Effect of urea cream on sorafenib-associated hand-foot skin reaction in patients with hepatocellular carcinoma: A multicenter, randomised, double-blind controlled study.

BACKGROUND: Hand-foot skin reaction (HFSR) is the most common adverse event during sorafenib treatment in patients with hepatocellular carcinoma (HCC). In the present study, we aimed to investigate the role of urea cream in the prevention of HFSR or amelioration of HFSR severity. PATIENTS AND METHODS: Patients with HCC were treated with either placebo cream or urea cream for 12 weeks concomitantly with sorafenib treatment. HFSR development, the Hand-Foot Skin Reaction and Quality of Life (HF-QoL) questionnaire score, and adverse events were assessed at 2, 4, 8 and 12 weeks. RESULTS: Of the 288 patients, 247 patients, with 117 patients in the placebo control group and 130 patients in the urea cream group, were analysed. The urea cream group showed a trend towards a lower cumulative incidence of any-grade HFSR (log-rank, P = 0.247) and severe HFSR of grade II or higher (log-rank, P = 0.394) without statistical significance. In the incidence by time point, the incidence of severe HFSR of grade II or higher was significantly lower in the urea cream group than in the placebo control group at 2 weeks (13.8% versus 23.9%, P = 0.042). The urea cream group showed a significantly better HF-QoL questionnaire score than the placebo control group (11.8 versus 19.7, P = 0.014) at 12 weeks. CONCLUSIONS: Treatment with urea cream showed a lower incidence of severe sorafenib-induced HFSR at 2 weeks and reduced the tendency of HFSR development in HCC patients. Therefore, treatment with urea cream may be considered for prophylaxis or improvement of HFSR grade in HCC patients treated with sorafenib. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03212625).

An optimized hepatocellular carcinoma prediction model for chronic hepatitis B with well-controlled viremia.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) risk in chronic hepatitis B (CHB) substantially decreased in the era of potent antiviral therapy. We developed an optimized HCC risk prediction model for CHB with well-controlled viremia by nucelos(t)ide analogs (NUCs). METHOD: We analysed those who achieved virological response (VR; serum HBV-DNA < 2000 IU/mL on two consecutive assessments) by NUCs. Liver stiffness by transient elastography, ultrasonography and laboratory tests was performed at the time of confirmed VR. Patients with decompensated cirrhosis or HCC at baseline were excluded. Multivariate Cox-regression analysis was used to determine key variables to construct a novel risk-scoring model. RESULTS: Among 1511 patients, 9.5% developed HCC. Cirrhosis on ultrasonography (adjusted HR [aHR] 2.47), age (aHR 1.04), male (aHR 1.90), platelet count <135 000/uL (aHR 1.57), albumin <4.5 g/dL (aHR 1.77) and liver stiffness ≥11 kPa (aHR 6.09) were independently associated with HCC. Using these, CAMPAS model was developed with c-index of 0.874. The predicted and observed HCC probabilities were calibrated with a reliable agreement. Such results were reproduced from internal validation and external validation among the independent cohort (n = 252). The intermediate-risk (CAMPAS model score 75 ~ 161) and high-risk (score >161) groups were more likely to develop HCC compared with the low-risk group (score ≤75) with statistical significances (HRs; 4.43 and 47.693 respectively; both P < .001). CONCLUSION: CAMPAS model derived through comprehensive clinical evaluation of liver disease allowed the more delicate HCC prediction for CHB patients with well-controlled viremia by NUCs.

Reconstruction of 12-lead ECG Using a Single-patch Device.

OBJECTIVES: The aim of this study is to develop an optimal electrode system in the form of a small and wearable single-patch ECG monitoring device that allows for the faithful reconstruction of the standard 12-lead ECG. METHODS: The optimized universal electrode positions on the chest and the personalized transformation matrix were determined using linear regression as well as artificial neural networks (ANNs). A total of 24 combinations of 4 neighboring electrodes on 35 channels were evaluated on 19 subjects. Moreover, we analyzed combinations of three electrodes within the four-electrode combination with the best performance. RESULTS: The mean correlation coefficients were all higher than 0.95 in the case of the ANN method for the combinations of four neighboring electrodes. The reconstructions obtained using the three and four sensing electrodes showed no significant differences. The reconstructed 12-lead ECG obtained using the ANN method is better than that using the MLR method. Therefore, three sensing electrodes and one ground electrode (forming a square) placed below the clavicle on the left were determined to be suitable for ensuring good reconstruction performance. CONCLUSIONS: Since the interelectrode distance was determined to be 5 cm, the suggested approach can be implemented in a single-patch device, which should allow for the continuous monitoring of the standard 12-lead ECG without requiring limb contact, both in daily life and in clinical practice.

Clonal evolution of multidrug resistant hepatitis B virus during entecavir rescue therapy.

BACKGROUND & AIMS: Analysing the mutation pattern of multidrug resistance (MDR) is important in the treatment of chronic hepatitis B (CHB). In this study, the evolutionary pattern of MDR mutations was investigated in patients receiving entecavir (ETV) rescue therapy. METHODS: Eight CHB patients with lamivudine (LAM)- and adefovir (ADV)-resistant mutations showing suboptimal response to ETV and to subsequent ETV-plus-ADV therapy were enrolled. The clonal evolution of the mutation pattern was investigated through direct sequencing, multiplex restriction fragment mass polymorphism (RFMP), and clonal analysis and the utility of these methods was compared. RESULTS: Among 160 clones at baseline, wild-type hepatitis B virus (HBV) was present in 62 (38.8%), LAM-resistant mutations in 92 (57.6%) and ADV-resistant mutations in 55 (34.4%). LAM-resistant mutations increased to 70.6% at the end of ETV therapy and increased to 74.4% at the 12th month of ETV-plus-ADV therapy. During the same time periods, ETV-resistant mutations were present in 46.3% and 38.8%, and ADV-resistant mutations were present in 3.1% and 9.4% respectively. When 256 nucleotides from 32 samples were examined for mutations, clonal analysis detected 93 mutations (36.3%), direct sequencing detected 36 mutations (14.1%) and RFMP detected 73 mutations (28.5%). The sensitivity (73.1%, 95% CI; 64.1-82.1%) and specificity (96.9%, 95% CI; 94.4-99.4%) of RFMP were high, showing a concordance rate of 88.3% with the results from clonal analysis. All mutations exceeding 40% of the total clones detected by clonal analysis were also detected by RFMP. CONCLUSIONS: The clonal evolution of the mutation pattern in MDR HBV showed the selection of LAM-resistant (±ETV-resistant) HBV during ETV rescue therapy, which may be the primary reason for patients' suboptimal response. Multiplex RFMP is a useful method for detecting MDR mutations in clinical practice.

Early on-treatment change in liver stiffness predicts development of liver-related events in chronic hepatitis B patients receiving antiviral therapy.

BACKGROUNDS/AIMS: Monitoring fibrosis is mandatory for detailed prognostification in patients with chronic liver disease. We developed optimized cut-offs for liver stiffness (LS) values, based on the histological subclassification of cirrhosis, and investigated whether early on-treatment changes in LS values can predict long-term prognosis in patients with hepatitis B virus (HBV)-related advanced liver fibrosis receiving antiviral therapy. METHODS: Between 2005 and 2008, 103 patients with F3 or F4 fibrosis on liver biopsy were enrolled prospectively. Cirrhosis was subclassified into three groups (F4A, F4B and F4C) according to Laennec system. The primary end-point was occurrence of liver-related event (LRE), including decompensation, hepatocellular carcinoma and liver-related death. RESULTS: Suggested LS cut-offs for predicting F4B-FC (vs. F3-F4A) and F4C (vs. F3-F4B) were 11.6 and 18.2 kPa respectively. As proportions of patients with LRE occurrence increased according to histological subclassifications stage F3-4A vs. F4B-4C (7.4% vs. 17.1%) and stage F3-4B vs. F4C (13.8% vs. 18.8%), they also increased according to LS cut-off value of 11.6 kPa (5.9% vs. 23.1%) and 18.2 kPa (9.8% vs. 33.3%) respectively (all P < 0.05). Similarly, according to stratified LS values (<11.6, 11.6-18.2 and ≥18.2 kPa), overall incidence of LREs and each constituent event increased significantly (all P < 0.05). In addition, the observed changes in LS values between baseline and 6 months of follow-up showed significant correlations with LRE development. CONCLUSIONS: Stratified LS values based on Laennec system and dynamic changes in LS values on follow-up may be helpful in assessing risk of LREs in subjects with HBV-related advanced liver fibrosis receiving antiviral therapy.

Activation-free printed carbon nanotube field emitters.

When a carbon nanotube paste is formulated based on highly functional hyperbranched polymers such as dipentaerythritol hexaacrylate, the volume shrinkage during thermal curing builds up internal stress that generates microcrack patterns on the printed surface. The nanotubes exposed in the cracks emit electrons successfully at such an extremely low electric field as 0.5 V µm( - 1), and reach 25.5 mA cm( - 2) of current density at 2 Vµm( - 1) from an optimized paste concerning mainly the size and spatial uniformity of the crack. In addition to the superior field emission properties with low manufacturing cost, this activation-free technology can provide a minimized nanohazard in the device fabrication process, compared to those conventional activation technologies developing serious nanoflakes by using destructive methods.

Predictive factors for long-term survival in patients with clinically significant portal hypertension following resection of hepatocellular carcinoma.

BACKGROUND: Hepatic resection for hepatocellular carcinoma (HCC) is not currently recommended for patients with clinically significant portal hypertension (PHT); however, recent studies have shown similar post-operative outcomes between patients with and without clinically significant PHT. AIM: To clarify the post-operative prognostic relevance of clinically significant PHT in Child-Pugh A cirrhotic patients. METHODS: A total of 100 Child-Pugh A cirrhotic patients who underwent curative resection of HCC were eligible for this analysis. Patients were divided into two groups: PHT group (n=47) and non-PHT group (n=53). RESULTS: Clinicopathological variables showed no significant differences except for prothrombine time. Liver-related complications were significantly higher in the PHT group (P=0.015), and the 5-year overall survival rate was significantly higher in the non-PHT group (78.7 vs. 37.9%, P<0.001). The proportion of patients who died because of complications of cirrhosis was significantly higher in the PHT group (P=0.001). Multivariate analysis indicated that the presence of clinically significant PHT was the most powerful adverse prognostic factor for overall survival. Multivariate analysis of the 47 patients with clinically significant PHT indicated that gross vascular invasion and non-single nodular type were poor prognostic factors. The 5-year survival rate of patients with single nodular type and without gross vascular invasion (n=17) was 78.4%. CONCLUSIONS: In Child-Pugh A cirrhotic patients, the presence of clinically significant PHT was significantly associated with post-operative hepatic decompensation and poor prognosis after resection of HCC. However, in patients with clinically significant PHT, those with single nodular tumours lacking gross vascular invasion may be good surgical candidates.

Open anatomical coracoclavicular ligament reconstruction using a tendon graft with an Endobutton loop.

We describe a technique of open anatomical coracoclavicular ligament reconstruction restoring both parts of the native ligament, aiming at achieving maximum stability of the acromioclavicular joint without disturbing the normal anatomy. Using the same anatomical principle of ligament reconstruction as in other joints, transosseous tunnels are created at the native footprints of the conoid and trapezoid ligaments. An autologous graft is fixed using an Endobutton continuous loop and a PEEK screw; adequate healing of the ligament is ensured with an appropriate working length. Although an open procedure, this technique offers several advantages. It can be easily reproduced using basic anatomical principles and simple cost-effective instrumentation. The implant does not have to be removed, important anatomical structures are respected, normal acromioclavicular joint kinematics are restored, the scar is cosmetically acceptable and post-operative morbidity is very low.

Clinical Features and Prognosis of Lung Cancer with Brain Metastasis.

PURPOSE: Brain metastasis is estimated to occur in 20~40% of solid tumor patients and the most common primary tumor is lung cancer. Even though the prognosis of brain metastasis is grave and the 1-year survival rate is only 15%, symptom palliations are made with whole brain radiation therapy. We retrospectively evaluated the clinical features and prognostic factors of lung cancer with brain metastasis. MATERIALS AND METHODS: From January 1987 to October 1999, 50 lung cancer patients with brain metastasis underwent whole brain radiation therapy. We reviewed the improvement in neurologic symptoms and survival according to the following parameters; performance status, histological type, presence of brain metastasis at the initial diagnosis of lung cancer, presence of extracranial metastasis, multiplicity of brain lesion, presence of primary lung symptom and treatment modalities. RESULTS: The most frequent symptom with brain metastasis was a headache (50%). Palliation of the headache and other symptoms was achieved in 81% of the patients. Median overall survival after brain metastasis was 21 weeks and the 1 year survival rate was 15%. Patients without extracranial metastasis had a longer median survival than those with, 38 weeks versus 15 weeks, respectively (p=0.01). CONCLUSION: In lung cancer with brain metastasis, neurologic symptoms can be palliated with whole brain radiation therapy, and in this study among such patients, absence of extracranial metastasis can be a good prognostic factor.

Discrepancies of the Values on the Withholding Futile Interventions between Physician and Family Members of Terminal Cancer Patients.

PURPOSE: To analyze the controversies surrounding therapeutic decision-making and the withholding of life- sustaining treatments, values held concerning therapeutic interventions of terminal cancer patients are compared between physicians and family members. MATERIALS AND METHODS: 42 advanced or terminal stage cancer patients were enrolled for the study. The questionnaires were administered to the duty doctor and the family of the patients. Questions included whether to use new agents with a 15% partial efficacy and whether to use opioid analgesics, intravenous nutrition, a feeding tube, antibiotics, and hemodialysis. Additionally, we asked about the administration of CPR, ventilator application, and euthanasia. If the family permitted, the same questionnaires were given to the patients. RESULTS: Of the 42 cases, 5 families refused to answer the questionnaire. Of the available 37 families, only 5 families permitted access to the patients. Of the 5 patients, 2 patients refused the questionnaire. Only 67.6% and 8.1% of families and the patients clearly understood the stage of cancer. The use of a new agent was accepted by 45.2% of the physicians and 45.9% of the families. The rankings of the acceptance of treatment in the physicians and in the families were similar. The concordance rate between the physicians and the families was lowest on ventilator application and CPR. 31% of the physicians and 43.2% of the families agreed on the issue of euthanasia. CONCLUSION: Values held on issues like therapeutic decision-making and the withholding of life-sustaining treatments in terminal cancer patients are discordant between physicians and family members. In order to resolve controversies on the role of physicians in end-of-life decisions, the values of physicians as well as patients and their family members should be considered in the final decision-making process.

Phase II Trial of Vinorelbine and Cisplatin Chemotherapy in Advanced Non-Small Cell Lung Cancer.

PURPOSE: Platinum-based chemotherapy has conferred a modest but significant survival benefit and the introduction of newer drugs has led to achieve higher response rate in patients with advanced non-small cell lung cancer (NSCLC). We performed a phase II trial in order to evaluate the efficacy and toxicity of combination chemotherapy with vinorelbine (Navelbine) and cisplatin in advanced NSCLC. MATERIALS AND METHODS: Patients with previously untreated, unresectable stage IIIB or IV NSCLC with measurable lesion (s) were eligible for entry into the study. NP chemotherapy consisted of intravenous vinorelbine 25 mg/m2, on day 1 and 8, and intravenous cisplatin 80 mg/m2 on day 1; this cycle was repeated every three weeks. RESULTS: A total of 33 patients were enrolled in the study between July 1999 and Feb 2000. Of the 30 patients deemed eligible for analysis, thirteen patients achieved a partial response and thirteen showed a stable disease. The overall response rate was 43.3%. The median duration of response was 5.7 months (95% CI: 2.8~8.5 months). The median time to progression was 7.6 months (95% CI: 5.5~9.7 months) and the overall median survival time was 15.1 months (95% CI: 9.8~20.4 months) in the intent-to-treat analysis. Chemotherapy-related grade 3 or 4 toxicities were anemia in 1.5%, leukopenia in 4.5%, nausea/vomiting in 2.3%, alopecia in 13.3%, and neurotoxicity in 3.3%. CONCLUSION: The combination of vinorelbine and cisplatin chemotherapy seems to be active and fairly tolerable in patients with advanced NSCLC.

Efficacy of Low-dose Paclitaxel and Cisplatin in Patients with Advanced Non-Small Cell Lung Cancer.

PURPOSE: To evaluate the efficacy and toxicity of combination chemotherapy with low-dose paclitaxel and cisplatin in patients with advanced non-small cell lung cancer. MATERIALS AND METHODS: Chemotherapy-naive patients with unresectable, pathologically proven non-small cell lung cancer were eligible for inclusion in the study. Patients received paclitaxel (145 mg/m2 iv 3 hour D1) and cisplatin (60 mg/m2 iv D1) every 3 weeks. RESULTS: Forty-two patients were enrolled between February 2000 and February 2001. The median age was 53.5 years. Patients with adenocarcinoma numbered 29, squamous cell carcinoma 7, large cell carcinoma 3, and undifferentiated carcinoma 3. Seventeen patients had stage IIIB, 19 had stage IV disease and the remaining 6 displayed recurred disease after previous surgical resection. Four patients terminated treatment early because of hypersensitivity (1) and severe emesis (3). Of the 38 evaluable patients, 14 had PR and the response rate was 36.8%. Among partial responders, 6 patients received additional chest radiation. The median duration of response was 47.9 weeks and the median overall survival was 54.0 weeks. Of the total 176 courses, 14 were delayed, 22 required dose reduction, and grade 3~4 neutropenia occurred in 5.6% of courses. Only one episode of neutropenic fever developed and there were no treatment- related mortalities. Other toxicities were generally mild. CONCLUSION: The combination chemotherapy with low-dose paclitaxel and cisplatin was effective and tolerable in patients with advanced non-small cell lung cancer.