Salvage liver transplantation for patients with recurrent hepatocellular carcinoma after curative resection

Objective

To summarize the experience with salvage liver transplantation (SLT) for patients with recurrent hepatocellular carcinoma (HCC) after primary hepatic resection in a single center.

Methods

A total of 376 adult patients with HCC underwent orthotopic liver transplantation (OLT) at Organ Transplantation Center, the First Affiliated Hospital of Sun Yat-sen University, between 2004 and 2008. Among these patients, 36 underwent SLT after primary liver curative resection due to intrahepatic recurrence. During the same period, one hundred and forty-seven patients with HCC within Milan criteria underwent primary OLT (PLTW group), the intra-operative and post-operative parameters were compared between these two groups. Furthermore, we compared tumor recurrence and patient survival of patients with SLT to 156 patients with HCC beyond Milan criteria (PLTB group). Cox Hazard regression was made to identify the risk factors for tumor recurrence.

Results

The median interval between initial liver resection and SLT was 35 months (1–63 months). The intraoperative blood loss (P<0.05) and transfusion volume (P<0.05) were larger in the SLT group than in the PLTW group. The operation time was longer in the SLT group (P<0.05). The post-operative complications incidence, tumor recurrence rate, patients'' survival rate, and tumor-free survival rate were comparable between these two groups (all P>0.05). When compared to those patients with HCC beyond Milan criteria undergoing primary OLT, patients undergoing SLT achieved a better survival and a lower tumor recurrence. Cox Proportional Hazards model showed that vascular invasion, including macrovascular and microvascular invasion, as well as AFP level >400 IU/L were risk factors for tumor recurrence after LT.

Conclusions

In comparison with primary OLT, although SLT is associated with increased operation difficulties, it provides a good option for patients with HCC recurrence after curative resection.     

Downgrading MELD improves the outcomes after liver transplantation in patients with acute-on-chronic hepatitis B liver failure

Background

High score of model for end-stage liver diseases (MELD) before liver transplantation (LT) indicates poor prognosis. Artificial liver support system (ALSS) has been proved to effectively improve liver and kidney functions, and thus reduce the MELD score. We aim to evaluate whether downgrading MELD score could improve patient survival after LT.

Methodology/Principal Findings

One hundred and twenty-six LT candidates with acute-on-chronic hepatitis B liver failure and MELD score ≥30 were included in this prospective study. Of the 126 patients, 42 received emergency LT within 72 h (ELT group) and the other 84 were given ALSS as salvage treatment. Of the 84 patients, 33 were found to have reduced MELD score (<30) on the day of LT (DGM group), 51 underwent LT with persistent high MELD score (N-DGM group). The median waiting time for a donor was 10 for DGM group and 9.5 days for N-DGM group. In N-DGM group there is a significantly higher overall mortality (43.1%) than that in ELT group (16.7%) and DGM group (15.2%). N-DGM (vs. ECT and DGM) was the only independent risk factor of overall mortality (P = 0.003). Age >40 years and the interval from last ALSS to LT >48 h were independent negative influence factors of downgrading MELD.

Conclusions/Significance

Downgrading MELD for liver transplant candidates with MELD score ≥30 was effective in improving patient prognosis. An appropriate ALSS treatment within 48 h prior to LT is potentially beneficial.     

HURP expression-assisted risk scores identify prognosis distinguishable subgroups in early stage liver cancer

Background

Hepatoma up-regulated protein (HURP) is a component of the chromatin-dependent pathway for spindle assembly. We examined the prognostic predictive value of HURP in human hepatocellular carcinoma (HCC).

Methods

HURP expression was evaluated by immunocytochemistry of fine needle aspirated hepatoma cells in 97 HCC patients with Barcelona Clinic Liver Cancer (BCLC) stage A. Subsequently, these patients underwent partial hepatectomy (n = 18) or radiofrequency ablation (n = 79) and were followed for 2 to 35 months. The clinicopathological parameters were submitted for survival analysis.

Results

HURP expression in aspirated HCC cells was detected in 19.6% patients. Kaplan-Meier survival analysis showed that positive HURP expression (P = 0.023), cytological grading ≥3 (P = 0.008), AFP ≥35 ng/mL (P = 0.039), bilirubin ≥1.3 mg/dL (P = 0.010), AST ≥50 U/L (P = 0.003) and ALT ≥35 U/L (P = 0.005) were all associated with a shorter disease-free survival. A stepwise multivariate Cox proportional hazard model revealed that positive HURP expression (HR, 2.334; 95% CI, 1.165–4.679, P = 0.017), AST ≥50 U/L (HR, 3.697; 95% CI, 1.868–7.319, p<0.001), cytological grade ≥3 (HR, 4.249; 95% CI, 2.061–8.759, P<0.001) and tumor number >1 (HR, 2.633; 95% CI, 1.212–5.722, P = 0.014) were independent predictors for disease-free survival. By combining the 4 independent predictors, patients with different risk scores (RS) showed distinguishable disease-free survival (RS≤1 vs. RS = 2, P = 0.001; RS = 2 vs. RS = 3, P<0.001). In contrast, the patients cannot be separated into prognosis distinguishable subgroups by using AJCC/UICC TNM staging system.

Conclusion

HCC patients with BCLC stage A can be separated into three prognosis-distinguishable groups by use of a risk score that is based upon HURP expression in aspirated HCC cells, ALT, cytological grade and tumor number.     

The Survival Benefit of Liver Transplantation for Hepatocellular Carcinoma Patients with Hepatitis B Virus Infection and Cirrhosis

Background

A precise predictive survival model of liver transplantation (LT) with antiviral prophylaxis for hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) and cirrhosis has not been established. The aim of our study was to identify predictors of outcome after LT in these patients based on tumor staging systems, antitumor therapy pre-LT, and antiviral prophylaxis in patients considered to be unfit by Milan or UCSF criteria.

Methods

From 2002 to 2008, 917 LTs with antiviral prophylaxis were performed on patients with HBV-cirrhosis, and 313 had concurrent HCC.

Results

Stratified univariate and multivariate analyses demonstrated that independent predictors for poor survival were tumor size >7.5 cm (P = 0.001), tumor number >1 (P = 0.005), vascular invasion (P = 0.001), pre-LT serum alpha-fetoprotein (AFP) level ≥1000 ng/ml (P = 0.009), and pre-LT aspartate aminotransferase (AST) level ≥120 IU/L (P = 0.044). Pre-LT therapy for HCC was an independent predictor of better survival (P = 0.028). Based on CLIP and TNM tumor staging systems, HCC patients with HBV-cirrhosis who met the following criteria: solitary tumor ≤7.5 cm, or ≤4 multifocal nodules, the largest lesion ≤5 cm and total tumor diameter ≤10 cm, or more nodules with the largest lesion ≤3 cm, and pre-LT serum AFP level <1000 µg/L and AST level <120 IU/L without vascular invasion and lymph node metastasis who were unfit for UCSF, had survival rates of 89% at 5 years. There was a 47% 5-year survival rate for patients with HCC exceeding the revised criteria.

Conclusions

The current criteria for LT based on tumor size, number and levels of AFP and AST may be modestly expanded while still preserving excellent survival after LT. The expanded criteria combined with antiviral prophylaxis and pre-LT adjuvant therapy for HCC may be a rational strategy to prolong survival after LT for HCC patients with HBV-associated cirrhosis.     

Blood vessel invasion as a strong independent prognostic indicator in non-small cell lung cancer: a systematic review and meta-analysis

Background and Objective

Blood vessel invasion plays a very important role in the progression and metastasis of cancer. However, blood vessel invasion as a prognostic factor for survival in non-small cell lung cancer (NSCLC) remains controversial. The aim of this study is to explore the relationship between blood vessel invasion and outcome in patients with NSCLC using meta-analysis.

Methods

A meta-analysis of published studies was conducted to investigate the effects of blood vessel invasion on both relapse-free survival (RFS) and overall survival (OS) for patients with NSCLC. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were used to assess the strength of this association.

Results

A total of 16,535 patients from 52 eligible studies were included in the systematic review and meta-analysis. In total, blood vessel invasion was detected in 29.8% (median; range from 6.2% to 77.0%) of patients with NSCLC. The univariate and multivariate estimates for RFS were 3.28 (95% CI: 2.14–5.05; P<0.0001) and 3.98 (95% CI: 2.24–7.06; P<0.0001), respectively. For the analyses of blood vessel invasion and OS, the pooled HR estimate was 2.22 (95% CI: 1.93–2.56; P<0.0001) by univariate analysis and 1.90 (95% CI: 1.65–2.19; P<0.0001) by multivariate analysis. Furthermore, in stage I NSCLC patients, the meta-risk for recurrence (HR = 6.93, 95% CI: 4.23–11.37, P<0.0001) and death (HR = 2.15, 95% CI: 1.68–2.75; P<0.0001) remained highly significant by multivariate analysis.

Conclusions

This study shows that blood vessel invasion appears to be an independent negative prognosticator in surgically managed NSCLC. However, adequately designed large prospective studies and investigations are warranted to confirm the present findings.     

Adjuvant chemotherapy, with or without taxanes, in early or operable breast cancer: a meta-analysis of 19 randomized trials with 30698 patients

Background

Taxanes have been extensively used as adjuvant chemotherapy for the treatment of early or operable breast cancer, particularly in high risk, node-negative breast cancer. Previous studies, however, have reported inconsistent findings regarding their clinical efficacy and safety. We investigated disease-free survival (DFS), overall survival (OS), and drug-related toxicities of taxanes by a systematic review and meta-analysis.

Methodology and Principal Findings

We systematically searched PubMed, EMBASE, the Cochrane Center Register of Controlled Trials, proceedings of major meetings, and reference lists of articles for studies conducted between January 1980 and April 2011. Randomized controlled trials (RCTs) comparing chemotherapy with and without taxanes in the treatment of patients with early-stage or operable breast cancer were eligible for inclusion in our analysis. The primary endpoint was DFS. Nineteen RCTs including 30698 patients were identified, including 8426 recurrence events and 3803 deaths. Taxanes administration yielded a 17% reduction of hazard ratio (HR) for DFS (HR = 0.83, 95% CI 0.79–0.88, p<0.001) and a 17% reduction of HR for OS (HR = 0.83, 95% CI 0.77–0.90, p<0.001). For high risk, node-negative breast cancer, the pooled HR also favoured the taxane-based treatment arm over the taxane-free treatment arm (HR = 0.82, 95% CI 0.77–0.87, p = 0.022). A significantly increased rate of neutropenia, febrile neutropenia, fatigue, diarrhea, stomatitis, and oedema was observed in the taxane-based treatment arm.

Conclusions/Significance

Adjuvant chemotherapy with taxanes could reduce the risk of cancer recurrence and death in patients with early or operable breast cancer, although the drug-related toxicities should be balanced. Furthermore, we also demonstrated that patients with high risk, node-negative breast cancer also benefited from taxanes therapy, a result that was not observed in previous studies.     

An Inflammation Based Score Can Optimize the Selection of Patients with Advanced Cancer Considered for Early Phase Clinical Trials

Background

Adequate organ function and good performance status (PS) are common eligibility criteria for phase I trials. As inflammation is pathogenic and prognostic in cancer we investigated the prognostic performance of inflammation-based indices including the neutrophil (NLR) and platelet to lymphocyte ratio (PLR).

Methods

We studied inflammatory scores in 118 unselected referrals. NLR normalization was recalculated at disease reassessment. Each variable was assessed for progression-free (PFS) and overall survival (OS) on uni- and multivariate analyses and tested for 90 days survival (90DS) prediction using receiving operator curves (ROC).

Results

We included 118 patients with median OS 4.4 months, 23% PS>1. LDH≥450 and NLR≥5 were multivariate predictors of OS (p<0.001). NLR normalization predicted for longer OS (p<0.001) and PFS (p<0.05). PS and NLR ranked as most accurate predictors of both 90DS with area under ROC values of 0.66 and 0.64, and OS with c-score of 0.69 and 0.60. The combination of NLR+PS increased prognostic accuracy to 0.72. The NLR was externally validated in a cohort of 126 subjects.

Conclusions

We identified the NLR as a validated and objective index to improve patient selection for experimental therapies, with its normalization following treatment predicting for a survival benefit of 7 months. Prospective validation of the NLR is warranted.     

The Influence of Hepatitis B Viral Load and Pre-S Deletion Mutations on Post-Operative Recurrence of Hepatocellular Carcinoma and the Tertiary Preventive Effects by Anti-Viral Therapy

Background

Whether or not hepatitis B virus (HBV) genotypes, mutations, and viral loads determine outcomes for patients with HBV-induced hepatocellular carcinoma (HCC) remains controversial.

Aims

To study the influence of HBV viral factors on prognoses for patients with HBV-induced HCC after resection surgery and investigate if antiviral therapy could counteract the adverse effects of viral factors.

Methods

A total of 333 HBV-related HCC patients who underwent tumor resection were enrolled retrospectively. Serum HBV DNA levels, mutations, anti-viral therapy, and other clinical variables were analyzed for their association with post-operative recurrence.

Results

After a median follow-up of 45.9 months, 208 patients had HCC recurrence after resection. The 5-year overall survival and recurrence-free survival rates were 55.4% and 35.3%, respectively. Multivariate analysis showed indocyanine green retention rate at 15 minutes >10%, gamma-glutamyltransferase (GGT) level >60 U/L, macroscopic and microscopic venous invasion, and the absence of anti-viral therapy were significant risk factors for recurrence. Anti-viral therapy could decrease recurrence in patients with early stage HCC, but the effect was less apparent in those with the Barcelona-Clinic Liver Cancer stage C HCC. For patients without antiviral therapy after resection, serum HBV DNA levels >10⁶ copies/mL, GGT >60 U/L, and macroscopic and microscopic venous invasion were significant risk factors predicting recurrence. Among the 216 patients without anti-viral therapy but with complete HBV surface gene mapping data, 73 were with pre-S deletion mutants. Among patients with higher serum HBV DNA levels, those with pre-S deletion had significantly higher rates of recurrence. Moreover, multivariate analysis showed multi-nodularity, macroscopic venous invasion, cirrhosis, advanced tumor cell differentiation, and pre-S deletion were significant risk factors predictive of recurrence.

Conclusions

Ongoing HBV viral replication and pre-S deletion are crucial for determining post-operative tumor recurrence. Anti-viral therapy can help reduce recurrence and improve prognosis, especially for those with early stage HCC.     

Radiofrequency Ablation versus Hepatic Resection for Small Hepatocellular Carcinomas: A Meta-Analysis of Randomized and Nonrandomized Controlled Trials

Objectives

To evaluate the efficacy and safety of radiofrequency ablation (RFA) versus hepatic resection (HR) for early hepatocellular carcinoma (HCC) meeting the Milan criteria.

Methods

A meta-analysis was conducted, and PubMed, Web of Science, the Cochrane Library, CBM, CNKI and VIP databases were systematically searched through November 2012 for randomized and nonrandomized controlled trials (RCTs and NRCTs). The Cochrane Collaboration''s tool and modified MINORS score were applied to assess the quality of RCTs and NRCTs, respectively. The GRADE approach was employed to evaluate the strength of evidence.

Results

Three RCTs and twenty-five NRCTs were included. Among 11,873 patients involved, 6,094 patients were treated with RFA, and 5,779 with HR. The pooled results of RCTs demonstrated no significant difference between groups for 1- and 3-year overall survival (OS), recurrence-free survival (RFS) and disease-free survival (DFS) (p>0.05). The 5-year OS (Relative Risk, RR 0.72, 95% CI 0.60 to 0.88) and RFS (RR 0.56, 95% CI 0.40 to 0.78) were lower with RFA than with HR. The 3- and 5-year recurrences with RFA were higher than with HR (RR 1.48, 95% CI 1.14 to 1.94, and RR 1.52, 95% CI 1.18 to 1.97, respectively), but 1-year recurrence and in-hospital mortality showed no significant differences between groups (p>0.05). The complication rate (RR 0.18, 95% CI 0.06 to 0.53) was lower and hospital stays (Mean difference -8.77, 95% CI −10.36 to −7.18) were shorter with RFA than with HR. The pooled results of NRCTs showed that the RFA group had lower 1-, 3- and 5-year OS, RFS and DFS, and higher recurrence than the HR group (p<0.05). But for patients with very early stage HCC, RFA was comparable to HR for OS and recurrence.

Conclusion

The effectiveness of RFA is comparable to HR, with fewer complications but higher recurrence, especially for very early HCC patients.     

Genetic variations in plasma circulating DNA of HBV-related hepatocellular carcinoma patients predict recurrence after liver transplantation

Background

Recurrence prediction of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT) present a great challenge because of a lack of biomarkers. Genetic variations play an important role in tumor development and metastasis.

Methods

Oligonucleotide microarrays were used to evaluate the genetic characteristics of tumor DNA in 30 HBV-related HCC patients who were underwent LT. Recurrence-related single-nucleotide polymorphism were selected, and their prognostic value was assessed and validated in two independent cohorts of HCC patients (N = 102 and N = 77), using pretransplant plasma circulating DNA. Prognostic significance was assessed by Kaplan-Meier survival estimates and log-rank tests. Multivariate analyses were performed to evaluate prognosis-related factors.

Results

rs894151 and rs12438080 were significantly associated with recurrence (P = .003 and P = .004, respectively). Multivariate analyses demonstrated that the co-index of the 2 SNPs was an independent prognostic factor for recurrence (P = .040). Similar results were obtained in the third cohort (N = 77). Furthermore, for HCC patients (all the 3 cohorts) exceeding Milan criteria, the co-index was a prognostic factor for recurrence and survival (P<.001 and P = .002, respectively).

Conclusions

Our study demonstrated first that genetic variations of rs894151 and rs12438080 in pretransplant plasma circulating DNA are promising prognostic markers for tumor recurrence in HCC patients undergoing LT and identify a subgroup of patients who, despite having HCC exceeding Milan criteria, have a low risk of post-transplant recurrence.     

Postoperative Neutrophil-to-Lymphocyte Ratio Change Predicts Survival of Patients with Small Hepatocellular Carcinoma Undergoing Radiofrequency Ablation

Background

An elevated preoperative neutrophil-to-lymphocyte ratio (NLR) has been reported to be a prognostic factor for hepatocellular carcinoma (HCC) patients after treatment. However, the clinical implication of postoperative NLR change remains unclear.

Materials and Methods

From May 2005 to Aug 2008, a cohort of consecutive 178 small HCC patients treated with radiofrequency ablation (RFA) was retrospectively reviewed. The NLR was recorded within 3 days before and 1 month after RFA. Baseline characteristics, overall survival (OS) and recurrence free survival (RFS) were compared according to preoperative NLR and/or postoperative NLR change. Prognostic factors were assessed by multivariate analysis.

Results

Compared with preoperative NLR level, postoperative NLR decreased in 87 patients and increased in 91 patients after RFA. No significant differences were identified between two groups in commonly used clinic-pathologic features. The 1, 3, 5 years OS was 98.8%, 78.6%, 67.1% for NLR decreased group, and 92.2%, 55.5%, 35.4% for NLR increased group respectively (P<0.001); the corresponding RFS was 94.2%, 65.2%, 33.8% and 81.7%, 46.1%, 12.4% respectively (P<0.001). In subgroup analysis, the survival of patients with lower or higher preoperative NLR can be distinguished more accurate by postoperative NLR change. Multivariate analysis showed that postoperative NLR change, but not preoperative NLR, was an independent prognostic factor for both OS (P<0.001, HR = 2.39, 95%CI 1.53–3.72) and RFS (P = 0.003, HR = 1.69, 95%CI 1.87–8.24).

Conclusion

The postoperative NLR change was an independent prognostic factor for small HCC patient undergoing RFA, and patients with decreased NLR indicated better survival than those with increased NLR.     

CCND1 as a predictive biomarker of neoadjuvant chemotherapy in patients with locally advanced head and neck squamous cell carcinoma

Background

Cyclin D1 (CCND1) has been associated with chemotherapy resistance and poor prognosis. In this study, we tested the hypothesis that CCND1 expression determines response and clinical outcomes in locally advanced head and neck squamous cell carcinoma (HNSCC) patients treated with neoadjuvant chemotherapy followed by surgery and radiotherapy.

Methodology and Findings

224 patients with HNSCC were treated with either cisplatin-based chemotherapy followed by surgery and radiotherapy (neoadjuvant group, n = 100) or surgery and radiotherapy (non-neoadjuvant group, n = 124). CCND1 expression was assessed by immunohistochemistry. CCND1 levels were analyzed with chemotherapy response, disease-free survival (DFS) and overall survival (OS). There was no significant difference between the neoadjuvant group and non-neoadjuvant group in DFS and OS (p = 0.929 and p = 0.760) when patients treated with the indiscriminate administration of cisplatin-based chemotherapy. However, in the neoadjuvant group, patients whose tumors showed a low CCND1 expression more likely respond to chemotherapy (p<0.001) and had a significantly better OS and DFS than those whose tumors showed a high CCND1 expression (73% vs 8%, p<0.001; 63% vs 6%, p<0.001). Importantly, patients with a low CCND1 expression in neoadjuvant group received more survival benefits than those in non-neoadjuvant group (p = 0.016), however patients with a high CCND1 expression and treated with neoadjuvant chemotherapy had a significantly poor OS compared to those treated with surgery and radiotherapy (p = 0.032). A multivariate survival analysis also showed CCND1 expression was an independent predictive factor (p<0.001).

Conclusions

This study suggests that some but not all patients with HNSCC may benefit from neoadjuvant chemotherapy with cisplatin-based regimen and CCND1 expression may serve as a predictive biomarker in selecting patients undergo less than two cycles of neoadjuvant chemotherapy.     

Chromogranin A (CgA) as poor prognostic factor in patients with small cell carcinoma of the cervix: results of a retrospective study of 293 patients

Background

Small cell carcinoma of the cervix (SCCC) is a very rare tumor. Due to its rarity and the long time period, there is a paucity of information pertaining to prognostic factors associated with survival. The objective of this study was to determine whether clinicopathologic finings or immunohistochemical presence of molecular markers predictive of clinical outcome in patients with SCCC.

Methodology and Findings

We retrospectively reviewed a total of 293 patients with SCCC (47 patients from Cancer Center of Sun Yat-sen University in china, 71 patients from case report of china journal, 175 patients from case report in PubMed database). Of those 293 patients with SCCC, the median survival time is 23 months. The 3-year overall survival rates (OS) and 3-year disease-free survival rates (DFS) for all patients were 34.5% and 31.1%, respectively. Univariate and multivariate analysis showed that FIGO stage (IIb–IV VS I–IIa, Hazard Ratio (HR) = 3.08, 95% confidence interval (CI) of ratio = [2.05, 4.63], P<0.001), tumor mass size (≥4 cm VS <4 cm, HR = 2.37, 95% CI = [1.28, 4.36], P = 0.006) and chromogranin A (CgA) (Positive VS Negative, HR = 1.81, 95% CI = [1.12, 2.91], P = 0.015) were predictive of poor prognosis. CgA stained positive was found to be highly predictive of death in early-stage (FIGO I–IIa) patient specifically.

Conclusions

Patients with SCCC have poor prognosis. FIGO stage, tumor mass size and CgA stained positive may act as a surrogate for factors prognostic of survival. CgA may serve as a useful marker in prognostic evaluation for early-stage patients with SCCC.     

Antiviral therapy and outcomes of patients with pneumonia caused by influenza A pandemic (H1N1) virus

Background

There is limited data on the clinical outcome of patients with pandemic H1N1 (pH1N1) pneumonia who received oseltamivir treatment, especially when the treatment was administered more than 48 hours after symptom onset.

Methods

During the pandemic in 2009, a cohort of pH1N1 influenza pneumonia was built in China, and their clinical information was collected systematically, and analyzed with Cox models.

Results

920 adults and 541 children with pneumonia who didn''t receive corticosteroids were analyzed. In-hospital mortality was higher in adults who did not receive antiviral therapy (18.2%) than those with who received oseltamivir ≤ 2days (2.9%), between 2–5 days (4.6%) and >5 days after illness onset (4.9%), p<0.01. A similar trend was observed in pediatric patients. Cox regression showed that at 60 days after symptoms onset, 11 patients (10.8%) who did not receive antivirals died versus 4 (1.8%), 18 (3.3%), and 23 (3.7%) patients whose oseltamivir treatment was started ≤ 2days, between 2–5days, and >5 days, respectively. For males patients, aged ≥ 14 years and baseline PaO₂/FiO₂<200, oseltamivir administration reduced the mortality risk by 92.1%, 88% and 83.5%, respectively. Higher doses of oseltamivir (>3.8 mg/kg/d) did not improve clinical outcome (mortality, higher dose 2.5% vs standard dose 2.8%, p>0.05).

Conclusions

Antiviral therapy might reduce mortality of patients with pH1N1 pneumonia, even when initiated more than 48 hours after onset of illness. Greater protective effects might be in males, patients aged 14–60 years, and patients with PaO₂/FiO₂<200.     

Zoledronic Acid as an adjuvant therapy in patients with breast cancer: a systematic review and meta-analysis

Background

Zoledronic acid is widely used as adjuvant chemotherapy for the treatment of breast cancer. However, previous trials reported inconsistent findings regarding their clinical efficacy and safety. We carried out a comprehensive systematic review and meta-analysis to evaluate the effects of zoledronic acid on disease-free survival (DFS), overall survival (OS), and drug-related toxicities.

Methodology and Principal Findings

We systematically searched Medline, EmBase, the Cochrane Central Register of Controlled Trials, reference lists of articles and proceedings of major meetings for relevant literatures with a time limit of Dec. 1, 2011. Randomized controlled trials evaluated the effects of zoledronic acid on OS, DFS, and RFS compared with control were eligible for inclusion in our research. Of 175 identified studies, we collected data from 7 randomized controlled trials of zoledronic acid that had OS, DFS, and RFS reported as one of the endpoint. Overall, we noted that patients receiving zoledronic acid therapy had significant longer OS than the group with non-zoledronic acid therapy (HR, 0.85, 95%CI, 0.73 to 1.00, P = 0.047). Furthermore, zoledronic acid therapy also had a clear effect on frature events (RR, 0.66, 95%CI, 0.52 to 0.84, P<0.001). Subgroup analysis indicated that zoledronic acid therapy showed a great beneficial effect on disease recurrence in patients with early-stage breast cancer, however, it also significantly increased the harm of disease recurrence in patients with advanced breast cancer. Bone pain, neutropenic fever, pyrexia, rash were more frequent in the zoledronic acid therapy group.

Conclusion/Significance

Treatment with zoledronic acid had a clear effect on fracture events, and it might contribute an important role for overall survival.     

A simple scoring system to differentiate between relapse and re-infection in patients with recurrent melioidosis

Background

Melioidosis is an important cause of morbidity and mortality in East Asia. Recurrent melioidosis occurs in around 10% of patients following treatment either because of relapse with the same strain or re-infection with a new strain of Burkholderia pseudomallei. Distinguishing between the two is important but requires bacterial genotyping. The aim of this study was to develop a simple scoring system to distinguish re-infection from relapse.

Methods

In a prospective study of 2,804 consecutive adult patients with melioidosis presenting to Sappasithiprasong Hospital, NE Thailand, between1986 and 2005, there were 141 patients with recurrent melioidosis with paired strains available for genotyping. Of these, 92 patients had relapse and 49 patients had re-infection. Variables associated with relapse or re-infection were identified by multivariable logistic regression and used to develop a predictive model. Performance of the scoring system was quantified with respect to discrimination (area under receiver operating characteristic curves, AUC) and categorization (graphically). Bootstrap resampling was used to internally validate the predictors and adjust for over-optimism.

Findings

Duration of oral antimicrobial treatment, interval between the primary episode and recurrence, season, and renal function at recurrence were independent predictors of relapse or re-infection. A score of <5 correctly identified relapse in 76 of 89 patients (85%), whereas a score ≥5 correctly identified re-infection in 36 of 52 patients (69%). The scoring index had good discriminative power, with a bootstrap bias-corrected AUC of 0.80 (95%CI: 0.73–0.87).

Conclusions

A simple scoring index to predict the cause of recurrent melioidosis has been developed to provide important bedside information where rapid bacterial genotyping is unavailable.     

Performance of local light microscopy and the ParaScreen Pan/Pf rapid diagnostic test to detect malaria in health centers in Northwest Ethiopia

Background

Diagnostic tests are recommended for suspected malaria cases before treatment, but comparative performance of microscopy and rapid diagnostic tests (RDTs) at rural health centers has rarely been studied compared to independent expert microscopy.

Methods

Participants (N = 1997) with presumptive malaria were recruited from ten health centers with a range of transmission intensities in Amhara Regional State, Northwest Ethiopia during October to December 2007. Microscopy and ParaScreen Pan/Pf® RDT were done immediately by health center technicians. Blood slides were re-examined later at a central laboratory by independent expert microscopists.

Results

Of 1,997 febrile patients, 475 (23.8%) were positive by expert microscopists, with 57.7% P.falciparum, 24.6% P.vivax and 17.7% mixed infections. Sensitivity of health center microscopists for any malaria species was >90% in five health centers (four of which had the highest prevalence), >70% in nine centers and 44% in one site with lowest prevalence. Specificity for health center microscopy was very good (>95%) in all centers. For ParaScreen RDT, sensitivity was ≥90% in three centers, ≥70% in six and <60% in four centers. Specificity was ≥90% in all centers except one where it was 85%.

Conclusions

Health center microscopists performed well in nine of the ten health centers; while for ParaScreen RDT they performed well in only six centers. Overall the accuracy of local microscopy exceeded that of RDT for all outcomes. This study supports the introduction of RDTs only if accompanied by appropriate training, frequent supervision and quality control at all levels. Deficiencies in RDT use at some health centers must be rectified before universal replacement of good routine microscopy with RDTs. Maintenance and strengthening of good quality microscopy remains a priority at health center level.     

LAPTM4B allele *2 is a marker of poor prognosis following hepatic tumor resection for hepatocellular carcinoma

Background

Lysosomal protein transmembrane 4 beta (LAPTM4B) is a gene related to hepatocellular carcinoma that has two alleles designated LAPTM4B*1 and LAPTM4B*2. This study aimed to investigate the correlation of LAPTM4B genotype with prognosis and clinicopathologic features in patients who have undergone resection for hepatocellular carcinoma (HCC).

Methodology/Principal Findings

The LAPTM4B genotype was analyzed by PCR in 68 patients who had undergone curative hepatic resection for hepatocellular carcinoma. The correlation of LAPTM4B genotype with clinicopathologic parameters was assessed with the Chi-squared test. Differences in patient survival were determined by the Kaplan–Meier method. Multivariate analysis of prognostic factors was carried out with Cox regression analysis. Patients with LAPTM4B *2 had both significantly shorter overall survival (OS) and shorter disease-free survival (DFS) (both P<0.001). Multivariate analysis showed that LAPTM4B genotype is an independent prognostic factor for OS and DFS (both P<0.001).

Conclusions/Significance

Allele *2 of LAPTM4B is a risk factor associated with poor prognosis in patients with resected HCC. LAPTM4B status may be useful preoperatively as an adjunct in evaluation of the operability of HCC.     

Prognostic Role of Pre-Treatment Serum AFP-L3% in Hepatocellular Carcinoma: Systematic Review and Meta-Analysis

Background

Serum lens culinaris agglutinin-reactive fraction of α-fetoprotein (AFP-L3%) has been widely used for HCC diagnosis and follow-up surveillance as tumor serologic marker. However, the prognostic value of high pre-treatment serum AFP-L3% in patients with hepatocellular carcinoma (HCC) remains controversial. We therefore conduct a meta-analysis to assess the relationship between high pre-treatment serum AFP-L3% and clinical outcome of HCC.

Methods

Eligible studies were identified through systematic literature searches. A meta-analysis of fifteen studies (4,465 patients) was carried out to evaluate the association between high pre-treatment serum AFP-L3% and overall survival (OS) and disease-free survival (DFS) in HCC patients. Sensitivity and subgroup analyses were also conducted in this meta-analysis.

Results

Our analysis results showed that high pre-treatment serum AFP-L3% implied poor OS (HR: 1.65, 95%CI: 1.45–1.89 p<0.00001) and DFS (HR: 1.80, 95% CI: 1.49–2.17 p<0.00001) of HCC. Subgroup analysis revealed that there was association between pre-treatment serum AFP-L3% and endpoint (OS and DFS) in low AFP concentration HCC patients (HR: 1.96, 95% CI: 1.24–3.10, p = 0.004; HR: 2.53, 95% CI: 1.09–5.89, p = 0.03, respectively).

Conclusion

The current evidence suggests that high pre-treatment serum AFP-L3% levels indicated a poor prognosis for patients with HCC and AFP-L3% may have significant prognostic value in HCC patients with low AFP concentration.     

Human rhinovirus infections in rural Thailand: epidemiological evidence for rhinovirus as both pathogen and bystander

Background

We describe human rhinovirus (HRV) detections in SaKaeo province, Thailand.

Methods

From September 1, 2003–August 31, 2005, we tested hospitalized patients with acute lower respiratory illness and outpatient controls without fever or respiratory symptoms for HRVs with polymerase chain reaction and molecularly-typed select HRVs. We compared HRV detection among hospitalized patients and controls and estimated enrollment adjusted incidence.

Results

HRVs were detected in 315 (16%) of 1919 hospitalized patients and 27 (9.6%) of 280 controls. Children had the highest frequency of HRV detections (hospitalized: <1 year: 29%, 1–4 year: 29%, ≥65 years: 9%; controls: <1 year: 24%, 1–4 year: 14%, ≥65 years: 2.8%). Enrollment adjusted hospitalized HRV detection rates were highest among persons aged <1 year (1038/100,000 persons/year), 1–4 years (457), and ≥65 years (71). All three HRV species were identified, HRV-A was the most common species in most age groups including children aged <1 year (61%) and all adult age groups. HRV-C was the most common species in the 1–4 year (51%) and 5–19 year age groups (54%). Compared to controls, hospitalized adults (≥19 years) and children were more likely to have HRV detections (odds ratio [OR]: 4.8, 95% confidence interval [CI]: 1.5, 15.8; OR: 2.0, CI: 1.2, 3.3, respectively) and hospitalized children were more likely to have HRV-A (OR 1.7, CI: 0.8, 3.5) or HVR-C (OR 2.7, CI: 1.2, 5.9) detection.

Conclusions

HRV rates were high among hospitalized children and the elderly but asymptomatic children also had substantial HRV detection. HRV (all species), and HRV-A and HRV-C detections were epidemiologically-associated with hospitalized illness. Treatment or prevention modalities effective against HRV could reduce hospitalizations due to HRV in Thailand.