Tonicity-responsive enhancer-binding protein promotes hepatocellular carcinogenesis, recurrence and metastasis.

OBJECTIVES: Hepatocellular carcinoma (HCC) is a common cancer with high rate of recurrence and mortality. Diverse aetiological agents and wide heterogeneity in individual tumours impede effective and personalised treatment. Tonicity-responsive enhancer-binding protein (TonEBP) is a transcriptional cofactor for the expression of proinflammatory genes. Although inflammation is intimately associated with the pathogenesis of HCC, the role of TonEBP is unknown. We aimed to identify function of TonEBP in HCC. DESIGN: Tumours with surrounding hepatic tissues were obtained from 296 patients with HCC who received completion resection. TonEBP expression was analysed by quantitative reverse transcription-quantitative real-time PCR (RT-PCR) and immunohfistochemical analyses of tissue microarrays. Mice with TonEBP haplodeficiency, and hepatocyte-specific and myeloid-specific TonEBP deletion were used along with HCC and hepatocyte cell lines. RESULTS: TonEBP expression is higher in tumours than in adjacent non-tumour tissues in 92.6% of patients with HCC regardless of aetiology associated. The TonEBP expression in tumours and adjacent non-tumour tissues predicts recurrence, metastasis and death in multivariate analyses. TonEBP drives the expression of cyclo-oxygenase-2 (COX-2) by stimulating the promoter. In mouse models of HCC, three common sites of TonEBP action in response to diverse aetiological agents leading to tumourigenesis and tumour growth were found: cell injury and inflammation, induction by oxidative stress and stimulation of the COX-2 promoter. CONCLUSIONS: TonEBP is a key component of the common pathway in tumourigenesis and tumour progression of HCC in response to diverse aetiological insults. TonEBP is involved in multiple steps along the pathway, rendering it an attractive therapeutic target as well as a prognostic biomarker.

Prognostic impact of telomere maintenance gene polymorphisms on hepatocellular carcinoma patients with chronic hepatitis B.

UNLABELLED: Our goal was to determine whether single-nucleotide polymorphisms (SNPs) of telomere maintenance genes influence the development and clinical outcomes of patients with hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). We evaluated 20 SNPs of five telomere maintenance genes in 702 patients with HCC and 351 hepatitis B virus surface antigen-positive controls without HCC. Significant SNPs were then validated in an independent cohort of 857 HCC patients and 429 controls. We assessed the association of each SNP with the development of HCC and overall survival through a multivariate Cox proportional analysis. A significantly increased risk of HCC development was identified for the telomerase-associated protein 1 (TEP1) rs1713449 SNP in both the discovery and replication phases (combined odds ratio = 1.42, P = 9.378 × 10(-5) ). In addition, the TEP1 rs1713449, TEP1 rs872072, protection of telomeres 1 homolog rs7784168, telomerase reverse transcriptase rs13167280, and telomeric repeat binding factor 1 rs2306494 SNPs had a significant effect on the overall survival, and a similar survival effect was validated in the replication cohort. Moreover, there was a significant dose-dependent association between the number of putatively high-risk genotypes of the five aforementioned SNPs and overall survival. The median survival time was significantly prolonged for patients with HCC with two or fewer putatively high-risk genotypes versus those with three or more high-risk genotypes (85 versus 44 months, log-rank P = 4.483 × 10(-5) ), and this was demonstrated in the replication cohort (52 versus 37 months, log-rank P = 0.026). CONCLUSION: These observations suggest that the SNPs of telomere maintenance genes play a potential role in the development of HCC and the survival of HCC patients with chronic HBV infections.

Tenofovir-based rescue therapy for chronic hepatitis B patients who had failed treatment with lamivudine, adefovir, and entecavir.

BACKGROUND AND AIM: In the past decade, many chronic hepatitis B (CHB) patients have undergone sequential treatment with lamivudine (LAM), adefovir (ADV), and entecavir (ETV) to manage antiviral resistance or insufficient suppression of HBV-DNA. Very limited data are available on the efficacy of tenofovir (TDF) rescue regimens in patients with multidrug resistance (MDR). METHODS: We investigated the antiviral efficacy of TDF/LAM combination therapy versus TDF/ETV combination therapy in 52 patients who failed three previous antiviral therapies. RESULTS: The study subjects were treated with TDF/LAM combination therapy (n = 25) or TDF/ETV combination therapy (n = 27) for more than six months. Virologic response (VR) occurred in 39 (75%) patients (19 patients belonged to the TDF/LAM group and 20 patients belonged to the TDF/ETV group). The VR rates were not different between the TDF/LAM and TDF/ETV groups (56.0% vs 51.9% at month 12, and 72.0% vs 78.8% at month 18; log rank P = 0.515). In addition, treatment efficacy of TDF/LAM combination or TDF/ETV combination was not statistically different according to types of MDR. In multivariate analysis, absolute HBV-DNA level at the start of TDF rescue treatment (P < 0.001; OR, 0.452; 95% CI, 0.306-0.666) was only significantly associated with VR. CONCLUSIONS: TDF/ETV combination therapy was not associated with higher rate of VR compared with TDF/LAM combination therapy in MDR CHB patients. These results raise the suspicion about the superiority of the combination therapy over TDF monotherapy. The lower HBV-DNA levels at the start of TDF-based rescue therapy were associated with higher VR.

Use of the cardiac power index to predict fluid responsiveness in the prone position: A proof-of-concept study.

BACKGROUND: The primary aim of this proof-of-concept study was to investigate whether the Cardiac Power Index (CPI) could be a novel alternative method to assess fluid responsiveness in the prone position. METHODS: Patients undergoing scheduled elective lumbar spine surgery in the prone position under general anesthesia were enrolled in the criteria of patients aged 19-75 years with American Society of Anesthesiologists (ASA) physical status I-II. The hemodynamic variables were evaluated before and after changes in posture after administering a colloid bolus (5 mL.kg-1) in the prone position. Fluid responsiveness was defined as an increase in the Stroke Volume Index (SVI) ≥10%. RESULTS: A total of 28 patients were enrolled. In responders, the CPI (median [1/4Q-3/4Q]) decreased to 0.34 [0.28-0.39] W.m-2 (p = 0.035) after the prone position. After following fluid loading, CPI increased to 0.48 [0.37-0.52] W.m-2 (p < 0.008), and decreased SVI (median [1/4Q-3/4Q]) after prone increased from 26.0 [24.5-28.0] mL.m-2 to 33.0 [31.0-37.5] mL.m-2 (p = 0.014). Among non-responders, CPI decreased to 0.43 [0.28-0.53] W.m-2 (p = 0.011), and SVI decreased to 29.0 [23.5-34.8] mL.m-2 (p < 0.009). CPI exhibited predictive capabilities for fluid responsiveness as a receiver operating characteristic curve of 0.78 [95% Confidence Interval, 0.60-0.95; p = 0.025]. CONCLUSION: This study suggests the potential of CPI as an alternative method to existing preload indices in assessing fluid responsiveness in clinical scenarios, offering potential benefits for responders and non-responders.

Assessing different brain oxygenation components in elderly patients under propofol or sevoflurane anesthesia: A randomized controlled study.

STUDY OBJECTIVE: Elderly patients undergoing pathophysiological changes necessitate clinical tools for cerebral monitoring. This prospective randomized controlled study aimed to explore how cerebral monitoring using Δo2Hbi, ΔHHbi, and ΔcHbi manifests in elderly patients under either propofol or sevoflurane anesthesia. DESIGN: Single-center, prospective, randomization. SETTING: A single tertiary hospital (Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea). PATIENTS: Enrolled 100 patients scheduled for urologic surgery under general anesthesia. Inclusion criteria were (a) age 70-80 years, (b) American Society of Anesthesiologists (ASA) physical status I-II. INTERVENTION: Patients were double-blind randomized to receive propofol-based or sevoflurane anesthesia. Cerebral oximetry-related parameters were measured at 5, 10, 15, 20, and 30 min in a setting devoid of surgery-related factors. MEASUREMENTS: The primary outcome focused on the Δo2Hbi pattern in the left and right sides within the propofol and sevoflurane groups. MAIN RESULTS: We analyzed 100 patients, 50 patients in each group. In the propofol group, the left Δo2Hbi decreased from 1.4 (3.7) at 5 min to -0.1 (1.8) at 30 min (P < 0.0001), and the right Δo2Hbi decreased from 2.9 (4.2) at 5 min to -0.06 (2.3) at 30 min (P < 0.0001). In the sevoflurane group, the left Δo2Hbi decreased from 1.1 (3.4) at 5 min to -1.4 (4.4) at 30 min (P < 0.0001), and the right Δo2Hbi decreased from 2.0 (3.2) at 5 min to -1.2 (3.9) at 30 min (P < 0.0001). There were no significant differences between the two groups. ΔHHbi did not exhibit significant changes after an initial decrease at 5 min and showed no significant differences between the two groups. CONCLUSIONS: In cerebral oximetry, Δo2Hbi and ΔHHbi could emerge as a valuable approach for discerning changes in the underlying baseline status of the brain in elderly patients during anesthesia.

A stepwise lung recruitment maneuver using I-gel can improve respiratory parameters: A prospective observational study.

I-gel has been used in various clinical situations. The study investigated alterations in respiratory parameters following a stepwise lung recruitment maneuver (LRM) using the i-gel. The research involved 60 patients classified as American Society of Anesthesiologists class I-II, aged 30 to 75 years, undergoing elective urologic surgery. Various respiratory parameters, including lung compliance, airway resistance, leak volume, airway pressure, and oxygen reserve index, were recorded at different time points: before LRM, immediately after LRM, and at 5, 15, and 30 minutes after LRM, as well as at the end of the surgery. The primary outcome was to assess an improvement in lung compliance. Dynamic lung compliance (mean ±â€…SD) was significantly increased from 49.2 ±â€…1.8 to 70.15 ±â€…3.2 mL/cmH2O (P < .05) after LRM. Static lung compliance (mean ±â€…SD) was increased considerably from 52.4 ±â€…1.7 to 65.0 ±â€…2.5 mL/cmH2O (P < .05) after the LRM. Both parameters maintained a statistically significant increased status for a certain period compared to baseline despite a decreased degree of increment. Airway resistance (mean ±â€…SD) was significantly reduced after the LRM from 12.05 ±â€…0.56 to 10.41 ±â€…0.64 L/cmH2O/s (P < .05). Stepwise LRM using i-gel may improve lung compliance and airway resistance. Repeated procedures could lead to prolonged improvements in respiratory parameters.

Analgesic Effect of SKI306X on Chronic Postischemic Pain and Spinal Nerve Ligation-Induced Neuropathic Pain in Mice.

Neuropathic pain (NP) results from lesions or diseases affecting the peripheral or central somatosensory system. However, there are currently no drugs that are particularly effective in treating this condition. SKI306X is a blend of purified extracts of three oriental herbs (Clematis mandshurica, Trichosanthes kirilowii, and Prunella vulgaris) commonly used to treat osteoarthritis for their chondroprotective effects. Chronic postischemic pain (CPIP) and spinal nerve ligation (SNL) models were created by binding the upper left ankle of mice with an O-ring for 3 h and ligating the L5 spinal nerve, respectively. Mice with allodynia were injected intraperitoneally with 0.9% normal saline (NS group) or different doses (25, 50, or 100 mg/kg) of SKI306X (SKI groups). We assessed allodynia using von Frey filaments before injection and 30, 60, 90, 120, 180, and 240 min and 24 h after injection to confirm the antiallodynic effect of SKI306X. We also measured glial fibrillary acidic protein (GFAP) levels in the spinal cord and dorsal root ganglia to confirm the change of SKI306X administration. Both models exhibited significant mechanical allodynia. The intraperitoneal injection of SKI306X significantly increased the paw withdrawal threshold in a dose-dependent manner, as the paw withdrawal threshold was significantly increased after SKI306X administration compared with at baseline or after NS administration. GFAP levels in the SKI group decreased significantly (p < 0.05). Intraperitoneal administration of SKI306X dose-dependently attenuated mechanical allodynia and decreased GFAP levels, suggesting that GFAP is involved in the antiallodynic effect of SKI306X in mice with CPIP and SNL-induced NP.

The Effects of an Order-Assist Mobile Application on Pediatric Anesthesia Safety: An Observational Study.

Pediatric anesthesia requires the rapid creation, communication, and execution of anesthesia orders, and there is a risk of human error. The authors developed an order-assisted mobile application (app) to reduce human error during pediatric anesthesia preparation. The authors conducted an observational study that compared the effects of the application by comparing anesthesiologists' errors, nurses' errors, nurses leaving the operating room, and delays in surgery, between the Conventional group (n = 101) and the App group (n = 101). The app was associated with reduced human error by anesthesiologists and nurses, and it lowered the frequency and duration of nurses leaving the operating room during anesthesia. In addition, the authors surveyed anesthesia nurses regarding the effectiveness of the app. The nurses confirmed that the app was convenient and reduced human error. This study revealed that the order-assisted mobile app developed by a pediatric anesthesiologist could reduce human errors by anesthesiologists and nurses during pediatric anesthesia preparation.

Prediction of hypotension during the alveolar recruitment maneuver in spine surgery: a prospective observational study.

BACKGROUND: Atelectasis can occur in many clinical practices. One way to prevent this complication is through the alveolar recruitment maneuver (ARM). However, hemodynamic compromise can accompany ARM. This study aims to predict ARM-induced hypotension using a non-invasive method. METHODS: 94 American Society of Anesthesiologists physical status I-II patients aged 19 to 75 with scheduled spinal surgery were enrolled. After anesthesia, we performed a stepwise ARM. Data on perfusion index, mean arterial pressure, heart rate, pleth variability index, cardiac index, and stroke volume variation was collected before induction of anesthesia (T0), just before ARM (T1), at the start of ARM (T2), 0.5 min (T3), 1 min (T4), 1.5 min (T5, end of ARM), and 2 min after the beginning of ARM (T6). Hypotension was defined as when the mean arterial pressure at T5 decreased by 20% or more compared to the baseline. The primary endpoint is that the perfusion index measuring before induction of anesthesia, which reflects the patients' own vascular tone, was correlated with hypotension during ARM. RESULTS: Seventy-five patients (79.8%) patients developed hypotension during ARM. The pre-induction persufion index (Pi) (95% confidence interval) was 1.7(1.4-3.1) in the non-hypotension group and 3.4(2.4-3.9) in the hypotension group. (p < 0.004) The hypotension group showed considerably higher Pi than the non-hypotension group before induction. The decrease of Pi (%) [IQR] in the non-hypotensive group (52.8% [33.3-74.7]) was more significant than in the hypotensive group. (36% [17.6-53.7]) (p < 0.05) The area under the receiver operating characteristic curve of Pi for predicting hypotension during ARM was 0.718 (95% CI 0.615-0.806; p = 0.004), and the threshold value of the Pi was 2.4. CONCLUSION: A higher perfusion index value measuring before induction of anesthesia can be used to predict the development of hypotension during ARM. Prophylactic management of the following hypotension during ARM could be considered in high baseline Pi patients.

A Quantitative Measure of Pain with Current Perception Threshold, Pain Equivalent Current, and Quantified Pain Degree: A Retrospective Study.

Background: As a subjective sensation, pain is difficult to evaluate objectively. The assessment of pain degree is largely dependent on subjective methods such as the numeric rating scale (NRS). The PainVisionTM system has recently been introduced as an objective pain degree measurement tool. The purpose of this study was to analyze correlations between the NRS and the current perception threshold (CPT), pain equivalent current (PEC), and quantified pain degree (QPD). Methods: Medical records of 398 subjects who visited the pain clinic in a university hospital from March 2017 to February 2019 were retrospectively reviewed. To evaluate the pain degree, NRS, CPT, PEC, and QPD were measured. Subjects were categorized into two groups: the Pain group (n = 355) and the No-pain group (n = 43). Results: The NRS showed a negative correlation with CPT (R = -0.10, p = 0.054) and a positive correlation with QPD (R = 0.13, p = 0.008). Among various diseases, only spinal disease patients showed a negative correlation between CPT and NRS (R = -0.22, p = 0.003). Additionally, there were significant differences in CPT and QPD between the Pain and No-pain groups (p = 0.005 and p = 0.002, respectively). Conclusions: CPT and QPD measured using the PainVisionTM system could be used to estimate pain intensity and the presence of pain. These parameters would be considered useful for predicting pain itself and its intensity.

Polymorphisms of DNA repair genes in Korean hepatocellular carcinoma patients with chronic hepatitis B: possible implications on survival.

BACKGROUND & AIMS: We aimed at determining whether single nucleotide polymorphisms (SNPs) of DNA repair genes influence the development and clinical outcomes of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). METHODS: We evaluated 14 SNPs of eight DNA repair genes in 708 patients with HCC and 388 HBsAg positive controls without HCC. The Kaplan-Meier methods with log-rank test and Cox regression models were used to compare survival of HCC patients according to the genotype. RESULTS: The SNP of XRCC4 rs1805377 was significantly associated with decreased risk of HCC development (OR, 0.592; p=0.028) and improved overall survival of patients with HCC (median survival time (MST) of 48, 72, and 89 months for the AA, AG, and GG genotypes, respectively; p=0.044). In addition, SNP of OGG1 rs1053133 was significantly associated with postoperative recurrence (OR, 0.604; p=0.049), tumor differentiation (OR, 0.571; p=0.041), and improved survival of resected HCC (MST of 55 and 108 months for the GG and GC/CC genotypes, p=0.001). The multivariate analysis showed that OGG1 rs1052133, XRCC1 rs25487, ERCC5 rs2018836, ERCC5 rs3818356, and XRCC4 rs1805377 had a significant effect on survival. Moreover, a strong dose-dependent association was observed between the number of putative high-risk genotypes of OGG1, XRCC1, ERCC5, and XRCC4 with the overall survival. The MST of HCC with ≥2 putative high-risk genotypes was significantly prolonged compared to those with ≥3 high-risk genotypes (76 vs. 46 months, respectively, p=0.002). CONCLUSIONS: Polymorphisms of DNA repair genes play a potential role in the development, progression, and survival of Korean HCC patients with chronic HBV infection.

The expression kinetics of CD137 in chronic hepatitis C patients treated with pegylated-interferon and ribavirin.

OBJECTIVE: CD137, a member of the tumor necrosis factor receptor family, generates co-stimulatory signals leading to T-cell activation and proliferation for viral eradication. We examined the expression kinetics of CD137 to validate whether it can affect treatment outcomes of chronic hepatitis C (CHC) patients. METHODS: The expression of CD137 on peripheral blood mononuclear cells (PBMC) from 50 CHC patients and 20 healthy controls was analyzed by flow cytometry. CD137 expression levels were examined before treatment, and every 4 weeks during treatment until week 24 or 48, and at the 24-week follow-up. RESULTS: CD137 expression on PBMC was significantly lower in CHC patients than controls (15.5 ± 7.8% vs 23.4 ± 5.2%; p < 0.05). Patients with sustained virological response (SVR) showed higher level of CD137 expression on PBMC than treatment failures at week 4 (20.11% vs 10.97%; p < 0.05) and week 12 (15.48% vs 5.74%; p < 0.01). CD137 expression on CD4 T cells was also higher in patients with SVR at week 8 (7.75% vs 3.29%; p < 0.05). CD137 expression on PBMC from patients with SVR recovered to the control level at the 24-week follow-up. In multivariate analysis, the increased expression of CD137 at week 4 and genotype non-1 were significantly associated with SVR. CONCLUSIONS: The increased expression of CD137 within 12 weeks after the initiation of interferon therapy might be associated with a successful treatment outcome. Modulation to improve expression of CD137 might improve efficacy of CHC treatment.

The analgesic effect of lumbar sympathetic ganglion block in patients with failed back surgery syndrome.

Background: Persistent or recurrent lumbosacral pain is a common symptom after spinal surgery. Several interventions have been introduced for failed back surgery syndrome; however, their clinical efficacy, safety, and cost-effectiveness are insufficient. Sympathetic ganglion block has been selected for pain associated with the sympathetic nervous system. In this study, we compared pain and quality of life in patients with failed back surgery syndrome who responded and did not respond to lumbar sympathetic ganglion block. Methods: We included 84 patients diagnosed with failed back surgery syndrome who had lumbosacral pain and underwent lumbar sympathetic ganglion block between January 2020 and April 2021. The patients' data were retrospectively analyzed; clinical outcomes were assessed before (T0), 1 week after (T1), and 4 weeks after (T4) lumbar sympathetic ganglion block. Based on the pain difference from T0 to T1, we categorized patients into two groups: patients with ≥ 50% pain reduction (responder group) and patients with < 50% pain reduction (non-responder group). Demographic, clinical, surgical, and fluoroscopic data were evaluated and compared. The primary outcome was pain scores and the EuroQol-5D score from T0 to T4. Results: Among the 84 patients analyzed, 41 (48.8%) experienced ≥ 50% pain reduction at 1 week after lumbar sympathetic ganglion block. Lumbar sympathetic ganglion block significantly improved pain at T1 and T4 compared to T0 in both groups. Lumbar sympathetic ganglion block improved the EuroQol-5D score at T1 compared to T0 in the responder group. The responder group had a significant decrease in pain at T1 from T0 and T4 from T0 and a significant decrease in the EuroQol-5D score at T1 from T0 compared with the non-responder group. Coldness of the leg over time did not differ between the groups. No serious adverse events occurred in either of the groups. Conclusion: Lumbar sympathetic ganglion block may improve pain at 1 and 4 weeks in patients with failed back surgery syndrome. Patients with ≥ 50% pain reduction at 1 week showed simultaneous improvement in quality of life and pain reduction at 4 weeks. Clinical trial registration: https://cris.nih.go.kr/cris/index/index.do, identifier KCT0007236.

Association between Successful Palpation of the Cricothyroid Membrane and the 3-3-2 Rule for Predicting Difficult Airway in Female Patients Undergoing Non-Neck Surgery: A Prospective Observational Cohort Study.

Background: Prediction of difficult airway is important for airway management in patients undergoing surgery. The assessment of airway structures and establishment of protective airway strategies are essential to improve patient safety. However, the association between successful palpation of the cricothyroid membrane and airway predictions has not been fully elucidated in patients undergoing surgery. We investigated this in female patients undergoing non-neck surgery. Methods: A total of 68 female patients were enrolled in this prospective observational cohort study between January 2021 and June 2021 at Eunpyeong St. Mary's Hospital, College of Medicine, Catholic University of Korea, Seoul, Republic of Korea. Exclusion criteria were male patients and those with neck pathology or neck surgery. The assessment of difficult airway was performed before the induction of anesthesia and was defined by one of the following conditions: inter-incisor distance < 3 fingerbreadths, hyoid-to-mental distance < 3 fingerbreadths, and thyroid-to-hyoid distance < 2 fingerbreadths (the "3-3-2 rule"). The accuracy of palpable identification of the cricothyroid membrane was confirmed by ultrasonography (US). The patients were divided into the non-difficult airway (NDA) group (n = 30) and the difficult airway (DA) group (n = 30). Results: The two groups were comparable in terms of age, but the DA group had higher body mass index (BMI). In airway assessment, 9 patients showed inter-incisor distance < 3 fingerbreadths, 3 patients showed hyoid-to-mental distance < 3 fingerbreadths, and 24 patients showed thyroid-to-hyoid distance < 2 fingerbreadths in the DA group. The rate of successful palpation of the cricothyroid membrane was higher in the patients without than in those with difficult airway variables. Conclusions: Patients with a positive 3-3-2 rule showed a poor palpability of cricothyroid membrane.

Clinical Implication of the Acumen Hypotension Prediction Index for Reducing Intraoperative Haemorrhage in Patients Undergoing Lumbar Spinal Fusion Surgery: A Prospective Randomised Controlled Single-Blinded Trial.

We investigated the clinical implication of the Hypotension Prediction Index (HPI) in decreasing amount of surgical haemorrhage and requirements of blood transfusion compared to the conventional method (with vs. without HPI monitoring). A prospective, randomised controlled-trial of 19- to 73-year-old patients (n = 76) undergoing elective lumbar spinal fusion surgery was performed. According to the exclusion criteria, the patients were divided into the non-HPI (n = 33) and HPI (n = 35) groups. The targeted-induced hypotension systolic blood pressure was 80−100 mmHg (in both groups), with HPI > 85 (in the HPI group). Intraoperative bleeding was lower in the HPI group (299.3 ± 219.8 mL) than in the non-HPI group (532 ± 232.68 mL) (p = 0.001). The non-HPI group had a lower level of haemoglobin at the end of the surgery with a larger decline in levels. The incidence of postoperative transfusion of red blood cells was higher in the non-HPI group than in the HPI group (9 (27.3%) vs. 1 (2.9%)). The use of HPI monitoring may play a role in providing timely haemodynamic information that leads to improving the quality of induced hypotension care and to ameliorate intraoperative surgical blood loss and postoperative demand for blood transfusion in patients undergoing lumbar fusion surgery.

Clinical usefulness of sequential hepatitis B virus DNA measurement (the roadmap concept) during adefovir treatment in lamivudine-resistant patients.

BACKGROUND: Sequential on-treatment monitoring of hepatitis B virus (HBV) DNA levels, known as the roadmap concept, might predict the efficacy of oral therapy with nucleoside/nucleotide analogues among patients naive to this treatment. The goal of this study was to verify the usefulness of the roadmap concept to predict clinical outcomes of adefovir dipivoxil monotherapy in hepatitis B e antigen (HBeAg)-positive patients with lamivudine resistance. METHODS: In 231 patients, serum HBeAg, antibody against HBeAg and HBV DNA levels were measured at weeks 12, 24 and 48 of treatment and every 3 months thereafter. RESULTS: Complete (HBV DNA<60 IU/ml by PCR), partial (HBV DNA 60-<2,000 IU/ml) and inadequate (HBV DNA> or =2,000 IU/ml) virological responses at week 24 were observed in 49 (21.2%), 66 (28.6%) and 116 (50.2%) lamivudine-resistant patients, respectively, who were treated with adefovir dipivoxil monotherapy. At final assessment, rates of complete virological response in these groups were 100%, 71.2%, and 22.4%. Of the total 42 virological breakthroughs, 33 (78.6%) and 8 (19.1%) developed in the inadequate and partial response groups, respectively. Among the 91 patients who had HBV DNA<200 IU/ml at week 48, complete virological response and HBeAg seroconversion were finally achieved in 87 (95.6%) and 39 (42.9%) patients, respectively. Of these 91 patients, virological breakthrough and genotype mutations developed in only 4 (4.4%) and 3 (3.3%) patients. The roadmap concept predicted virological response, HBeAg seroconversion and breakthrough (odds ratios 3.68, 9.67 and 0.15, respectively). CONCLUSIONS: The roadmap concept is useful for choosing between continuation of adefovir dipivoxil monotherapy or early switching to another therapy, or to suggest additional therapy in patients showing lamivudine resistance.

Genetic alterations of the Cdx2 gene in gastric cancer.

Gastric atrophy and intestinal metaplasia are generally considered precancerous lesions of the stomach; Cdx2 plays an important role in intestinal metaplasia and gastric carcinogenesis. To elucidate the potential etiological role of the Cdx2 gene in gastric carcinogenesis, we analyzed genetic mutations and allelic loss in the Cdx2 gene of 95 sporadic gastric cancers. We found two somatic missense mutations in the Cdx2 gene, P63L in exon 1 and E204K in exon 2, encoding the caudal-like protein activation region (codon 13-180) and the homeobox domain (codon 188-243) of the gene, in the gastric cancers. In addition, 9 (25.0%) of 36 informative cases showed allelic loss at D13S220 and/or D13S260. In 11 cases with a genetic alteration, Cdx2 nuclear staining was observed only in 8 cases of gastric mucosa with intestinal metaplasia. Loss or reduced expression of the Cdx2 gene in cancer cells was found in two cases with a somatic mutation and in three cases with LOH. Interestingly, all of the cases were intestinal-type gastric cancers. Thus, these results suggest that genetic alterations of the Cdx2 gene may contribute to the loss of Cdx2 expression and to the development of gastric cancer, especially in the intestinal-type.

Genetic analysis of the DBC2 gene in gastric cancer.

The DBC2 (Deleted in breast cancer, RhoBTB2) has been identified as a tumor suppressor gene that has growth inhibitory function. To investigate whether genetic alterations of the DBC2 gene are involved in the development of gastric cancer, we analyzed mutations and allelic loss in the DBC2 gene in 95 primary gastric cancers by PCR-SSCP, sequencing and LOH analysis. In the mutational analysis, we found one missense somatic mutation (CGG-->TGG, R275W) in the BTB/POZ domain of the gene in a patient with advanced gastric cancer and lymph node metastasis. In addition, we found one known polymorphism and three novel polymorphisms in the coding region of DBC2, which showed an amino acid change, and was detected in both the cancer cells and corresponding normal cells. On LOH analysis, 62 cases were heterozygous for at least one marker and 18 cases (29.0%) showed allelic loss at these markers. In conclusion, the mutations and allelic loss in the DBC2 gene are uncommon in gastric cancers in Korean patients. Further studies to identify the target gene at 8q21 responsible for the development of gastric cancer should be explored.

Genetic and epigenetic analysis of the VHL gene in gastric cancers.

The von Hippel-Lindau tumor suppressor gene (VHL), which is located on chromosome 3p25, plays an important role in tumorigenesis, particularly in tumor growth and vascularization. Mutations of the VHL gene have been observed in the hereditary VHL syndrome and a variety of other sporadic cancers. In this study, in order to investigate whether the VHL gene is involved in gastric carcinogenesis, we have examined the genetic alterations, including somatic mutations and allelic loss, with the two microsatellite markers, D3S1038 and D3S1110, as well as promoter hypermethylation of the VHL gene in 88 sporadic gastric adenocarcinomas. No mutation was detected in the coding region of the VHL gene. Allelic loss was found in 20 (33.9%) of 59 informative cancer cases at one or both markers. In addition, promoter hypermethylation was not detected in the gastric cancer samples. This is the first investigation of the genetic and epigenetic alterations of the VHL gene in gastric cancers. Our results suggest that genetic and epigenetic alterations of the VHL gene may be not involved in the development or progression of gastric cancers. The findings also provide evidence for the presence of another gastric cancer specific tumor suppressor gene at the 3p25 region.

Genetic alterations of the ATBF1 gene in gastric cancer.

PURPOSE: Alpha-fetoprotein (AFP)-producing gastric cancers are aggressive tumors with venous and lymphatic invasion and hepatic metastasis. The goal of the present study was to investigate whether somatic changes of the AFP-negative regulator AT motif binding factor-1 (ATBF1) gene are involved in the development or progression of gastric cancers and the production of AFP in gastric cancer cells. EXPERIMENTAL DESIGN: We searched for genetic alterations of the ATBF1 gene by single-strand conformational polymorphism and sequencing methods as well as allelic loss analysis with the microsatellite markers D16S3066 and D16S3139. Immunochemistry for AFP expression in gastric cancer cells was also done. RESULTS: In 81 sporadic gastric cancers, four mutations were detected in seven cases: one was a missense mutation and three were deletions; loss of heterozygosity at the ATBF1 locus was detected in 52.9% of informative samples. Five of the eight cancers with AFP expression showed ATBF1 genetic alterations. CONCLUSIONS: These results suggest that genetic alteration of the ATBF1 gene may contribute to the aggressive nature of gastric cancers and the production of AFP in gastric cancer cells.