 h-group 4 h) was 0.49 (- 0.18 to 1.17) cm2, and it was within the non-inferiority margin (Δ = 2.1 cm2). There was no difference in the incidence of at-risk stomach (P = 0.514). There was no significant difference in the incidence of major and minor complications between the two groups. CONCLUSION: Two-hour fasting in pediatric patients who need an echocardiography did not increase major and minor complications and CSA significantly.

Inhibition of pyruvate dehydrogenase kinase 4 ameliorates kidney ischemia-reperfusion injury by reducing succinate accumulation during ischemia and preserving mitochondrial function during reperfusion.

Ischemia-reperfusion (IR) injury, a leading cause of acute kidney injury (AKI), is still without effective therapies. Succinate accumulation during ischemia followed by its oxidation during reperfusion leads to excessive reactive oxygen species (ROS) and severe kidney damage. Consequently, the targeting of succinate accumulation may represent a rational approach to the prevention of IR-induced kidney injury. Since ROS are generated primarily in mitochondria, which are abundant in the proximal tubule of the kidney, we explored the role of pyruvate dehydrogenase kinase 4 (PDK4), a mitochondrial enzyme, in IR-induced kidney injury using proximal tubule cell-specific Pdk4 knockout (Pdk4ptKO) mice. Knockout or pharmacological inhibition of PDK4 ameliorated IR-induced kidney damage. Succinate accumulation during ischemia, which is responsible for mitochondrial ROS production during reperfusion, was reduced by PDK4 inhibition. PDK4 deficiency established conditions prior to ischemia resulting in less succinate accumulation, possibly because of a reduction in electron flow reversal in complex II, which provides electrons for the reduction of fumarate to succinate by succinate dehydrogenase during ischemia. The administration of dimethyl succinate, a cell-permeable form of succinate, attenuated the beneficial effects of PDK4 deficiency, suggesting that the kidney-protective effect is succinate-dependent. Finally, genetic or pharmacological inhibition of PDK4 prevented IR-induced mitochondrial damage in mice and normalized mitochondrial function in an in vitro model of IR injury. Thus, inhibition of PDK4 represents a novel means of preventing IR-induced kidney injury, and involves the inhibition of ROS-induced kidney toxicity through reduction in succinate accumulation and mitochondrial dysfunction.

Randomized phase III trial of a neoadjuvant regimen of four cycles of adriamycin plus cyclophosphamide followed by four cycles of docetaxel (AC4-D4) versus a shorter treatment of three cycles of FEC followed by three cycles of docetaxel (FEC3-D3) in node-positive breast cancer (Neo-shorter; NCT02001506).

PURPOSE: To determine whether six cycles of FEC3-D3 has a comparable efficacy to eight of AC4-D4. METHODS: The enrolled patients (pts) were clinically diagnosed with stage II or III breast cancer. The primary endpoint was a pathologic complete response (pCR), and the secondary endpoints were 3 year disease-free survival (3Y DFS), toxicities, and health-related quality of life (HRQoL). We calculated that 252 pts were needed in each treatment group to enable the detection of non-inferiority (non-inferiority margin of 10%). RESULTS: In terms of ITT analysis, 248 pts were finally enrolled. The 218 pts who completed the surgery were included in the current analysis. The baseline characteristics of these subjects were well balanced between the two arms. By ITT analysis, pCR was achieved in 15/121 (12.4%) pts in the FEC3-D3 arm and 18/126 (14.3%) in the AC4-D4 arm. With a median follow up of 64.1 months, the 3Y DFS was comparable between the two arms (75.8% in FEC3-D3 vs. 75.6% in AC4-D4). The most common adverse event (AE) was Grade 3/4 neutropenia, which arose in 27/126 (21.4%) AC4-D4 arm pts vs 23/121 (19.0%) FEC3-D3 arm cases. The primary HRQoL domains were similar between the two groups (FACT-B scores at baseline, P = 0.35; at the midpoint of NACT, P = 0.20; at the completion of NACT, P = 0.44). CONCLUSION: Six cycles of FEC3-D3 could be an alternative to eight of AC4-D4. Trial registration ClinicalTrials.gov NCT02001506. Registered December 5,2013. https://clinicaltrials.gov/ct2/show/NCT02001506.

Synthesis and biological evaluation of xanthine derivatives with phenacyl group as tryptophan hydroxylase 1 (TPH1) inhibitors for obesity and fatty liver disease.

Tryptophan hydroxylase 1 (TPH1) has emerged as a target for the treatment of metabolic diseases including obesity and fatty liver disease. A series of xanthine derivatives were synthesized and evaluated for their TPH1 inhibition. Among the synthesized compounds, compound 40 showed good in vitro activity and liver microsomal stability. Docking studies revealed that compound 40 showed better binding to TPH1 via key intermolecular interactions involving the xanthine scaffold, imidazo-thiazolyl ring, and hydroxyl-containing phenacyl moiety. In addition, compound 40 effectively suppressed the adipocyte differentiation of 3 T3-L1 cells.

Association between body composition and chronic low back pain in Korean adults aged over 50 years: The Korea National Health and Nutrition Examination Survey (KNHANES) 2010-2011.

Background The relationship between overweight or obesity and low back pain (LBP) has previously been investigated. Several recent studies have focused on the relationship between other indicators of obesity, particularly indicators of fat and the risk of LBP. However, the results of body composition and LBP have been inconsistent. Methods All data for the present retrospective, cross-sectional study was extracted from the Korea National Health and Nutrition Examination Survey (KNHANES) versions V-1 and 2 conducted in 2010 and 2011 by the Korean Centers for Disease Control and Prevention. In KNHANES V-1 (2010) and V-2 (2011), those over 50 years of age completed the surveys on LBP, body weight, and body composition assessed using dual-energy X-ray absorptiometry (DXA) were included. The multivariable logistic regression analysis was used to examine the relationship between the presence of chronic LBP and body composition adjusting for confounders. Results We analyzed 3,579 persons who completed the question. In the multivariable analyses adjusting for age and sex, none of the variables, including fat mass and fat-free mass, remained positively or negatively associated with LBP. Additionally, when depression, smoking, alcohol intake, physical activity, diabetes mellitus, and fat or lean tissue mass were included in the multivariable logistic model, no significant associations were found between all measures of fat mass, fat-free mass, and LBP Conclusion This study is contrary to previous studies that concluded that there is a correlation between obesity and fat mass and LBP. LBP is not associated with increased levels of obesity and fat mass.

Body Map of Droplet Distributions During Oropharyngeal Suction to Protect Health Care Workers From Airborne Diseases.

PURPOSE: Health care workers (HCWs), and in particular anesthesia providers, often must perform aerosol-generating medical procedures (AGMPs). However, no studies have analyzed droplet distributions on the bodies of HCWs during AGMPs. Therefore, the purpose of this study was to assess and analyze droplet distributions on the bodies of HCWs during suction of oral cavities with and without oral airways and during extubations. DESIGN: Using a quasi-experiemental design, we assumed the HCWs perform suction and extubation on intubated patients, and we prepared an intubated mannequin mimicking a patient. This study performed the oral suction and extubation on the intubated mannequin (with or without oral airways in place) and analyzed the droplet distributions. METHODS: We prepared a mannequin intubated with an 8.0 mm endotracheal tube, assuming the situation of general anesthesia. We designed the body mapping gown, and divided it into 10 areas including the head, neck, chest, abdomen, upper arms, forearms, and hands. We classified experiments into group O when suctions were performed on the mannequin with an oral airway, and into group X when the suctions were performed on the mannequin without an oral airway. An experienced board-certified anesthesiologist performed 10 oral suctions on each mannequin, and 10 extubations. We counted the droplets on the anesthesiologist's gown according to the divided areas after each procedure. FINDINGS: The mean droplet count after suction was 6.20 ± 2.201 in group O and 13.6 ± 4.300 in group X, with a significant difference between the two groups (P < .001). The right and left hands were the most contaminated areas in group O (2.8 ± 1.033 droplets and 2.0 ± 0.943 droplets, respectively). The abdomen, right hand, left forearm, and left hand showed many droplets in group X. (1.3 ± 1.337 droplets, 3.1 ± 1.792 droplets, 3.2 ± 3.910 droplets, and 4.3 ± 2.214 droplets, respectively). The chest, abdomen, and left hand presented significantly more droplets in group X than in group O. The trunk area (chest and abdomen) was exposed to more droplets during extubations than during suctions. CONCLUSIONS: During suctions, more droplets are splattered from mannequins without oral airways than from those with oral airways. The right and left hands were the most contaminated areas in group O. Moreover, the abdomen, right hand, left forearm, and left hand presented a lot of droplets in group X. In addition, extubations contaminate wider areas (the head, neck, chest and abdomen) of an HCW than suctions.

Dynamic Arterial Elastance as a Predictor of Supine-to-Prone Hypotension (SuProne Study): An Observational Study.

Background and Objectives: Supine-to-prone hypotension is caused by increased intrathoracic pressure and decreased venous return in the prone position. Dynamic arterial elastance (Eadyn) indicates fluid responsiveness and can be used to predict hypotension. This study aimed to investigate whether Eadyn can predict supine-to-prone hypotension. Materials and Methods: In this prospective, observational study, 47 patients who underwent elective spine surgery in the prone position were enrolled. Supine-to-prone hypotension is defined as a decrease in Mean Arterial Pressure (MAP) by more than 20% in the prone position compared to the supine position. Hemodynamic parameters, including systolic blood pressure (SAP), diastolic blood pressure, MAP, stroke volume variation (SVV), pulse pressure variation (PPV), stroke volume index, cardiac index, dP/dt, and hypotension prediction index (HPI), were collected in the supine and prone positions. Supine-to-prone hypotension was also assessed using two different definitions: MAPprone < 65 mmHg and SAPprone < 100 mmHg. Hemodynamic parameters were analyzed to determine the predictability of supine-to-prone hypotension. Results: Supine-to-prone hypotension occurred in 13 (27.7%) patients. Eadyn did not predict supine-to-prone hypotension [Area under the curve (AUC), 0.569; p = 0.440]. SAPsupine > 139 mmHg (AUC, 0.760; p = 0.003) and dP/dtsupine > 981 mmHg/s (AUC, 0.765; p = 0.002) predicted supine-to-prone hypotension. MAPsupine, SAPsupine, PPVsupine, and HPIsupine predicted MAPprone <65 mm Hg. MAPsupine, SAPsupine, SVVsupine, PPVsupine, and HPIsupine predicted SAPprone < 100 mm Hg. Conclusions: Dynamic arterial elastance did not predict supine-to-prone hypotension in patients undergoing spine surgery. Systolic arterial pressure > 139 mmHg and dP/dt > 981 mmHg/s in the supine position were predictors for supine-to-prone hypotension. When different definitions were employed (mean arterial pressure < 65 mmHg in the prone position or systolic arterial pressure < 100 mmHg in the prone position), low blood pressures in the supine position were related to supine-to-prone hypotension.

A Propensity Score-matched Analysis of Long-term Oncologic Outcomes After Nipple-sparing Versus Conventional Mastectomy for Locally Advanced Breast Cancer.

OBJECTIVES: To compare the long-term oncologic outcomes of nipple-sparing mastectomy (NSM) with those of conventional mastectomy (CM) in patients with locally advanced breast cancer (LABC) receiving neoadjuvant chemotherapy (NACT). SUMMARY OF BACKGROUND DATA: NSM has been increasingly implemented in patients with breast cancer. However, oncologic efficacy of NSM in patients with LABC has not been sufficiently demonstrated. METHODS: The study group comprised 850 patients with clinical stage IIB to IIIC breast cancer who underwent NACT followed by either NSM and immediate breast reconstruction or CM alone. After propensity score-matching, 418 patients were included in the analysis. Local recurrence-free survival, disease-free survival (DFS), distant metastasis-free survival, and overall survival (OS) rates were calculated using the Kaplan-Meier method and compared using log-rank tests between the NSM and CM groups. RESULTS: After matching, the mean follow-up period was 70 ± 25 months for the NSM group and 74 ± 27 months for the CM group ( P = 0.181). There were no significant differences between the groups in terms of 6-year local recurrence-free survival (91.6% vs. 95.8%; P = 0.239), DFS (70.5% vs. 73.4%; P = 0.583), distant metastasis-free survival (79.8% vs. 77.4%; P = 0.320), or OS (87.6% vs. 84.8%; P = 0.465) rates. Additionally, we identified 30 patients in the NSM group who initially presented with tumor extension in the subareolar area; the nipple-areola complex was successfully preserved after NACT, and no recurrence at the nipple was observed in these patients. CONCLUSIONS: In this matched control study, we demonstrated comparable long-term oncologic outcomes between NSM with immediate reconstruction and CM alone after NACT for LABC. In patients who had tumors extending to the subareolar area before NACT, NSM can be tried if tumor involvement of the nipple-areola complex appears resolved on imaging studies after chemotherapy.

Identification of New Non-BBB Permeable Tryptophan Hydroxylase Inhibitors for Treating Obesity and Fatty Liver Disease.

Serotonin (5-hydroxytryptophan) is a hormone that regulates emotions in the central nervous system. However, serotonin in the peripheral system is associated with obesity and fatty liver disease. Because serotonin cannot cross the blood-brain barrier (BBB), we focused on identifying new tryptophan hydroxylase type I (TPH1) inhibitors that act only in peripheral tissues for treating obesity and fatty liver disease without affecting the central nervous system. Structural optimization inspired by para-chlorophenylalanine (pCPA) resulted in the identification of a series of oxyphenylalanine and heterocyclic phenylalanine derivatives as TPH1 inhibitors. Among these compounds, compound 18i with an IC50 value of 37 nM was the most active in vitro. Additionally, compound 18i showed good liver microsomal stability and did not significantly inhibit CYP and Herg. Furthermore, this TPH1 inhibitor was able to actively interact with the peripheral system without penetrating the BBB. Compound 18i and its prodrug reduced body weight gain in mammals and decreased in vivo fat accumulation.

Identification and Characterization of a Novel Large-Conductance Calcium-Activated Potassium Channel Activator, CTIBD, and Its Relaxation Effect on Urinary Bladder Smooth Muscle.

The large-conductance calcium-activated potassium channel (BKCa channel) is expressed on various tissues and is involved in smooth muscle relaxation. The channel is highly expressed on urinary bladder smooth muscle cells and regulates the repolarization phase of the spontaneous action potentials that control muscle contraction. To discover novel chemical activators of the BKCa channel, we screened a chemical library containing 8364 chemical compounds using a cell-based fluorescence assay. A chemical compound containing an isoxazolyl benzene skeleton (compound 1) was identified as a potent activator of the BKCa channel and was structurally optimized through a structure-activity relationship study to obtain 4-(4-(4-chlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol (CTIBD). When CTIBD was applied to the treated extracellular side of the channel, the conductance-voltage relationship of the channel shifted toward a negative value, and the maximum conductance increased in a concentration-dependent manner. CTIBD altered the gating kinetics of the channel by dramatically slowing channel closing without effecting channel opening. The effects of CTIBD on bladder muscle relaxation and micturition function were tested in rat tissue and in vivo. CTIBD concentration-dependently reduced acetylcholine-induced contraction of urinary bladder smooth muscle strips. In an acetic acid-induced overactive bladder (OAB) model, intraperitoneal injection of 20 mg/kg CTIBD effectively restored frequent voiding contraction and lowered voiding volume without affecting other bladder function parameters. Thus, our results indicate that CTIBD and its derivatives are novel chemical activators of the bladder BKCa channel and potential candidates for OAB therapeutics. SIGNIFICANCE STATEMENT: The novel BKCa channel activator CTIBD was identified and characterized in this study. CTIBD directly activates the BKCa channel and relaxes urinary bladder smooth muscle of rat, so CTIBD can be a potential candidate for overactive bladder therapeutics.

Final results of the randomized phase 2 LEO trial and bone protective effects of everolimus for premenopausal hormone receptor-positive, HER2-negative metastatic breast cancer.

The phase 2 LEO study showed that everolimus (EVE) plus letrozole (LET) with ovarian suppression increased progression-free survival (PFS) in tamoxifen-exposed premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer with visceral metastases. Here we report final survival outcomes from the LEO study, and the results of exploratory analyses of bone turnover marker changes and bone-specific progressive disease. Patients who were exposed to or progressed on tamoxifen as adjuvant/palliative treatments were randomly assigned (2:1) to the EVE (leuprorelin + LET + EVE, n = 92) or LET (leuprorelin + LET, n = 45) arm. In a median 51-months of follow-up, the median PFS was 17.5 and 13.8 months in the EVE and LET arms, respectively (P = .245). Patients in the EVE arm with baseline visceral (median PFS 16.4 vs 9.5 months, P = .040) and bone (median PFS 17.1 vs 10.9, P = .003) metastases had greater PFS compared to the LET arm. No differences in overall survival (OS) were observed (median OS, 48.3 vs 50.8 months, P = .948). The 1-year cumulative incidences of bone-specific disease progression were 6.0% and 23.4% in the EVE and LET arms, respectively (hazard ratio 0.26, P < .001). Bone turnover markers at 6 and 12 weeks after treatment decreased in the EVE arm but were increased or stationary in the LET arm. Skeletal-related events occurred in 6.5% and 11.1% of patients in the EVE and LET arms, respectively. EVE + LET with ovarian suppression prolonged PFS in patients with baseline visceral or bone metastases and offered bone-protective effects in the overall study population. However, these clinical benefits did not translate into an OS benefit.

Prognostic effects of cytokine levels on patients treated with taxane and zoledronic acid for metastatic breast cancer in bone (BEAT-ZO) (KCSG BR 10-13).

Advanced breast cancer frequently metastasizes to the skeleton causing major mobility issues and hazards to quality of life. To manage osteolytic bone metastasis, bone-modifying agents and chemotherapy are recommended as the standard of care. Here, we investigated serologic biomarkers that might be associated with prognosis in breast cancer patients treated with zoledronic acid (ZA) and taxane-based chemotherapy. We collected serum samples from breast cancer patients with bone metastasis who received taxane plus ZA as palliative treatment. Fourteen biomarkers of angiogenesis, immunogenicity, and apoptosis were assessed, and the correlation between serum cytokine levels and patient's prognosis was statistically analyzed. Sixty-six patients were enrolled, and samples from 40 patients were analyzed after laboratory quality control. Patients with low baseline PDGF-AA, high IFN-γ, low MCP-2, low TGF-ß1, and low TNF-α were significantly associated with longer progression-free survival (PFS). Decreasing VEGF and TNF-α and increasing FGF-2 and PDGF-AA in the early treatment phase indicated longer PFS. In univariate and multivariate analyses, low TGF-ß1 and TNF-α and high IFN-γ at baseline were associated with a significantly low hazard ratio for disease progression. Further, we designed a risk score with TGF-ß1, TNF-α, and IFN-γ levels, which could prognosticate patients for PFS. In conclusion, serum cytokine level, such as TGF-ß1, TNF-α, and IFN-γ, could be a potential prognostic biomarker for breast cancer patients with bone metastasis treated with ZA and taxane-based chemotherapy.

Effects of prophylactic atropine on the time to tracheal intubation with the pre-administration of remifentanil.

BACKGROUND: Pre-administration of remifentanil in target-controlled propofol and remifentanil anaesthesia could prolong the time of onset of muscle relaxation owing to haemodynamic effects, thereby prolonging the time to tracheal intubation. Although the sympatholytic effects of remifentanil result in bradycardia and hypotension, these responses can be attenuated by the administration of atropine. Therefore, we investigated whether prophylactic administration of atropine could prevent the prolongation of the time to tracheal intubation. METHODS: Sixty-four patients were included in this study. They were randomised into Group A (atropine 0.5 mg, n = 32) and Group S (saline 0.9%, n = 32), immediately before the pre-administration of remifentanil. The primary outcome was the time to tracheal intubation and the secondary outcomes were rocuronium onset time, time to loss of consciousness (LOC), time to reach a value of 60 on the bispectral index (BIS) and haemodynamic variables. RESULTS: The median [Interquartile range] of the time to tracheal intubation was 240 [214, 288]s in Group S and 190 [176, 212]s in Group A(median difference: 50 s, 95% confidence interval: 27-80 s, P = .001). Rocuronium onset time was significantly decreased in Group A compared to that in Group S (129 [110, 156] vs 172 [154, 200], P = .001). The times to LOC and reach 60 on the BIS were not significantly different between the two groups. Cardiac output(CO) and heart rate were less decreased in Group A than in Group S (P = .02, P < .001, respectively). CONCLUSIONS: Prophylactic administration of atropine could compensate for the reduction in CO in cases pre-administered with remifentanil in target-controlled propofol and remifentanil anaesthesia. This in turn prevented the prolongation of rocuronium onset time and reduced the time to tracheal intubation.

Preoperative Oral Carbohydrate Loading in Laparoscopic Gynecologic Surgery: A Randomized Controlled Trial.

STUDY OBJECTIVE: To determine whether carbohydrate loading improves the postoperative quality of recovery (QoR) better than the midnight fasting policy in laparoscopic gynecologic surgeries. DESIGN: Randomized, parallel-group trial. SETTING: Tertiary university hospital. PATIENTS: Female patients scheduled for laparoscopic gynecologic surgery for nonmalignant gynecologic diseases. INTERVENTIONS: Eighty-eight women were randomly assigned to the midnight fasting group (nil per os, NPO group) or the carbohydrate loading group (carbohydrate group). Patients in both groups adhered to the enhanced recovery after surgery protocol except for carbohydrate intake in the carbohydrate group. MEASUREMENTS AND MAIN RESULTS: The postoperative QoR was evaluated using the QoR 15-item questionnaire on postoperative day 2. The times to readiness for discharge of the groups were compared. The QoR 15-item questionnaire scores were 97.7 ± 23.0 in the NPO group and 99.6 ± 22.4 in the carbohydrate group; they were not statistically different (p = .702). The times to readiness for discharge of both groups were also not different: 36.8 ± 12.2 hours in the NPO group and 37.6 ± 11.8 hours in the carbohydrate group (p = .684). CONCLUSION: The benefit of carbohydrate beverage intake was not significant in laparoscopic gynecologic surgeries when following the enhanced recovery after surgery protocol.

Utility of ultrasound evaluation of I-Gel® placement in children: An observational study.

BACKGROUND: Ultrasound is not widely used to evaluate optimal supraglottic airway positioning even though it could potentially be used to identify and correct problem areas. AIMS: We evaluated a new ultrasound scoring method to identify the position of the supraglottic airway and detect the location of air leaks during ventilation in pediatric patients. METHODS: Using a prospective observational study design, we enrolled 90 pediatric patients of ASA physical status I-III scheduled for elective surgery under general anesthesia. After anesthesia induction, patients were assigned to a noncorrection group or a correction group after their first ultrasound evaluation. Noncorrection group comprised patients with tolerable I-Gel positioning based on ultrasound evaluation and no problems with clinical parameters, while the correction group comprised patients with I-Gel mispositioning based on ultrasound. RESULTS: After the first ultrasound evaluation, 61 patients did not need I-Gel correction (noncorrection group), while 29 patients needed I-Gel correction (correction group) and underwent a second ultrasound evaluation. Airway sealing pressure and total ultrasound score showed a negative correlation (r = -.845, p < .001). The area under the receiver operating curve for total ultrasound score was 0.97 (95% confidence interval, 0.94-0.99; p < .001). In the correction group, ultrasound score and ventilation parameters improved after correction based on ultrasound evaluation. CONCLUSIONS: Ultrasound scores were negatively correlated with airway sealing pressure in pediatric patients. Ultrasound evaluation is useful for detecting misplacement of the I-Gel and can be a useful tool for correction.

Neurochemical Effects of 4-(2Chloro-4-Fluorobenzyl)-3-(2-Thienyl)-1,2,4-Oxadiazol-5(4H)-One in the Pentylenetetrazole (PTZ)-Induced Epileptic Seizure Zebrafish Model.

Epilepsy is one of the most common neurological disorders, and it is characterized by spontaneous seizures. In a previous study, we identified 4-(2-chloro-4-fluorobenzyl)-3-(2-thienyl)-1,2,4-oxadiazol-5(4H)-one (GM-90432) as a novel anti-epileptic agent in chemically- or genetically-induced epileptic zebrafish and mouse models. In this study, we investigated the anti-epileptic effects of GM-90432 through neurochemical profiling-based approach to understand the neuroprotective mechanism in a pentylenetetrazole (PTZ)-induced epileptic seizure zebrafish model. GM-90432 effectively improved PTZ-induced epileptic behaviors via upregulation of 5-hydroxytryptamine, 17-ß-estradiol, dihydrotestosterone, progesterone, 5α -dihydroprogesterone, and allopregnanolone levels, and downregulation of normetanephrine, gamma-aminobutyric acid, and cortisol levels in brain tissue. GM-90432 also had a protective effect against PTZ-induced oxidative stress and zebrafish death, suggesting that it exhibits biphasic neuroprotective effects via scavenging of reactive oxygen species and anti-epileptic activities in a zebrafish model. In conclusion, our results suggest that neurochemical profiling study could be used to better understand of anti-epileptic mechanism of GM-90432, potentially leading to new drug discovery and development of anti-seizure agents.