IMMUNOHISTOCHEMICAL EXPRESSION OF INSULIN-LIKE GROWTH FACTOR-1 RECEPTOR (IGF-1R) AND ITS ASSOCIATION WITH CLINICOPATHOLOGICAL PARAMETERS IN HEPATOCELLULAR CARCINOMA.

INTRODUCTION: Hepatocellular carcinoma (HCC) carcinogenesis is not yet fully known. Insulin-like Growth Factor-1 Receptor (IGF-1R) can translocate to the nucleus and modulate cellular growth, possibly participating in HCC development and aggressiveness. This study aims to evaluate the immunoexpression of IGF-1R in HCC, the cellular compartment involved, and its association with clinicopathological parameters and clinical outcomes. METHODS: Liver specimens from 111 HCC patients who underwent liver transplantation or partial surgical resections at a Brazilian referral hospital center were studied. IGF-1R expression was determined by immunohistochemistry, clinical data were collected from medical records, and pathological parameters were obtained from path review. RESULTS: IGF-1R nuclear expression was higher in the tumor than in the adjacent cirrhosis (p < 0.001). The odds of IGF-1R expression in the nucleus compared to the membrane are lower in the cirrhosis condition than in the tumor, suggesting an increase in the prevalence of nucleus expression relative to the membrane from cirrhosis to tumor. There was an association between IGF-1R nuclear expression in HCC and the moderate/poor grade of histologic differentiation (p < 0.001). However, long-term clinical outcomes were not associated with IGF-1R nuclear expression. CONCLUSION: The data presented here suggest the role of IGF-1R in HCC progression and carcinogenesis as its expression increases in the nucleus relative to the membrane, from cirrhosis to tumor, and it was associated with a poorer differentiated tumor grade. Further research is awaited to fully understand the mechanisms underlying this association.

Brain tissue oxygenation monitoring in subarachnoid hemorrhage for the detection of delayed ischemia: a systematic review and meta-analysis.

INTRODUCTION: Subarachnoid hemorrhage (SAH) is a severe subtype of stroke which can be caused by the rupture of an intracranial aneurysm. Following SAH, about 30% of patients develop a late neurologic deterioration due to a delayed cerebral ischemia (DCI). This is a metanalysis and systematic review on the association between values of brain tissue oxygenation (PbtO2) and DCI in patients with SAH. EVIDENCE ACQUISITION: The protocol was written according to the PRISMA-P (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and approved by the International Prospective Register of Systematic Reviews (PROSPERO registration number CRD42021229338). Relevant literature published up to August 1, 2022 was systematically searched throughout the databases MEDLINE, WEB OF SCIENCE, SCOPUS. A systematic review and metanalysis was carried out. The studies considered eligible were those published in English; that enrolled adult patients (≥18years) admitted to neurointensive care units with aneurysmal SAH (aSAH); that reported presence of multimodality monitoring including PbtO2 and detection of DCI during the period of monitoring. EVIDENCE SYNTHESIS: We founded 286 studies, of which six considered eligible. The cumulative mean of PbtO2 was 19.5 mmHg in the ischemic group and 24.1mmHg in the non ischemic group. The overall mean difference of the values of PbtO2 between the patients with or without DCI resulted significantly different (-4.32 mmHg [IC 95%: -5.70, -2.94], without heterogeneity, I2 = 0%, and a test for overall effect with P<0.00001). CONCLUSIONS: PbtO2 values were significantly lower in patients with DCI. Waiting for definitive results, monitoring of PbtO2 should be considered as a complementary parameter for multimodal monitoring of the risk of DCI in patients with SAH.

Continuous EEG monitoring by a new simplified wireless headset in intensive care unit.

BACKGROUND: In critically ill patients continuous EEG (cEEG) is recommended in several conditions. Recently, a new wireless EEG headset (CerebAir®,Nihon-Kohden) is available. It has 8 electrodes, and its positioning seems to be easier than conventional systems. Aim of this study was to evaluate the feasibility of this device for cEEG monitoring, if positioned by ICU physician. METHODS: Neurological patients were divided in two groups according with the admission to Neuro-ICU (Study-group:20 patients) or General-ICU (Control-group:20 patients). In Study group, cEEG was recorded by CerebAir® assembled by an ICU physician, while in Control group a simplified 8-electrodes-EEG recording positioned by an EEG technician was performed. RESULTS: Time for electrodes applying was shorter in Study-group than in Control-group: 6.2 ± 1.1' vs 10.4 ± 2.3'; p < 0.0001. Thirty five interventions were necessary to correct artifacts in Study-group and 11 in Control-group. EEG abnormalities with or without epileptic meaning were respectively 7(35%) and 7(35%) in Study-group, and 5(25%) and 9(45%) in Control-group;p > 0.05. In Study-group, cEEG was interrupted for risk of skin lesions in 4 cases after 52 ± 4 h. cEEG was obtained without EEG technician in all cases in Study-group; quality of EEG was similar. CONCLUSIONS: Although several limitations should be considered, this simplified EEG system could be feasible even if EEG technician was not present. It was faster to position if compared with standard techniques, and can be used for continuous EEG monitoring. It could be very useful as part of diagnostic process in an emergency setting.

Predicting Factors of Functional Outcome in Patients with Acute Ischemic Stroke Admitted to Neuro-Intensive Care Unit-A Prospective Cohort Study.

Although thrombectomy is beneficial for most stroke patients with large vessel occlusion (LVO), it has added new issues in acute management due to intensive care support. In this prospective cohort study, we described the patients admitted to our neuro-intensive care unit (NICU) after thrombectomy in order to assess factors linked to functional outcomes. The outcome was independency assessed for stroke patients consecutively admitted to NICU for an ischemic stroke due to LVO of the anterior cerebral circulation that underwent intra-arterial mechanical thrombectomy (IAMT), either in combination with intravenous thrombolysis (IVT) in eligible patients or alone in patients with contraindications for IVT. Overall, 158 patients were enrolled. IVT (odds ratio (OR), 3.78; 95% confidence interval (CI), 1.20-11.90; p = 0.023) and early naso-gastric tube removal (OR, 3.32; 95% CI, 1.04-10.59 p = 0.042) were associated with good outcomes, whereas a high baseline National Institutes of Health Stroke Scale (NIHSS) score (OR, 0.72 for each point of increase; 95% CI, 0.61-0.85; p < 0.001) was a predictor of poor outcomes at 3 months. Older age (OR, 0.95 for each year of increase; 95% CI, 0.92-0.99; p = 0.020) and hemorrhagic transformation (OR, 0.31; 95% CI, 0.11-0.84; p = 0.022) were predictors of poor outcomes after IAMT, whereas a modified Treatment in Cerebral Infarction (mTICI) score of 2b/3 was a predictor of good outcomes (OR, 7.86; 95% CI, 1.65-37.39; p = 0.010) at 6 months. Our results show that acute stroke patients with LVO who require NICU management soon after IAMT may show specific clinical factors influencing short- and long-term neurologic independency.

Expression of MAPK and PI3K/AKT/mTOR Proteins according to the Chronic Liver Disease Etiology in Hepatocellular Carcinoma.

AIMS: Chronic liver disease (CLD) of different etiologies leads to hepatocellular carcinoma (HCC) by multiple mechanisms that may be translated into clinicopathological differences. We evaluated the tissue expression of the MAPK and PI3K/Akt/mTOR pathway proteins and their association with long-term outcome and other parameters, according to the etiology of the CLD, in HCC patients. METHODS: Clinicopathological data from 80 patients who underwent orthotopic liver transplantation for HCC treatment in a Brazilian referral center were compared according to CLD etiology. Event (tumor recurrence or death from any cause) occurrence and event-free survival (EFS) were analyzed. Pathway protein expression was assessed by immunohistochemistry (IHQ) in both tumor and underlying cirrhosis and by RT-PCR in tumor tissue. RESULTS: Strong expression (SE) of KRAS was more frequent in tumors arising from viral (26.8%) than the nonviral group of liver disease (7.7%, p=0.024) and also than cirrhotic parenchyma (0%, p=0.004). SE of PI3K was more frequent in tumor than in cirrhosis (p=0.048, p < 0.01), without differences in its tumor expression among etiologic groups (p=0.111). mRNA of ERK, PI3K, and BRAF was expressed in the tumor, without differences between CLD etiologies, and there was no association with IHQ findings. Older age and microvascular invasion (MIV) were the only parameters independently associated with the event. MIV was also associated with shorter EFS. CONCLUSIONS: Hepatitis B and C virus can lead to HCC by different mechanisms compared with nonviral hepatopathy. KRAS and PI3K may have a role in carcinogenesis. The prognostic and therapeutic implications need to be investigated.

Clinical and laboratory parameters as predictors of long-term outcome according to the etiology of underlying chronic liver disease in patients who underwent liver transplantation for hepatocellular carcinoma treatment.

OBJECTIVES: This study aimed to analyze clinical and laboratory parameters and their association with long-term outcomes in patients who underwent liver transplantation for hepatocellular carcinoma treatment, according to the etiology of the underlying chronic liver disease, in order to identify predictors of response to this therapeutic modality. METHODS: Demographic, clinical, and laboratory data from a cohort of 134 patients who underwent orthotopic liver transplantation for hepatocellular carcinoma treatment at a referral center in Brazil were retrospectively selected and compared according to the etiologic group of the underlying chronic liver disease. Events, defined as tumor recurrence or death from any cause, and event-free survival were also analyzed, and multivariate analysis was performed. RESULTS: The etiologies comprised hepatitis C and B virus infection, alcohol abuse, and cryptogenic disorder. Although liver transplantation was performed outside the Milan criteria in 33.3% of the subjects, according to pathologic examination of the explanted liver, the Model for End-Stage Liver Disease score was low (<22) in most patients (70.6%) and recurrence was identified in only 10 (7.9%) patients. Events occurred in 37 patients (28.5%), and the median event-free survival was 75 months (range, 24-116 months). No difference among etiologic groups was found in the parameters analyzed, which were not independently associated with outcome. CONCLUSION: Clinical and laboratory characteristics according to etiologic groups were not different, which might have led to comparable long-term outcomes among these patient groups and failure to identify predictors that could aid in better selection of subjects for liver transplantation in the management of this cancer.

Clinical and laboratory parameters as predictors of long-term outcome according to the etiology of underlying chronic liver disease in patients who underwent liver transplantation for hepatocellular carcinoma treatment

OBJECTIVES: This study aimed to analyze clinical and laboratory parameters and their association with long-term outcomes in patients who underwent liver transplantation for hepatocellular carcinoma treatment, according to the etiology of the underlying chronic liver disease, in order to identify predictors of response to this therapeutic modality. METHODS: Demographic, clinical, and laboratory data from a cohort of 134 patients who underwent orthotopic liver transplantation for hepatocellular carcinoma treatment at a referral center in Brazil were retrospectively selected and compared according to the etiologic group of the underlying chronic liver disease. Events, defined as tumor recurrence or death from any cause, and event-free survival were also analyzed, and multivariate analysis was performed. RESULTS: The etiologies comprised hepatitis C and B virus infection, alcohol abuse, and cryptogenic disorder. Although liver transplantation was performed outside the Milan criteria in 33.3% of the subjects, according to pathologic examination of the explanted liver, the Model for End-Stage Liver Disease score was low (<22) in most patients (70.6%) and recurrence was identified in only 10 (7.9%) patients. Events occurred in 37 patients (28.5%), and the median event-free survival was 75 months (range, 24-116 months). No difference among etiologic groups was found in the parameters analyzed, which were not independently associated with outcome. CONCLUSION: Clinical and laboratory characteristics according to etiologic groups were not different, which might have led to comparable long-term outcomes among these patient groups and failure to identify predictors that could aid in better selection of subjects for liver transplantation in the management of this cancer.

Beneficial hemodynamic effects of prone positioning in patients with acute respiratory distress syndrome.

RATIONALE: The effects of prone positioning during acute respiratory distress syndrome on all the components of cardiac function have not been investigated under protective ventilation and maximal alveolar recruitment. OBJECTIVES: To investigate the hemodynamic effects of prone positioning. METHODS: We included 18 patients with acute respiratory distress syndrome ventilated with protective ventilation and an end-expiratory positive pressure titrated to a plateau pressure of 28-30 cm H2O. Before and within 20 minutes of starting prone positioning, hemodynamic, respiratory, intraabdominal pressure, and echocardiographic data were collected. Before prone positioning, preload reserve was assessed by a passive leg raising test. MEASUREMENTS AND MAIN RESULTS: In all patients, prone positioning increased the ratio of arterial oxygen partial pressure over inspired oxygen fraction, the intraabdominal pressure, and the right and left cardiac preload. The pulmonary vascular resistance decreased along with the ratio of the right/left ventricular end-diastolic areas suggesting a decrease of the right ventricular afterload. In the nine patients with preload reserve, prone positioning significantly increased cardiac index (3.0 [2.3-3.5] to 3.6 [3.2-4.4] L/min/m(2)). In the remaining patients, cardiac index did not change despite a significant decrease in the pulmonary vascular resistance. CONCLUSIONS: In patients with acute respiratory distress syndrome under protective ventilation and maximal alveolar recruitment, prone positioning increased the cardiac index only in patients with preload reserve, emphasizing the important role of preload in the hemodynamic effects of prone positioning.

End-expiratory occlusion test predicts preload responsiveness independently of positive end-expiratory pressure during acute respiratory distress syndrome.

OBJECTIVE: A 15-second end-expiratory occlusion increases cardiac preload and allows detection of preload dependence. We tested whether the reliability of this test depends upon positive end-expiratory pressure. DESIGN: : Prospective study. SETTING: Medical ICU. PATIENTS: Thirty-four patients presenting with acute circulatory failure and acute respiratory distress syndrome ventilated with a tidal volume of 6.7 mL/kg (interquartile range, 6.3-7.1). MEASUREMENTS: At positive end-expiratory pressure = 5 cm H2O, we measured the changes in cardiac index induced by end-expiratory occlusion and a passive leg raising test. Preload dependence was defined by a passive leg raising-induced increase in cardiac index greater than or equal to 10%. Positive end-expiratory pressure was increased to a plateau pressure of 30 cm H2O, and end-expiratory occlusion and passive leg raising were performed again. MAIN RESULTS: At positive end-expiratory pressure = 5 cm H2O, 29% of patients were passive leg raising responders. An end-expiratory occlusion-induced increase in cardiac index greater than or equal to 5% detected a passive leg raising-induced increase in cardiac index greater than or equal to 10% with a sensitivity of 90% (95% CI, 56-100) and a specificity of 88% (95% CI, 68-97). At higher positive end-expiratory pressure (15 cm H2O [interquartile range, 13-15]), the plateau pressure - positive end-expiratory pressure difference did not change (15 mm Hg [14-17] vs 15 mm Hg [13-18] before the positive end-expiratory pressure increase). Increasing positive end-expiratory pressure significantly reduced cardiac index in passive leg raising responders (-27% [interquartile range, -6 to -56]) but not in other patients. At high positive end-expiratory pressure, passive leg raising increased cardiac index to a larger extent than at positive end-expiratory pressure = 5 cm H2O (19% [interquartile range, 15-34] vs 16% [interquartile range, 13-23], respectively). The proportion of passive leg raising responders significantly increased (34 vs 29%, respectively), meaning preload dependence had increased. At higher positive end-expiratory pressure, an end-expiratory occlusion-induced increase in cardiac index greater than or equal to 6% detected a passive leg raising-induced increase in cardiac index greater than or equal to 10% with a sensitivity of 100% (95% CI, 75-100) and a specificity of 90% (95% CI, 70-99). CONCLUSIONS: The end-expiratory occlusion test is reliable for detecting preload dependence whatever the positive end-expiratory pressure during acute respiratory distress syndrome.

Extravascular lung water is an independent prognostic factor in patients with acute respiratory distress syndrome.

OBJECTIVE: Acute respiratory distress syndrome might be associated with an increase in extravascular lung water index and pulmonary vascular permeability index, which can be measured by transpulmonary thermodilution. We tested whether extravascular lung water index and pulmonary vascular permeability index are independent prognostic factors in patients with acute respiratory distress syndrome. DESIGN: Retrospective study. SETTING: Medical intensive care unit. PATIENTS: Two hundred consecutive acute respiratory distress syndrome patients (age = 57 ± 17, Simplified Acute Physiology Score II = 57 ± 20, overall day-28 mortality = 54%). MEASUREMENTS: Extravascular lung water index and pulmonary vascular permeability index were collected (PiCCO device, Pulsion Medical Systems) at each day of the acute respiratory distress syndrome episode. MAIN RESULTS: The maximum values of extravascular lung water index and pulmonary vascular permeability index recorded during the acute respiratory distress syndrome episode (maximum value of extravascular lung water index and maximum value of pulmonary vascular permeability index, respectively) were significantly higher in nonsurvivors than in survivors at day-28 (mean ± SD: 24 ± 10 mL/kg vs. 19 ± 7 mL/kg of predicted body weight, p < 0.001 [t-test] for maximum value of extravascular lung water index and median [interquartile range]: 4.4 [3.3-6.1] vs. 3.5 [2.8-4.4], p = 0.001 for maximum value of pulmonary vascular permeability index, Wilcoxon's test). In multivariate analyses, maximum value of extravascular lung water index or maximum value of pulmonary vascular permeability index, Simplified Acute Physiology Score II, maximum blood lactate, mean positive end-expiratory pressure, mean cumulative fluid balance, and the minimal ratio of arterial oxygen pressure over the inspired oxygen fraction were all independently associated with day-28 mortality. A maximum value of extravascular lung water index >21 mL/kg predicted day-28 mortality with a sensitivity of (mean [95% confidence interval]) 54% (44-63)% and a specificity of 73% (63-82)%. The mortality rate was 70% in patients with a maximum value of extravascular lung water index >21 mL/kg and 43% in the remaining patients (p = 0.0003). A maximum value of pulmonary vascular permeability index >3.8 predicted day-28 mortality with a sensitivity of (mean [95% confidence interval]) 67% (57-76)% and a specificity of 65% (54-75)%. The mortality rate was 69% in patients with a maximum value of pulmonary vascular permeability index >3.8 and 37% in the group with a maximum value of pulmonary vascular permeability index ≤ 3.8 (p < 0.0001). CONCLUSIONS: Extravascular lung water index and pulmonary vascular permeability index measured by transpulmonary thermodilution are independent risk factors of day-28 mortality in patients with acute respiratory distress syndrome.

Effects of norepinephrine on mean systemic pressure and venous return in human septic shock.

OBJECTIVES: Norepinephrine exerts venoconstriction that could increase both the mean systemic pressure and the resistance to venous return, but this has not yet been investigated in human septic shock. We examined the relative importance of both effects and the resulting effect on venous return when decreasing the dose of norepinephrine. SETTING: Intensive care unit. PATIENTS: Sixteen septic shock patients. MEASUREMENTS: For estimating the venous return curve, we constructed the regression line between the pairs of cardiac index (pulse contour analysis) and central venous pressure values. These values were measured during 15-sec end-inspiratory and end-expiratory ventilatory occlusions performed at two levels of positive end-expiratory pressure, in view of widening the range of cardiac index:central venous pressure measurements and increasing the accuracy of the regression line. The x-axis intercept of the regression line was used to estimate the mean systemic pressure and the inverse of the slope of the regression line to quantify resistance to venous return. These measurements were obtained before and after decreasing the dose of norepinephrine. Passive leg raising was performed before and after decreasing the dose of norepinephrine. MAIN RESULTS: Decreasing the dose of norepinephrine from 0.30 (0.10-1.40) to 0.19 (0.08-1.15) µg/kg/min decreased the mean systemic pressure from 33 ± 12 mm Hg to 26 ± 10 mm Hg (p = .0003). The slope of the multipoint cardiac index:central venous pressure relationship increased (p = .02). The resistance to venous return decreased, i.e., 1/slope decreased. Simultaneously, cardiac index decreased from 3.47 ± 0.86 L/min/m2 to 3.28 ± 0.76 L/min/m (p = .04), indicating a decrease in venous return. Passive leg raising increased cardiac index to a larger extent after (8% ± 4%) than before (1% ± 4%) decreasing norepinephrine (p = .001), suggesting an increase in unstressed blood volume at the lowest dose of norepinephrine. CONCLUSIONS: In septic shock patients, decreasing the dose of norepinephrine decreased the mean systemic pressure and, to a lesser extent, the resistance to venous return. As a result, venous return decreased.

Defining the adequate arterial pressure target during septic shock: not a 'micro' issue but the microcirculation can help.

The Surviving Sepsis Campaign guidelines suggest targeting a mean arterial pressure of at least 65 mm Hg to maintain organ perfusion pressure during septic shock. However, the optimal mean arterial pressure can be higher in patients with a history of hypertension or other vascular comorbidities or in those with increased abdominal pressure. In a given individual, the adequate mean arterial pressure target can be difficult to define with the routine hemodynamic parameters (for example, cardiac output, central or mixed venous blood oxygen saturation, and urine output). Near-infrared spectroscopy and sidestream dark field imaging have emerged as promising technologies for monitoring the microcirculation at the bedside. These new methods could provide additional clues to help define the adequate blood pressure to target during the resuscitation phase of septic shock.

Nonthyroidal illness syndrome and prolonged mechanical ventilation in patients admitted to the ICU.

BACKGROUND: The effect of the nonthyroidal illness syndrome (NTIS) on the duration of mechanical ventilation (MV) has not been extensively investigated. This study aims to determine whether the NTIS is associated with the duration of MV in patients admitted to the ICU. METHODS: We evaluated all patients admitted over a 6-year period to our ICU who underwent invasive MV and had measurement of serum free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH) performed in the first 4 days after ICU admission and, subsequently, at least every 8 days during the time they received MV. The primary outcome measure was prolonged MV (PMV), which was defined as dependence on MV for > 13 days. RESULTS: Two hundred sixty-four patients were included. Fifty-six patients (normal-hormone group) had normal thyroid function test results, whereas 208 patients (low-fT3 group) had, at least in one hormone dosage, low levels of fT3 with normal (n = 145)/low (n = 63) levels of fT4 and normal (n = 189)/low (n = 19) levels of TSH. Patients in the low-fT3 group showed significantly higher mortality and simplified acute physiology score II, and significantly longer duration of MV and ICU length of stay compared with the normal-hormone group. Two of the variables studied were associated with PMV, as follows: the NTIS (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.18 to 4.29; p = 0.01); and the presence of pneumonia (OR, 1.17; 95% CI, 1.06 to 3.01; p = 0.03). CONCLUSION: The NTIS represents a risk factor for PMV in mechanically ventilated, critically ill patients.