Association Between Immune-Related Adverse Events and Survival in Patients with Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are effective for advanced hepatocellular carcinoma (HCC). However, there are few reports on the correlation between the clinical efficacy of ICIs and the development of immune-related adverse events (irAEs) in patients with HCC. The aim of this study was to investigate the association between irAE development and survival in patients with HCC treated with atezolizumab plus bevacizumab. PATIENTS AND METHODS: We enrolled 150 patients with advanced HCC treated with atezolizumab plus bevacizumab between October 2020 and October 2021 at 5 territorial institutions. We compared the efficacy of atezolizumab plus bevacizumab between patients who experienced irAEs (irAE group) and those who did not (non-irAE group). RESULTS: Thirty-two patients (21.3%) developed irAEs of any grade. Grade 3/4 irAEs were observed in 9 patients (6.0%). The median progression-free survivals (PFS) in the irAE and non-irAE groups were 273 and 189 days, respectively (P = .055). The median overall survivals (OS) in the irAE and non-irAE groups were not reached and 458 days, respectively (P = .036). Grade 1/2 irAEs significantly prolonged PFS (P = .014) and OS (P = .003). Grade 1/2 irAEs were significantly associated with PFS (hazard ratio [HR], 0.339; 95% confidence interval [CI], 0.166-0.691; P = .003) and OS (HR, 0.086; 95% CI, 0.012-0.641; P = .017) on multivariate analysis. CONCLUSION: The development of irAEs was associated with increased survival in a real-world population of patients with advanced HCC treated with atezolizumab plus bevacizumab. Grade 1/2 irAEs were strongly correlated with PFS and OS.

Deep breathing alleviates propofol-induced pain: a prospective, randomized, single-blind study.

PURPOSE: Propofol is commonly used to induce general anesthesia; however, the pain caused during propofol injection is a disadvantage. This study aimed to assess whether deep breathing attenuates propofol injection pain. METHODS: This prospective, single-blind, randomized controlled study included 200 patients who were scheduled to undergo elective surgery under general anesthesia and randomly and equally divided them into group D and group C. The observers were not blinded to the pain-relieving modality, but each patient was blinded. Group D patients were requested to repeatedly take deep breaths throughout general anesthesia induction with propofol. Group C patients were requested to breathe in the usual manner. The intensity of propofol injection pain was evaluated using the visual analog scale (VAS). Furthermore, we recorded the patients' pain expressions, including grimace or hand-withdrawal, and the recalled pain measured using a VAS in the post-anesthetic care units (PACU). RESULTS: Compared with patients in group C, those in group D showed significantly reduced VAS scores for propofol injection pain (20 [interquartile range (IQR): 0-48] vs. 37 [IQR 9-65], P = 0.017) and recalled pain in the PACU (16 [IQR 0-32] vs. 26 [IQR 0.5-51], P = 0.031). Further, the grimace incidence was significantly lower in group D (18%) than in group C (45%) (P < 0.001). There was no significant difference in the incidence of pain at induction, recalled pain, or hand-withdrawal. CONCLUSIONS: Deep breathing could be an easy, safe, and inexpensive method for reducing pain during propofol injection.

Validation of Continuous Noninvasive Blood Pressure Monitoring Using Error Grid Analysis.

BACKGROUND: Error grid analysis was recently proposed to compare blood pressure obtained by 2 measurement methods. This study aimed to compare continuous noninvasive blood pressure (CNBP) with invasive blood pressure (IBP) using the error grid analysis and investigate the confounding risk factors attributable to the differences between CNBP and IBP. METHODS: Sixty adult patients undergoing general anesthesia were prospectively enrolled. Simultaneous comparative data regarding CNBP and IBP were collected. The Bland-Altman analysis was conducted to compare CNBP and IBP for systolic blood pressure (SBP) and mean blood pressure (MBP; acceptable accuracy: mean bias <5 mm Hg; standard deviation <8 mm Hg). The clinical relevance of the discrepancies between CNBP and IBP was evaluated by the error grid analysis, which classifies the differences into 5 zones from "no risk" (A) to "dangerous risk" (E). Additionally, an ordinal logistic regression analysis was performed to evaluate the relationship between the risk zones for MBP, classified by the error grid analysis and covariates of interest. RESULTS: A total of 10,663 pairs of CNBP/IBP were finally analyzed. The Bland-Altman analysis showed an acceptable accuracy with a bias of -3.3 ± 5.6 mm Hg for MBP but a poor accuracy with a bias of 5.4 ± 10.5 mm Hg for SBP. The error grid analysis showed the proportions of zones A to E as 96.7%, 3.2%, 0.1%, 0%, and 0% for SBP, respectively, and 72.0%, 27.9%, 0.1%, 0%, and 0% for MBP, respectively. The finger cuff missed 23.9% of epochs when SBP <90 mm Hg and 55.3% of epochs when MBP <65 mm Hg. The ordinal logistic regression analysis revealed that older age (adjusted odds ratio for decade: 1.54, 95% confidence interval [CI], 1.15-2.08; P = .004) and length of time from the initiation of finger cuff inflation (adjusted odds ratio for 60 minutes: 1.40, 95% CI, 1.13-1.73; P = .002) were significant factors of being in a more dangerous zone of the error grid. CONCLUSIONS: The error grid analysis revealed the larger clinical discrepancy between CNBP and IBP in MBP compared with that in SBP. Old age and longer finger cuff inflation time were significant factors of being in a more dangerous zone of the error grid, which could affect the hemodynamic management during surgery.

Changes in corrected carotid flow time induced by recruitment maneuver predict fluid responsiveness in patients undergoing general anesthesia.

Non-invasive methods to assess patients' fluid responsiveness during lung-protective ventilation are needed. We hypothesized changes in the corrected carotid flow time induced by the recruitment maneuver predict fluid responsiveness under general anesthesia. Thirty patients undergoing general anesthesia in the supine position were prospectively enrolled. The study protocol was conducted when the patient was hemodynamically stable during surgery. Flow time was measured on Doppler images of the common carotid artery. Carotid flow time, heart rate, stroke volume, stroke volume variation, and pulse pressure variation were recorded before and after a recruitment maneuver at a continuous airway pressure of 30 cmH2O for 30 s, and before and after volume expansion with 250 mL for 10 min. Patients were defined as fluid responders if the increase in stroke volume was > 10% after volume expansion. Twenty patients (67%) were fluid responders. All Doppler images for carotid flow time were obtained within 30 s. Changes in the corrected flow time accurately predicted fluid responsiveness (area under the curve: 0.82, 95% confidence interval [CI] 0.64-0.94, p = 0.002). The optimal threshold for changes in the corrected flow time was - 11.7% with a sensitivity of 95.0% (95% CI 75.1-99.9%) and a specificity of 80.0% (95% CI 44.4-97.5%). The gray-zone of changes in the corrected flow time was from - 25.1 to - 12.2% and included 12 patients (40%). Changes in the corrected carotid flow time were a useful, technically easy-to-perform, and non-invasive method to predict fluid responsiveness without a need for hemodynamic monitoring or arterial cannulation.

Hemodynamic Changes via the Lung Recruitment Maneuver Can Predict Fluid Responsiveness in Stroke Volume and Arterial Pressure During One-Lung Ventilation.

BACKGROUND: We aimed to evaluate the ability of lung recruitment maneuver-induced hemodynamic changes to predict fluid responsiveness in patients undergoing lung-protective ventilation during one-lung ventilation (OLV). METHODS: Thirty patients undergoing thoracic surgery with OLV (tidal volume: 6 mL/kg of ideal body weight and positive end-expiratory pressure: 5 cm H2O) were enrolled. The study protocol began 30 minutes after starting OLV. Simultaneous recordings were performed for hemodynamic variables of heart rate, mean arterial pressure (MAP), stroke volume (SV), pulse pressure variation (PPV), and stroke volume variation (SVV) were recorded at 4 time points: before recruitment maneuver (continuous airway pressure: 30 cm H2O for 30 seconds), at the end of recruitment maneuver, and before and after volume loading (250 mL over 10 minutes). Patients were recognized as fluid responders if the increase in SV or MAP was >10%. Receiver operating characteristic curves for percent decrease in SV and MAP by recruitment maneuver (ΔSVRM and ΔMAPRM, respectively) were generated to evaluate the ability to discriminate fluid responders from nonresponders. The gray-zone approach was applied for ΔSVRM and ΔMAPRM. RESULTS: Of 30 patients, there were 17 SV-responders (57%) and 12 blood pressure (BP)-responders (40%). Area under the curve (AUC) for ΔSVRM to discriminate SV-responders from nonresponders was 0.84 (95% confidence interval [CI], 0.67-0.95; P < .001). The best threshold for ΔSVRM to discriminate the SV-responders was -23.7% (95% CI, -41.2 to -17.8; sensitivity, 76.5% [95% CI, 50.1-93.2]; specificity, 84.6% [95% CI, 54.6-98.1]). For BP-responders, AUC for ΔMAPRM was 0.80 (95% CI, 0.61-0.92, P < .001). The best threshold for ΔMAPRM was -17.3% (95% CI, -23.9 to -5.1; sensitivity, 75.0% [95% CI, 42.8-94.5]; specificity, 77.8% [95% CI, 52.4-93.6]). With the gray-zone approach, the inconclusive range of ΔSVRM for SV-responders was -40.1% to -13.8% including 13 (43%) patients, and that of ΔMAPRM was -23.9% to -5.1%, which included 16 (53%) patients. CONCLUSIONS: ΔSVRM and ΔMAPRM could predict hemodynamic responses after volume expansion during OLV.

Changes in stroke volume induced by lung recruitment maneuver can predict fluid responsiveness during intraoperative lung-protective ventilation in prone position.

BACKGROUND: The present study aimed to evaluate the reliability of hemodynamic changes induced by lung recruitment maneuver (LRM) in predicting stroke volume (SV) increase after fluid loading (FL) in prone position. METHODS: Thirty patients undergoing spine surgery in prone position were enrolled. Lung-protective ventilation (tidal volume, 6-7 mL/kg; positive end-expiratory pressure, 5 cmH2O) was provided to all patients. LRM (30 cmH2O for 30 s) was performed. Hemodynamic variables including mean arterial pressure (MAP), heart rate, SV, SV variation (SVV), and pulse pressure variation (PPV) were simultaneously recorded before, during, and at 5 min after LRM and after FL (250 mL in 10 min). Receiver operating characteristic curves were generated to evaluate the predictability of SVV, PPV, and SV decrease by LRM (ΔSVLRM) for SV responders (SV increase after FL > 10%). The gray zone approach was applied for ΔSVLRM. RESULTS: Areas under the curve (AUCs) for ΔSVLRM, SVV, and PPV to predict SV responders were 0.778 (95% confidence interval: 0.590-0.909), 0.563 (0.371-0.743), and 0.502 (0.315-0.689), respectively. The optimal threshold for ΔSVLRM was 30% (sensitivity, 92.3%; specificity, 70.6%). With the gray zone approach, the inconclusive values ranged 25 to 75% for ΔSVLRM (including 50% of enrolled patients). CONCLUSION: In prone position, LRM-induced SV decrease predicted SV increase after FL with higher reliability than traditional dynamic indices. On the other hand, considering the relatively large gray zone in this study, future research is needed to further improve the clinical significance. TRIAL REGISTRATION: UMIN Clinical Trial Registry UMIN000027966 . Registered 28th June 2017.

Effect of Systemic Vascular Resistance on the Reliability of Noninvasive Hemodynamic Monitoring in Cardiac Surgery.

OBJECTIVE: To assess the effect of systemic vascular resistance (SVR) on the reliability of the ClearSight system (Edwards Lifesciences, Irvine, CA) for measuring blood pressure (BP) and cardiac output (CO). DESIGN: Observational study. SETTING: University hospital. PARTICIPANTS: Twenty-five patients undergoing cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: BP, measured using ClearSight and an arterial line, and CO, measured using ClearSight and a pulmonary artery catheter, were recorded before (T1) and two minutes after phenylephrine or ephedrine administration. Bland-Altman analysis was used to compare BP and CO measurements at T1. A polar plot was used to assess trending abilities. Patients were divided into the following three groups according to the SVR index (SVRI) at T1: low (<1,200 dyne s/cm5/m2), normal (1,200-25,00 dyne s/cm5/m2), and high (>2,500 dyne s/cm5/m2). The bias in BP and CO was -4.8 ± 8.9 mmHg and 0.10 ± 0.81 L/min, respectively, which was correlated significantly with SVRI (p < 0.05). The percentage error in CO was 40.6%, which was lower in the normal SVRI group (33.3%) than the low and high groups (46.3% and 47.7%, respectively). The angular concordance rate was 96.3% and 95.4% for BP and 87.0% and 92.5% for CO after phenylephrine and ephedrine administration, respectively. There was a low tracking ability for CO changes after phenylephrine administration in the low-SVRI group (angular concordance rate 33.3%). CONCLUSION: The ClearSight system showed an acceptable accuracy in measuring BP and tracking BP changes in various SVR states; however, the accuracy of CO measurement and its trending ability in various SVR states was poor.

Radiotherapy for Hepatocellular Carcinoma Results in Comparable Survival to Radiofrequency Ablation: A Propensity Score Analysis.

Potentially curative treatments for early-stage hepatocellular carcinoma (HCC) have drawbacks and contraindications. Recently, radiotherapy has achieved good outcomes. We compared the outcomes of radiotherapy and radiofrequency ablation (RFA) for early-stage HCC. Consecutive patients with ≤3 early-stage HCC lesions and tumor diameters ≤3 cm treated with RFA or radiotherapy were reviewed. RFA was the first choice for HCC unsuitable for surgery. Otherwise, stereotactic body radiotherapy in five fractions was mainly performed. For HCC adjacent to the gastrointestinal tract, radiotherapy with mild hypofractionation was performed. Propensity score matching was performed to reduce the selection bias between the RFA and radiotherapy groups. Between 2012 and 2016, a total of 231 patients with 474 tumors and 143 patients with 221 tumors were eligible and were treated with RFA and radiotherapy, respectively. In an unmatched comparison, the 3-year local recurrence rate was significantly lower for radiotherapy than for RFA (5.3%; 95% confidence interval [CI], 2.7-9.2; versus 12.9%, 95% CI, 9.9-16.2) (P < 0.01). A propensity score matching analysis of 106 patients in each group successfully matched the two treatment groups with regard to Barcelona Clinic Liver Cancer staging, T stage, and tumor size but not the adjacency of the tumor to risk organs or first or salvage treatment. The 3-year overall survival rates for RFA and radiotherapy patients were comparable (69.1%; 95% CI, 58.2-77.7; and 70.4%; 95% CI, 58.5-79.4, respectively; P = 0.86). Conclusion: Radiotherapy has excellent local control and comparable overall survival in patients with well-compensated liver function, exhibiting advantageous characteristics and compensating for the deficiencies of other treatment modalities; radiotherapy appears to be an acceptable alternative treatment option for patients who are not candidates for RFA.

Is platelet monitoring during 7-day lusutrombopag treatment necessary in chronic liver disease patients with thrombocytopenia undergoing planned invasive procedures? A phase IIIb open-label study.

AIM: Lusutrombopag is approved for thrombocytopenia in chronic liver disease patients planned to undergo invasive procedures. In previous clinical studies, lusutrombopag treatment was stopped in patients with an increase in platelet count (PC) of ≥20 × 109 /L from baseline and whose PC was ≥50 × 109 /L (discontinuation criteria). We assessed the influence of platelet monitoring during lusutrombopag treatment in lusutrombopag-naïve patients. METHODS: In this open-label study, Child-Pugh class A and B (A/B) patients were enrolled and treated with lusutrombopag (3 mg/day) for 7 days. In the treatment-naïve A/B-1 group, the discontinuation criteria were applied on day 6. In the treatment-naïve A/B-2 group, the criteria were not applied. In a non-naïve A/B group, the criteria were applied on days 3 and 5-7. The main efficacy end-point was the proportion of patients without platelet transfusion (PT) before the primary invasive procedure. RESULTS: In the A/B-1, A/B-2, and non-naïve A/B groups, the proportions of patients without PT were 80.9% (38/47), 83.0% (39/47), and 75.0% (6/8), respectively. The mean durations of PC ≥ 50 × 109 /L without PT were 20.7, 20.3, and 22.8 days, respectively. Excessive PC increases (≥200 × 109 /L) were not detected in any group. Treatment-related adverse events occurred in 4.3%, 6.4%, and 0% of A/B-1, A/B-2, and non-naïve A/B patients, respectively. Severe portal vein thrombosis occurred in one A/B-2 patient (PC 75 × 109 /L at onset). CONCLUSIONS: No meaningful efficacy and safety differences were observed among the groups with or without discontinuation criteria and the non-naïve group. These findings support lusutrombopag treatment without platelet monitoring and retreatment with lusutrombopag.

Impact of intraoperative goal-directed fluid therapy on major morbidity and mortality after transthoracic oesophagectomy: a multicentre, randomised controlled trial.

BACKGROUND: Transthoracic oesophagectomy is associated with major morbidity and mortality, which may be reduced by goal-directed therapy (GDT). The aim of this multicentre, RCT was to evaluate the impact of intraoperative GDT on major morbidity and mortality in patients undergoing transthoracic oesophagectomy. METHODS: Adult patients undergoing transthoracic oesophagectomy were randomised to receive either minimally invasive intraoperative GDT (stroke volume variation <8%, plus systolic BP maintained >90 mm Hg by pressors as necessary) or haemodynamic management left to the discretion of attending senior anaesthetists (control group; systolic BP >90 mm Hg alone). The primary outcome was the incidence of death or major complications (reoperation for bleeding, anastomotic leakage, pneumonia, reintubation, >48 h ventilation). A Cox proportional hazard model was used to examine whether the effects of GDT on morbidity and mortality were independent of other potential confounders. RESULTS: A total of 232 patients (80.6% male; age range: 36-83 yr) were randomised to either GDT (n=115) or to the control group (n=117). After surgery, major morbidity and mortality were less frequent in 22/115 (19.1%) subjects randomised to GDT, compared with 41/117 (35.0%) subjects assigned to the control group {absolute risk reduction: 15.9% (95% confidence interval [CI]: 4.7-27.2%); P=0.006}. GDT was also associated with fewer episodes of atrial fibrillation (odds ratio [OR]: 0.18 [95% CI: 0.05-0.65]), respiratory failure (OR: 0.27 [95% CI: 0.09-0.83]), use of mini-tracheotomy (OR: 0.29 [95% CI: 0.10-0.81]), and readmission to ICU (OR: 0.09 [95% CI: 0.01-0.67]). GDT was independently associated with morbidity and mortality (hazard ratio: 0.51 [95% CI: 0.30-0.87]; P=0.013). CONCLUSIONS: Intraoperative GDT may reduce major morbidity and mortality, and shorten hospital stay, after transthoracic oesophagectomy. CLINICAL TRIAL REGISTRATION: UMIN000018705.

Impact of deep breathing on predictability of stroke volume variation in spontaneous breathing patients.

BACKGROUND: This study investigated the ability of stroke volume variation (SVV) during deep breathing to discriminate fluid responders among spontaneously breathing patients. METHODS: Thirty patients undergoing general anaesthesia were enrolled and assessed before anaesthetic induction. Haemodynamic variables, including stroke volume (SV) and SVV, were measured using the ClearSight system during normal breathing. After these measurements, each patient was required to maintain deep breathing (6 breaths min-1 ) and haemodynamic variables were recorded. Then, the table was adjusted to the Trendelenburg position (15°) for 2 minutes, and haemodynamic variables were measured. Receiver operating characteristic curves were created for SVV during normal and deep breathing, and the difference in SVV between normal and deep breathing (ΔSVV) to discriminate fluid responders (SV increase >10% after changing position). The correlation between SV increase and ΔSVV was examined using Pearson's correlation coefficient. The grey zone approach was used to assess the inconclusive range of the haemodynamic variables. RESULTS: Receiver operating characteristic curve analysis indicated that ΔSVV showed good reliability in predicting fluid responsiveness (AUC: 0.850; 95% CI: 0.672-0.953; threshold: 4%, sensitivity: 75.0%, specificity: 88.9%], while SVV during normal breathing did not (AUC: 0.579; 95% CI: 0.386-0.756)]. Although SVV during deep breathing exhibited acceptable predictability (AUC: 0.778; 95% CI: 0.589-0.908), the sensitivity was not good (58.3%). With the grey zone approach, the inconclusive range of ΔSVV was small with the range of 1.4%-4.2% (23% of patients). CONCLUSION: Deep breathing could improve the reliability of dynamic indices in spontaneously breathing patients. TRIAL REGISTRATION: UMIN-CTR, identifer: UMIN000027970. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000032040.

Clinical course of 2019 novel coronavirus disease (COVID-19) in individuals present during the outbreak on the Diamond Princess cruise ship.

We investigated the clinical course of individuals with 2019 novel coronavirus disease (COVID-19) who were transferred from the Diamond Princess cruise ship to 12 local hospitals. The conditions and clinical courses of patients with pneumonia were compared with those of patients without pneumonia. Among 70 patients (median age: 67 years) analyzed, the major symptoms were fever (64.3%), cough (54.3%), and general fatigue (24.3%). Forty-three patients (61.4%) had pneumonia. Higher body temperature, heart rate, and respiratory rate as well as higher of lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and C-reactive protein (CRP) levels and lower serum albumin level and lymphocyte count were associated with the presence of pneumonia. Ground-glass opacity was found in 97.7% of the patients with pneumonia. Patients were administered neuraminidase inhibitors (20%), lopinavir/ritonavir (32.9%), and ciclesonide inhalation (11.4%). Mechanical ventilation and veno-venous extracorporeal membrane oxygenation was performed on 14 (20%) and 2 (2.9%) patients, respectively; two patients died. The median duration of intubation was 12 days. The patients with COVID-19 transferred to local hospitals during the outbreak had severe conditions and needed close monitoring. The severity of COVID-19 depends on the presence of pneumonia. High serum LDH, AST and CRP levels and low serum albumin level and lymphocyte count were found to be predictors of pneumonia. It was challenging for local hospitals to admit and treat these patients during the outbreak of COVID-19. Assessment of severity was crucial to manage a large number of patients.

Comparison of the venous-arterial CO2 to arterial-venous O2 content difference ratio with the venous-arterial CO2 gradient for the predictability of adverse outcomes after cardiac surgery.

This study aimed to compare the prognostic performance of the ratio of mixed and central venous-arterial CO2 tension difference to arterial-venous O2 content difference (Pv-aCO2/Ca-vO2 and Pcv-aCO2/Ca-cvO2, respectively) with that of the mixed and central venous-to-arterial carbon dioxide gradient (Pv-aCO2 and Pcv-aCO2, respectively) for adverse events after cardiac surgery. One hundred and ten patients undergoing cardiac surgery with cardiopulmonary bypass were enrolled. After catheter insertion, three blood samples were withdrawn simultaneously through arterial pressure, central venous, and pulmonary artery catheters, before and at the end of the operation, and preoperative and postoperative values were determined. The primary end-point was set as the incidence of postoperative major organ morbidity and mortality (MOMM). Receiver operating characteristic (ROC) curve and multivariate logistic regression analyses were performed to evaluate the prognostic reliability of Pv-aCO2, Pcv-aCO2, Pv-aCO2/Ca-vO2, and Pcv-aCO2/Ca-cvO2 for MOMM. MOMM events occurred in 25 patients (22.7%). ROC curve analysis revealed that both postoperative Pv-aCO2/Ca-vO2 and Pcv-aCO2/Ca-cvO2 were significant predictors of MOMM. However, postoperative Pv-aCO2 was the best predictor of MOMM (area under the curve [AUC]: 0.804; 95% confidence interval [CI] 0.688-0.921), at a 5.1-mmHg cut-off, sensitivity was 76.0%, and specificity was 74.1%. Multivariate analysis revealed that postoperative Pv-aCO2 was an independent predictor of MOMM (odds ratio [OR]: 1.42, 95% CI 1.01-2.00, p = 0.046) and prolonged ICU stay (OR: 1.45, 95% CI 1.05-2.01, p = 0.024). Pv-aCO2 at the end of cardiac surgery was a better predictor of postoperative complications than Pv-aCO2/Ca-vO2 and Pcv-aCO2/Ca-cvO2.

Lusutrombopag Reduces Need for Platelet Transfusion in Patients With Thrombocytopenia Undergoing Invasive Procedures.

BACKGROUND & AIMS: Platelet transfusion is used to prevent hemorrhagic events in patients with thrombocytopenia undergoing invasive procedures, but there are many disadvantages. We evaluated the efficacy and safety of lusutrombopag in patients with chronic liver disease and thrombocytopenia undergoing invasive procedures. METHODS: We performed a double-blind, parallel-group, phase 3 study of 96 patients with chronic liver disease and thrombocytopenia (platelet counts below 50,000/µL) undergoing invasive procedures from October 2013 to May 2014 at 81 centers in Japan. Patients were randomly assigned (1:1) to groups given once-daily lusutrombopag (3 mg) or placebo for up to 7 days. The primary efficacy endpoint was the proportion of patients not requiring platelet transfusion before the invasive procedure. The protocol-defined response (platelet count 50,000/µL or more with an increase of 20,000/µL or more from baseline) and the time course of the change in platelet count were also evaluated. Adverse events were recorded. RESULTS: The proportions of patients who did not require preoperative platelet transfusion were 79.2% (38/48) in the lusutrombopag group and 12.5% (6/48) in the placebo group (P < .0001). A response was observed in 77.1% (37/48) of patients in the lusutrombopag group and 6.3% (3/48) of patients in the placebo group (P < .0001). In the lusutrombopag group without platelet transfusion, the median platelet count was 50,000/µL or more after 5 days; the mean time to reach the maximum platelet count was 13.4 days; and the number of days (adjusted mean) during which the platelet count was 50,000/µL or more was 21.09 days. Adverse drug reactions were reported in 8.3% of patients in the lusutrombopag group and 2.1% of patients in the placebo group. Two patients (1 per group) had a thrombotic event, but neither were associated with an excessive increase in platelet count (200,000/µL or more). CONCLUSION: In a placebo-controlled trial, lusutrombopag was effective in achieving and maintaining the target platelet count in patients with chronic liver disease and thrombocytopenia undergoing invasive procedures. No significant safety concerns were raised. Japanese clinical trial registration no: JapicCTI-132323.

Randomized, phase II trial of sequential hepatic arterial infusion chemotherapy and sorafenib versus sorafenib alone as initial therapy for advanced hepatocellular carcinoma: SCOOP-2 trial.

BACKGROUND: The efficacy of hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (HCC) remains unclear. We conducted a multi-center randomized phase II study comparing a sequential HAIC-sorafenib regimen versus sorafenib alone as an initial therapy for HCC. METHODS: Patients were randomly assigned (ratio, 1:1) to receive sequential HAIC with cisplatin followed by sorafenib (HAIC group, n = 35) or sorafenib alone (sorafenib group, n = 33) as an initial therapy. The primary endpoint was the one-year survival rate. Secondary endpoint included overall survival (OS), the 2-year survival rate, the time-to-progression (TTP), the objective response rate (ORR), the disease control rate (DCR), and safety. RESULTS: For the primary endpoint, the one-year survival rates were 46% in the HAIC group and 58% in the sorafenib group. The median OS period was 10.0 months (95% CI, 7.0-18.8) in the HAIC group and 15.2 months (95% CI, 8.2-19.7) in the sorafenib group (hazard ratio [HR], 1.08; 95% CI, 0.63 to 1.86, P = 0.78). The median TTP, ORR and DCR in the HAIC group were 2.8 months (95% CI, 1.7-5.5), 14.3, and 45.7%, respectively, while those in the sorafenib group were 3.9 months (95% CI, 2.3-6.8), 9.1, and 45.5%, respectively. No unexpected adverse events related to HAIC or sorafenib were observed in either group. CONCLUSIONS: Sequential HAIC with cisplatin and sorafenib does not improve the survival benefit, compared with sorafenib alone, when used as an initial therapy for advanced HCC. However, this study was underpowered in regard to its primary and secondary endpoints, so the results should be interpreted with caution. TRIAL REGISTRATION: UMIN ID 000006147 , registration data: August 11, 2011.

Circulating microRNA-1246 as a possible biomarker for early tumor recurrence of hepatocellular carcinoma.

AIMS: Early tumor recurrence (ETR) after hepatic resection is a crucial predictor of poor prognosis in patients with hepatocellular carcinoma (HCC). The aim of this study was to identify clinically significant serum microRNAs (miRNAs) involved in the ETR of HCC. METHODS: We compared expression profiles of circulating miRNAs from serum samples between five HCC patients with ETR (recurrence within 12 months after hepatectomy) and five HCC patients without recurrence using microarray analysis of miRNA. The identified miRNA associated with ETR was further verified in 121 HCC patients, 73 liver disease patients, and 15 health controls by real-time quantitative reverse transcription-polymerase chain reaction (PCR). RESULTS: Of the approximately 2000 miRNAs analyzed, we identified 15 miRNAs for which expression levels correlated significantly with ETR. Of these miRNAs, we further investigated expression of miRNA-1246 (miR-1246). Quantitative PCR confirmed that miR-1246 was upregulated in HCC with ETR, compared to the level in HCC without ETR (P < 0.001). Serum miR-1246 showed a receiver operating characteristic curve area of 0.762, with 77.4% specificity and 54.1% sensitivity in discriminating HCC patients with ETR from HCC patients without ETR. Altered expression of miR-1246 was associated with aggressive tumor characteristics, including tumor-node-metastasis classification (P = 0.0413), tumor differentiation (P = 0.0419), and portal vein invasion (P = 0.0394). Moreover, multivariate Cox regression analysis identified serum miR-1246 level as an independent risk factor for overall survival (hazard ratio, 2.784; 95% confidence interval, 1.528-5.071; P = 0.0008). CONCLUSION: Circulating miR-1246 in serum has strong potential as a novel ETR and prognostic biomarker for HCC.

The Sum of Early Diastolic Annulus Velocities in the Mitral and Tricuspid Valve Can Predict Adverse Events After Cardiac Surgery.

OBJECTIVES: To assess whether a tissue Doppler imaging (TDI)-based parameter consisting of the sum of early diastolic velocities of the mitral annulus (Me') and tricuspid annulus (Te') can serve as a predictor of adverse outcomes after cardiac surgery. DESIGN: Prospective, observational study. SETTING: University hospital. PARTICIPANTS: The study comprised 100 patients undergoing cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After anesthetic induction, transesophageal echocardiography was performed to obtain the values of the early transmitral flow velocity (E), Me', and Te'. The primary endpoint was the incidence of postoperative major organ morbidity and mortality (MOMM) events, including death, redo surgery, prolonged ventilation, stroke, sternal infection, and dialysis. Receiver operating characteristic and multivariate logistic analyses were used to examine the prognostic performance of TDI-based parameters for predicting MOMM incidence. The secondary endpoint was the incidence of death or rehospitalization for cardiovascular disease within 1 year post-discharge. TDI-based parameters were measured in 87 of the 100 patients enrolled. Me' plus Te' had better prognostic ability (area under the curve 0.771; threshold 13 cm/s; sensitivity 86.7%; specificity 64.9%) than that of Me' or E to Me' (E/Me')% and was an independent predictor of MOMM (odds ratio 0.45; 95% confidence interval 0.28-0.74, p = 0.001), whereas Me' was not. Lower Me' plus Te' (≤13 cm/s) was associated with a significantly higher incidence and earlier onset of cardiovascular events within 1 year post-discharge (p = 0.012). CONCLUSIONS: Compared with Me' and E/Me', which traditionally are used for assessing diastolic function, Me' plus Te' showed better prognostic ability for both short- and long-term outcomes of cardiac surgery.

Comparison Between Low Mechanical Index and High Mechanical Index Contrast Modes of Contrast-Enhanced Ultrasonography: Evaluation of Perfusion Defects of Hypervascular Hepatocellular Carcinomas During the Post-Vascular Phase.

OBJECTIVES: We evaluated the detection rates for perfusion defects in hypervascular hepatocellular carcinomas comparing the low mechanical index (MI) and high MI contrast modes during the post-vascular phase (PVP) of contrast-enhanced ultrasonography. METHODS: Seventy-eight patients with 84 hypervascular hepatocellular carcinomas (mean diameter, 23.4 ± 11.2 mm) were selected for this retrospective study. All the patients underwent whole-liver scanning using conventional ultrasonography before injection of a perflubutane-based contrast agent (Sonazoid), and all the detected nodules were classified as either hypoechoic or hyperechoic nodules. Next, hypoechoic and hyperechoic nodules were evaluated using contrast-enhanced ultrasonography, and the presence of a perfusion defect was assessed for each nodule using both the low MI (0.2-0.3) and the high MI (0.7-1.2) contrast modes during the PVP (10 minutes after injection). The data were analyzed using the McNemar test. RESULTS: Forty-four nodules were classified as hypoechoic nodules, and the remaining 40 nodules were classified as hyperechoic nodules using conventional ultrasonography. The detection rate for perfusion defects determined using the high MI contrast mode was higher than that determined using the low MI contrast mode in hyperechoic nodules during the PVP (low MI, 58% [23 of 40]; high MI, 90% [36 of 40]; P < .0001). However, no significant difference was observed between the low MI and the high MI contrast modes in hypoechoic nodules (low MI, 80% [35 of 44]; high MI, 89% [39 of 44]; P = .125). CONCLUSION: Compared with the low MI contrast mode, the high MI contrast mode was more sensitive for detecting perfusion defects in hypervascular hepatocellular carcinomas in patients with hyperechoic nodules during the PVP.

General Anesthesia Management for Adult Mucopolysaccharidosis Patients Undergoing Major Spine Surgery.

OBJECTIVE: Mucopolysaccharidosis (MPS) are a group of rare systemic lysosomal storage diseases associated with severe airway obstruction and cardiac disease, making anesthesia management difficult. Contemporary treatment extends the lifespan of affected individuals, increasing the need for major surgery in adulthood. CLINICAL PRESENTATION AND INTERVENTION: We provided general anesthesia for 6 adult MPS patients undergoing spine surgery. The airway was assessed as difficult in all, with 2 receiving awake fiberoptic intubation and 1 successfully undergoing video-laryngoscopy, while 3 video-laryngoscopy procedures failed and required conversion to fiberoptic intubation. One patient developed ventricular fibrillation. CONCLUSION: Adult MPS patients have substantial anesthesia risk.

Pre-anesthetic stroke volume variation can predict cardiac output decrease and hypotension during induction of general anesthesia.

This study aimed to assess the reliability of stroke volume variation (SVV) in predicting cardiac output (CO) decrease and hypotension during induction of general anesthesia. Forty-five patients undergoing abdominal surgery under general anesthesia were enrolled. Before induction of anesthesia, patients were required to maintain deep breathing (6-8 times/min), and pre-anesthetic SVV was measured for 1 min by electrical cardiometry. General anesthesia was induced with propofol, remifentanil, rocuronium, and sevoflurane. Study duration was defined from the start of fluid administration till 5 min after tracheal intubation. Blood pressure (BP) was measured every minute. Cardiac output was measured continuously by electrical cardiometry. Receiver operating characteristics (ROC) curves were made regarding the incidence of decreased CO (less than 70% of the baseline) and hypotension (mean BP <65 mmHg). The risk of developing decreased CO and hypotension was evaluated by multivariate logistic regression analysis. The time from the start of the procedure to onset of decreased CO was analyzed by the Kaplan-Meier method. The area under the ROC curve and optimal threshold value of pre-anesthetic SVV for predicting decreased CO and hypotension were 0.857 and 0.693. Patients with lower SVV exhibited a significantly slower onset and lower incidence of decreased CO than those with higher SVV (p = 0.003). Multivariate logistic regression analysis indicated high pre-anesthetic SVV as being an independent risk factor for decreased CO and hypotension (odds ratio, 1.43 and 1.16, respectively). In conclusions, pre-anesthetic SVV can predict incidence of decreased CO and hypotension during induction of general anesthesia.