The Induced Membrane Technique for the Management of Segmental Tibial Defect or Nonunion: A Systematic Review and Meta-Analysis.

PURPOSE: To identify the predicting factors for union and infection after applying the induced membrane technique (IMT) for segmental tibial defects. METHODS: A systematic review was carried out following the PRISMA guidelines. All databases were searched for articles published between January 2000 and February 2018 using the keywords "Masquelet technique" and "induced membrane technique." Studies in English reporting more than 5 cases with accessible individual patient data were included. A meta-analysis was performed. Odds ratios (OR) with 95% confidence intervals were calculated. RESULTS: After reviewing, 11/243 studies (115 patients) were finally selected. The mean age of the patients was 43.6 years (range: 18-84 years), and the mean length of the tibial defect was 5.5 cm (range: 0-20 cm). The multivariate logistic regression analysis revealed that the risk factors of postoperative infection after IMT were infected nonunion (p = 0.0160) and defect length ≥ 7 cm (p = 0.0291). Patients with postoperative infection after IMT had a lower union rate (p = 0.0003). Additionally, the use of an antibiotic polymethyl methacrylate cement spacer reduced the need for surgical revision (p = 0.0127). Multiple logistic regression indicated no direct association between the union rate and length of the bone defect. CONCLUSIONS: IMT is a reliable and reproducible treatment for segmental tibial defects. However, initial infected nonunion and defect length greater than 7 cm are risk factors for post-IMT infection, and post-IMT infection was statistically related to nonunion.

Development of a prediction model for breast cancer based on the national cancer registry in Taiwan.

BACKGROUND: This study aimed to develop a prognostic model to predict the breast cancer-specific survival and overall survival for breast cancer patients in Asia and to demonstrate a significant difference in clinical outcomes between Asian and non-Asian patients. METHODS: We developed our prognostic models by applying a multivariate Cox proportional hazards model to Taiwan Cancer Registry (TCR) data. A data-splitting strategy was used for internal validation, and a multivariable fractional polynomial approach was adopted for prognostic continuous variables. Subjects who were Asian, black, or white in the US-based Surveillance, Epidemiology, and End Results (SEER) database were analyzed for external validation. Model discrimination and calibration were evaluated in both internal and external datasets. RESULTS: In the internal validation, both training data and testing data calibrated well and generated good area under the ROC curves (AUC; 0.865 in training data and 0.846 in testing data). In the external validation, although the AUC values were larger than 0.85 in all populations, a lack of model calibration in non-Asian groups revealed that racial differences had a significant impact on the prediction of breast cancer mortality. For the calibration of breast cancer-specific mortality, P values < 0.001 at 1 year and 0.018 at 4 years in whites, and P values ≤ 0.001 at 1 and 2 years and 0.032 at 3 years in blacks, indicated that there were significant differences (P value < 0.05) between the predicted mortality and the observed mortality. Our model generally underestimated the mortality of the black population. In the white population, our model underestimated mortality at 1 year and overestimated it at 4 years. And in the Asian population, all P values > 0.05, indicating predicted mortality and actual mortality at 1 to 4 years were consistent. CONCLUSIONS: We developed and validated a pioneering prognostic model that especially benefits breast cancer patients in Asia. This study can serve as an important reference for breast cancer prediction in the future.

Risk of hepatitis C virus related hepatocellular carcinoma between subjects with spontaneous and treatment-induced viral clearance.

BACKGROUND/AIMS: Both spontaneous hepatitis C virus (HCV) clearance and the achievement of sustained virological response (SVR) by anti-viral therapy greatly reduce the incidence of hepatocellular carcinoma (HCC). The current study aimed to compare the risk of HCC between the two patient groupsMethods: A total of 313 subjects with spontaneous HCV clearance (SC) and 564 age- and sex-matched patients in the treatment-induced SVR group were enrolled for analysis. RESULTS: Nineteen (2.2%) of the 877 patients developed HCC during 6,963 person-years of follow-up. Fourteen (2.5%) SVR patients and 5 (1.6%) SC patients developed HCC (P=0.004). Cox regression analysis of factors predictive of HCC included SVR (versus SC: hazard ratio [HR]/ 95% confidence interval [CI]: 5.83/1.27-26.88), diabetes (HR/CI:3.41/1.21-9.58), and age (HR/CI: 1.07/1.01-1.14). Of the 564 SVR patients, eleven (5.9%) of the 187 patients with fibrosis stage 2-4 (F2-4) and 2 (0.9%) of the 226 patients with F01 developed HCC (P=0.01). Compared to SC subjects, only SVR patients with F2-4 (P<0.001) but not F0-1(P=0.60) had a higher risk of HCC development. Cox-regression analysis using liver fibrosis as a variable demonstrated that factors associated with HCC included SVR with F2-4 (versus SC: HR/CI: 10.06/2.20-45.98), diabetes (HR/CI:3.23/1.14-9.19), and age (HR/CI: 1.08 1.02-1.15). CONCLUSIONS: Compared to subjects with spontaneous viral clearance, subjects with antiviral treatment-induced HCV viral clearance remain at high risk for HCC development, especially if they have significant hepatic fibrosis. These results may provide important information for decision-making regarding the prioritization of current direct antiviral agents in resource-limited countries.

Chronic hepatitis C virus infection and the risk for diabetes: a community-based prospective study.

BACKGROUND: The association between hepatitis C virus (HCV) infection and the occurrence of type II diabetes remains controversial. Prospective studies are needed to assess its causal temporality. METHODS: A cohort of 21 559 adults enrolled from seven townships in Taiwan during 1991-1992 and followed till the end of 2010. Incident diabetes over a study time period from 2000 to 2010 was ascertained through computerized linkage with the National Health Insurance database and the National Death Certification profiles. Cox's proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Antibodies against HCV (anti-HCV) were tested for all participants, and serum HCV RNA levels were measured for anti-HCV seropositives. RESULTS: During 180 244 person-years of follow-up, there were 1917 incident diabetes cases recorded. The cumulative risk for diabetes was 10.9% for anti-HCV seronegatives and 16.7% for anti-HCV seropositives respectively. The HR for diabetes of anti-HCV seropositivity was 1.53 (95% CI: 1.29-1.81) compared with anti-HCV seronegatives after adjustment for risk predictors. The adjusted HRs were 1.63 (1.31-2.02) for anti-HCV seropositives with positive HCV RNA compared to anti-HCV seronegatives (P<.001). CONCLUSION: Chronic HCV infection was associated with an increased risk for diabetes after adjustment for other risk predictors.

Polymorphisms near the IFNL3 Gene Associated with HCV RNA Spontaneous Clearance and Hepatocellular Carcinoma Risk.

The aims of this study were to investigate associations between single nucleotide polymorphisms (SNPs) near the genes IFNL2, IFNL3, and IFNL4 and spontaneous clearance of hepatitis C virus (HCV) and to evaluate variants for their risk of hepatocellular carcinoma (HCC) among subjects in whom spontaneous HCV RNA clearance did not occur. In the first study, 889 untreated anti-HCV-seropositive patients without HCC symptoms were followed from 1991 to 2005. The spontaneous HCV clearance rate was found to be 33.1%. The TT variant of rs8099917 near IFNL3 was associated with increased spontaneous HCV RNA clearance, with an adjusted odds ratio (95% CI) of 2.78 (1.43-5.39), as was the newly-identified TT/TT dinucleotide variant rs368234815 near IFNL4 (adjusted odds ratio 2.68, 95% CI: 1.42-5.05). In the second study, associations between SNPs and HCC risk were examined in 483 HCC cases with detectable HCV RNA and 516 controls. In participants with HCV genotype 1, unfavorable genotypes for HCV clearance near IFNL3 were associated with increased HCC risk, the adjusted odds ratio (95% CI) for rs12979860 and rs8099917 being 1.73 (1.00-2.99) and 1.84 (1.02-3.33), respectively. Host characteristics should be considered to identify high-risk patients to prioritize the use of new antiviral agents and intensive screening.

High Serum Transforming Growth Factor-ß1 Levels Predict Outcome in Hepatocellular Carcinoma Patients Treated with Sorafenib.

BACKGROUND: The TGF-ß signaling pathway is crucial in the progression and metastasis of malignancies. We investigated whether the serum TGF-ß1 level was related to the outcomes of patients treated with sorafenib for advanced hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: We selected patients who had received sorafenib-containing regimens as first-line therapy for advanced HCC between 2007 and 2012. Serum TGF-ß1 levels were measured and correlated with the treatment outcomes. The expression TGF-ß1 and the sensitivity to sorafenib were examined in HCC cell lines. RESULTS: Ninety-one patients were included; 62 (68%) were hepatitis B virus surface antigen (+), and 11 (12%) were anti-hepatitis C virus (+). High (≥ median) pretreatment serum TGF-ß1 levels (median 13.7 ng/mL; range, 3.0-41.8) were associated with high α-fetoprotein levels, but not with age, gender, or disease stage. Patients with high pretreatment serum TGF-ß1 levels exhibited significantly shorter progression-free survival (median, 2.5 vs. 4.3 months; P = 0.022) and overall survival (median 5.6 vs. 11.6 months; P = 0.029) than did patients with low serum TGF-ß1 levels. Compared with pretreatment levels, the serum TGF-ß1 levels were significantly increased at disease progression (n = 29, P = 0.010). In preclinical models of HCC, higher TGF-ß1 expression levels were associated with poorer sensitivity to sorafenib. CONCLUSIONS: High pretreatment serum TGF-ß1 levels were associated with poor prognoses, and increased serum TGF-ß1 levels were associated with the disease progression of advanced HCC patients. TGF-ß pathway may be explored as a therapeutic target for advanced HCC.

Treatment efficacy differences of sorafenib for advanced hepatocellular carcinoma: a meta-analysis of randomized clinical trials.

OBJECTIVES: Hepatocellular carcinoma (HCC) is a heterogeneous disease. We explored whether any specific subgroups of patients may gain more survival benefits from sorafenib as the first-line therapy for advanced HCC. METHODS: PubMed and the Cochrane library were searched for phase III clinical trials that compared sorafenib with other treatments as first-line therapy for advanced HCC. We retrieved data from the published articles and then calculated synthesized hazard ratios (HRs) of overall mortality for patients of different subgroups, using patients who received other treatments as the reference. RESULTS: Four phase III clinical trials comparing sorafenib with other treatments were included in this study. The HRs were not significantly different between patients from various geographic regions (p = 0.183), patients with different Eastern Cooperative Oncology Group performance statuses (p = 0.699), or patients with different tumor involvement (p = 0.221). By contrast, the synthesized HR for hepatitis C virus (HCV)+ patients was 0.65 [95% confidence interval (CI) 0.53-0.80], which was significantly lower than that for HCV- patients (0.87, 95% CI 0.79-0.96, p = 0.013). CONCLUSIONS: As the first-line therapy for advanced HCC, sorafenib might provide more survival benefits to HCV+ patients than to HCV- patients.

Clinical characteristics of advanced hepatocellular carcinoma patients with prolonged survival in the era of anti-angiogenic targeted-therapy.

BACKGROUND: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is poor despite treatment with sorafenib or other anti-angiogenic targeted-therapies. Patients with advanced HCC with prolonged survival may exhibit unique clinical characteristics. PATIENTS AND METHODS: We reviewed patients with Barcelona Clinic Liver Cancer stage C HCC, who were enrolled in six clinical trials for first-line anti-angiogenic targeted-therapy between May 2005 and December 2010 in a single Institute. Patients with prolonged survival were identified as those who exhibited overall survival (OS) of more than two years; their clinical variables were analyzed. RESULTS: Of the 189 enrolled patients, 22 (11.6%) patients with prolonged survival were identified. Their median OS was 58.7 (range=24.6-88.4) months, compared to an OS of 7.1 months for the overall patient cohort. A multivariate analysis showed that the patients with prolonged survival were less likely to have chronic hepatitis B virus infection, α-fetoprotein level >400 ng/ml, and liver involvement than were the remaining patients. In addition, the patients with prolonged survival experienced significantly higher response rates (50.0%) and disease control rates (86.4%) to the first-line targeted-therapy, and received more additional therapies than did the other patients. Seven patients remained disease-free for a median of 27.0 (range, 4.5-64.6) months after receiving additional locoregional therapies. CONCLUSION: Patients with advanced HCC who experienced prolonged survival exhibited certain clinical features and strong treatment responses to first-line anti-angiogenic targeted-therapies. Additional locoregional therapies could contribute to the long-term disease-free status in selected patients.

Prognosis of patients with advanced hepatocellular carcinoma who failed first-line systemic therapy.

BACKGROUND & AIMS: No approved therapy is available for patients with advanced hepatocellular carcinoma (HCC) who fail first-line therapy. The prognosis of these patients, especially those eligible for clinical trials of second-line therapy, is unclear. METHODS: All patients who participated in clinical trials of first-line systemic therapy for metastatic or locally advanced HCC in a referral center of Taiwan between 2005 and 2011 were included. Their clinicopathologic characteristics, when the first-line treatment failed, were analyzed and correlated with the overall survival (OS) from the date of first-line treatment failure. RESULTS: A total of 192 patients were included. Before the start of the first-line therapy, all patients had Child-Pugh class A liver reserves and Cancer of the Liver Italian Program (CLIP) scores ≤4. After the failure of the first-line therapy, the median OS of the entire group was 4.0 months. Patients with Child-Pugh class A liver reserves, when the first-line treatment failed, had significantly better OS than patients with Child-Pugh class B or C liver reserves (median, A vs. B vs. C=7.5 vs. 1.3 vs. 1.0 month, p<0.001). According to the key eligibility criteria of 3 published clinical trials for second-line therapy, 41%-56% of patients were potentially eligible. Compared to patients who were ineligible for clinical trials, potentially eligible patients had longer OS with a median of 7.8-8.6 months. CONCLUSIONS: Patients with advanced HCC who failed first-line therapy could have substantially improved prognosis if they had Child-Pugh A liver reserves or were potentially eligible for clinical trials.

Life expectancies and incidence rates of patients under prolonged mechanical ventilation: a population-based study during 1998 to 2007 in Taiwan.

INTRODUCTION: The present study examined the median survival, life expectancies, and cumulative incidence rate (CIR) of patients undergoing prolonged mechanical ventilation (PMV) stratified by different underlying diseases. METHODS: According to the National Health Insurance Research Database of Taiwan, there were 8,906,406 individuals who obtained respiratory care during the period from 1997 to 2007. A random sample of this population was performed, and subjects who had continuously undergone mechanical ventilation for longer than 21 days were enrolled in the current study. Annual incidence rates and the CIR were calculated. After stratifying the patients according to their specific diagnoses, latent class analysis was performed to categorise PMV patients with multiple co-morbidities into several groups. The life expectancies of different groups were estimated using a semiparametric method with a hazard function based on the vital statistics of Taiwan. RESULTS: The analysis of 50,481 PMV patients revealed that incidence rates increased as patients grew older and that the CIR (17 to 85 years old) increased from 0.103 in 1998 to 0.183 in 2004 before stabilising thereafter. The life expectancies of PMV patients suffering from degenerative neurological diseases, stroke, or injuries tended to be longer than those with chronic renal failure or cancer. Patients with chronic obstructive pulmonary disease survived longer than did those co-morbid with other underlying diseases, especially septicaemia/shock. CONCLUSIONS: PMV provides a direct means to treat respiratory tract diseases and to sustain respiration in individuals suffering from degenerative neurological diseases, and individuals with either of these types of conditions respond better to PMV than do those with other co-morbidities. Future research is required to determine the cost-effectiveness of this treatment paradigm.