High-dose chemotherapy followed by autologous stem cell transplantation as a first-line therapy for high-risk primary breast cancer: a meta-analysis

Background and Objectives

Several trials have generated conflicting results about the results of high-dose chemotherapy followed by autologous stem cell transplantation (HDCT) for primary breast cancer. This meta-analysis summarizes the available evidence from all suitable studies.

Design and Methods

Prospective, randomized trials with HDCT as a first-line therapy for primary breast cancer were included in this meta-analysis. The primary outcome of interest for our analysis was survival (disease-free survival and overall survival); secondary endpoints included treatment-related mortality (TRM) and second (non-breast) cancers. We used a median age of 47, a PR positive rate of 50% and a premenopausal rate of 70% as cutoff values to complete the subgroup analyses, which were pre-planned according to the prepared protocol.

Results

Fourteen trials with 5747 patients were eligible for the meta-analysis. Compared with non-HDCT, non-significant second (non-breast) cancers (RR = 1.28; 95% CI = 0.82–1.98) and higher TRM (RR = 3.42; 95% CI = 1.32–8.86) were associated with HDCT for primary breast cancer. A significant DFS benefit of HDCT was documented (HR = 0.89; 95% CI = 0.79–0.99). No difference in OS (overall survival) was found when the studies were pooled (HR = 0.91; 95% CI = 0.82–1.00, p = 0.062). In subgroup analysis, age and hormone receptor status had a significant interaction with prolonged DFS and OS.

Conclusions

HDCT has a benefit on DFS and OS compared to SDC in some special patients with high-risk primary breast cancer.     

Effect of ABCB1 and ABCC3 polymorphisms on osteosarcoma survival after chemotherapy: a pharmacogenetic study

Background

Standard treatment for osteosarcoma patients consists of a combination of cisplatin, adriamycin, and methotrexate before surgical resection of the primary tumour, followed by postoperative chemotherapy including vincristine and cyclophosphamide. Unfortunately, many patients still relapse or suffer adverse events. We examined whether common germline polymorphisms in chemotherapeutic transporter and metabolic pathway genes of the drugs used in standard osteosarcoma treatment may predict treatment response.

Methodology/Principal Findings

In this study we screened 102 osteosarcoma patients for 346 Single Nucleotide Polymorphisms (SNPs) and 2 Copy Number Variants (CNVs) in 24 genes involved in the metabolism or transport of cisplatin, adriamycin, methotrexate, vincristine, and cyclophosphamide. We studied the association of the genotypes with tumour response and overall survival. We found that four SNPs in two ATP-binding cassette genes were significantly associated with overall survival: rs4148416 in ABCC3 (per-allele HR = 8.14, 95%CI = 2.73-20.2, p-value = 5.1×10⁻⁵), and three SNPs in ABCB1, rs4148737 (per-allele HR = 3.66, 95%CI = 1.85–6.11, p-value = 6.9×10⁻⁵), rs1128503 and rs10276036 (r² = 1, per-allele HR = 0.24, 95%CI = 0.11–0.47 p-value = 7.9×10⁻⁵). Associations with these SNPs remained statistically significant after correction for multiple testing (all corrected p-values [permutation test] ≤0.03).

Conclusions

Our findings suggest that these polymorphisms may affect osteosarcoma treatment efficacy. If these associations are independently validated, these variants could be used as genetic predictors of clinical outcome in the treatment of osteosarcoma, helping in the design of individualized therapy.     

Patients present earlier and survival has improved, but pre-ART attrition is high in a six-year HIV cohort data from Ethiopia

Background

Previous studies showed higher early mortality rates among patients treated with antiretroviral drugs in settings with limited resources. One of the reasons was late presentation of patients to care. With improved access to HIV services, we expect improvements in disease stage at presentation. Our objective was to assess the effect of improved availability of HIV services on patient presentation to care and subsequent pre-ART and on-ART outcomes.

Methodology and Principal Findings

At Arba Minch Hospital in Ethiopia, we reviewed baseline characteristics and outcomes of 2191 adult HIV patients. Nearly a half were in WHO stage III at presentation. About two-thirds of the patients (1428) started ART. Patients enrolled in the early phase (OR = 4.03, 95% CI 3.07–5.27), men (OR = 1.78, 95%CI 1.47–2.16), and those aged 45 years and above (OR = 2.04, 95%CI 1.48–2.82) were at higher risk of being in advanced clinical stage at presentation. The pre-treatment mortality rate was 13.1 per 100 PYO, ranging from 1.4 in the rapid scale-up phase to 25.9 per 100 PYO in the early phase. A quarter of the patients were lost to follow-up before starting treatment. Being in less advanced stage (HR = 1.9, 95% CI = 1.6, 2.2), being in the recent cohort (HR = 2.0, 95% CI = 1.6, 2.6), and rural residence (HR = 1.8, 95% CI = 1.5, 2.2) were independent predictors of pre-ART loss to follow-up. Of those who started ART, 13.4% were lost to follow-up and 15.4% died. The survival improved during the study. Patients with advanced disease, men and older people had higher death rates.

Conclusions and Significance

Patients started to present at earlier stages of their illness and death has decreased among adult HIV patients visiting Arba Minch Hospital. However, many patients were lost from pre-treatment follow-up. Early treatment start contributed to improved survival. Both pre-ART and on-ART patient retention mechanisms should be strengthened.     

Self-rated health as a predictor of disability retirement--the contribution of ill-health and working conditions

Objective

Self-rated health is a generic health indicator predicting mortality, many diseases, and need for care. We examined self-rated health as a predictor of subsequent disability retirement, and ill-health and working conditions as potential explanations for the association.

Methods

Self-rated health and the covariates were obtained from the Helsinki Health Study baseline mail surveys in 2000–2002 conducted among municipal employees aged 40–60 years (n = 6525). Data for disability retirement events (n = 625) along with diagnoses were linked from the Finnish Centre for Pensions, with a follow-up by the end of 2010. Hazard ratios (HR) and their 95% confidence intervals (CI) were calculated using competing risks models.

Results

Less than good self-rated health predicted disability retirement due to all causes among both women (HR = 4.60, 95% CI = 3.84–5.51) and men (HR = 3.83, 95% CI = 2.64–5.56), as well as due to musculoskeletal diseases (HR = 5.17, 95% CI = 4.02–6.66) and mental disorders (HR = 4.80, 95% CI = 3.50–6.59) among women and men pooled. Ill-health and physical working conditions partly explained the found associations, which nevertheless remained after the adjustments. Among the measures of ill-health limiting long-standing illness explained the association most in all-cause disability retirement and disability retirements due to musculoskeletal diseases, whereas common mental disorders explained the association most in disability retirements due to mental health disorders. Among working conditions physical work load and hazardous exposures at work explained the association most, although much less than ill-health.

Conclusions

Self-rated health is a strong predictor of disability retirement. This can be partly explained by ill-health and working conditions. Poor self-rated health provides a useful marker for increased risk of work disability and subsequent disability retirement.     

Lack of association of SULT1A1 R213H polymorphism with colorectal cancer: a meta-analysis

Background

A number of case-control studies were conducted to investigate the association of SULT1A1 R213H polymorphisms with colorectal cancer (CRC) in humans. But the results were not always consistent. We performed a meta-analysis to examine the association between the SULT1A1 R213H polymorphism and CRC.

Methods and Findings

Data were collected from the following electronic databases: PubMed, Elsevier Science Direct, Excerpta Medica Database, and Chinese Biomedical Literature Database, with the last report up to September 2010. A total of 12 studies including 3,549 cases and 5,610 controls based on the search criteria were involved in this meta-analysis. Overall, no significant association of this polymorphism with CRC was found (H versus R: OR = 1.04, 95%CI = 0.94–1.16, P = 0.46; HR+HH versus RR: OR = 1.01, 95%CI = 0.92–1.11, P = 0.81; HH versus RR+HR: OR = 1.01, 95%CI = 0.74–1.38, P = 0.95; HH versus RR: OR = 1.00, 95%CI = 0.77–1.31, P = 0.98; HR versus RR: OR = 1.01, 95%CI = 0.92–1.11, P = 0.86). In subgroup analysis, we also did not find any significant association in Cauasians (H versus R: OR = 1.02, 95%CI = 0.92–1.15, P = 0.68; HR+HH versus RR: OR = 0.99, 95%CI = 0.91–1.09, P = 0.90; HH versus RR+HR: OR = 1.01, 95%CI = 0.73–1.39, P = 0.97; HH versus RR: OR = 0.99, 95%CI = 0.75–1.31, P = 0.94; HR versus RR: OR = 0.99, 95%CI = 0.90–1.09, P = 0.85). The results were not materially altered after the studies which did not fulfill Hardy-Weinberg equilibrium were excluded (H versus R: OR = 1.06, 95%CI = 0.95–1.19, P = 0.31; HR+HH versus RR: OR = 1.03, 95%CI = 0.93–1.13, P = 0.56; HH versus RR+HR: OR = 1.10, 95%CI = 0.78–1.56, P = 0.57; HH versus RR: OR = 1.09, 95%CI = 0.83–1.44, P = 0.53; HR versus RR: OR = 1.02, 95%CI = 0.92–1.13, P = 0.75).

Conclusion

This meta-analysis demonstrates that there is no association between the SULT1A1 R213H polymorphism and CRC.     

Postoperative Chemoradiotherapy versus Postoperative Chemotherapy for Completely Resected Gastric Cancer with D2 Lymphadenectomy: A Meta-Analysis

Background

Both chemoradiotherapy and chemotherapy are used in postoperative adjuvant therapy for resected gastric cancer. However, it is controversial whether chemoradiotherapy or chemotherapy is the optimal strategy for patients with gastric cancer after D2 lymphadenectomy. The present meta-analysis aims to provide more evidence on the relative benefits of adjuvant therapies in this setting.

Methods

We conducted a systematic review of randomized controlled trials, extracted time-to-event data using Tierney methods (when not reported), and performed meta-analysis to obtain the relative hazards of adjuvant chemoradiotherapy to chemotherapy on efficacy and toxicities.

Results

A total of 895 patients from 3 randomized controlled trials were identified for this meta-analysis. All patients were from Asian countries. Our results showed that postoperative chemoradiotherapy significantly improved locoregional recurrence-free survival [LRRFS: hazard ratio (HR) = 0.53, 95% CI = 0.32–0.87, p = 0.01] and disease-free survival (DFS: HR = 0.72, 95% CI = 0.59–0.89, p = 0.002); however, the improvement of distant metastasis recurrence-free survival (DMRFS: HR = 0.86; 95% CI = 0.66–1.11, p = 0.25) and overall survival (OS: HR = 0.79, 95% CI = 0.61–1.03, p = 0.08) were non-significant. The main grade 3 or 4 toxicities were equivalent between the two groups.

Conclusion

In non-selected Asian patients with resected gastric cancer who underwent D2 lymphadenectomy, postoperative chemoradiotherapy improved LRRFS and DFS but might not improve OS compared to postoperative chemotherapy.     

Patient's origin and lifestyle associated with CTX-M-producing Escherichia coli: a case-control-control study

Background

Global dissemination of Escherichia coli producing CTX-M extended-spectrum β-lactamases (ESBL) is a public health concern. The aim of the study was to determine factors associated with CTX-M- producing E. coli infections among patients hospitalised in the Assistance Publique-Hôpitaux de Paris, the largest hospital system in France (23 000 beds), through a prospective case-control-control study.

Methods/Principal Findings

From November 2008 to June 2009, 152 inpatients with a clinical sample positive for CTX-M-producing E. coli (cases), 152 inpatients with a clinical sample positive for non ESBL-producing E. coli on the day or within the three days following case detection (controls C1), and 152 inpatients with culture-negative clinical samples since the beginning of hospitalisation and until three days after case detection (controls C2) were included in ten hospitals of the Paris area. Factors studied were related to patient''s origin, lifestyle and medical history as well as care during hospitalisation. Those independently associated with CTX-M-producing E. coli were determined. Three independent factors were common to the two case-control comparisons: birth outside of Europe (cases vs C1: OR₁ = 2.4; 95%CI = [1.3–4.5] and cases vs C2: OR₂ = 3.1; 95%CI = [1.4–7.0]), chronic infections (OR₁ = 2.9; 95%CI = [1.3–6.9] and OR₂ = 8.7; 95%CI = [2.0–39.7]), and antibiotic treatment between hospital admission and inclusion (OR₁ = 2.0; 95%CI = [1.0–3.8] and OR₂ = 3.3; 95%CI = [1.5–7.2]). Cases were also more likely to be (i) functionally dependent before hospitalisation than C2 (OR₂ = 7.0; 95%CI = [2.1–23.5]) and (ii) living in collective housing before hospitalisation than C2 (OR₂ = 15.2; 95%CI = [1.8–130.7]) when CTX-M-producing E. coli was present at admission.

Conclusion

For the first time, patient''s origin and lifestyle were demonstrated to be independently associated with isolation of CTX-M-producing E. coli, in addition to health care-related factors.     

Body adiposity in later life and the incidence of dementia: the health in men study

Objective

To determine if adiposity in later life increases dementia hazard.

Methods

Cohort study of 12,047 men aged 65–84 years living in Perth, Australia. Adiposity exposures were baseline body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR). We used the Western Australian Data Linkage System (WADLS) to establish the presence of new cases of dementia between 1996 and 2009 according to the International Classification of Diseases (ICD). Crude and adjusted hazard ratio (HR, 95% confidence interval, 95%CI) of dementia for each adiposity marker was calculated using Cox regression models. Other measured factors included age, marital status, education, alcohol use, smoking, diet, physical activity, and prevalent hypertension, diabetes, dyslipidaemia and cardiovascular disease.

Results

Compared with men with BMI<25, participants with BMI between 25–30 had lower adjusted HR of dementia (HR = 0.82, 95% CI = 0.70–0.95). The HR of dementia for men with BMI≥30 was comparable to men with BMI<25 (HR = 0.82, 95%CI = 0.67–1.01). Waist circumference showed no obvious association with dementia hazard. Men with WHR≥0.9 had lower adjusted HR of dementia than men with WHR <0.9 (HR = 0.82, 95%CI = 0.69–0.98). We found a “J” shape association between measures of obesity and the hazard of dementia, with the nadir of risk being in the overweight range of BMI and about 1 for WHR.

Conclusions

Higher adiposity is not associated with incident dementia in this Australian cohort of older men. Overweight men and those with WHR≥0.9 have lower hazard of dementia than men with normal weight and with WHR<0.9.     

A Nationwide Population-Based Cohort Study: Will Anxiety Disorders Increase Subsequent Cancer Risk?

Background

The aim of this study was to evaluate a possible association between malignancy and anxiety disorders (AD) in Taiwan.

Methods

We employed data from the National Health Insurance system of Taiwan. The AD cohort contained 24,066 patients with each patient randomly frequency matched according to age and sex with 4 individuals from the general population without AD. Cox''s proportional hazard regression analysis was conducted to estimate the influence of AD on the risk of cancer.

Results

Among patients with AD, the overall risk of developing cancer was only 1% higher than among subjects without AD, and the difference was not significant (hazard ratio [HR] = 1.01, 95% confidence interval [95% CI] = 0.95–1.07). With regard to individual types of cancer, the risk of developing prostate cancer among male patients with AD was significantly higher (HR = 1.32, 95% CI = 1.02–1.71). On the other hand, the risk of cervical cancer among female patients with AD was marginally significantly lower than among female subjects without AD (HR = 0.72, 95% CI = 0.51–1.03).

Limitations

One major limitation is the lack of information regarding the life style or behavior of patients in the NHI database, such as smoking and alcohol consumption.

Conclusions

Despite the failure to identify a relationship between AD and the overall risk of cancer, we found that Taiwanese patients with AD had a higher risk of developing prostate cancer and a lower risk of developing cervical cancer.     

Risk factors of Streptococcus suis infection in Vietnam. A case-control study

Background

Streptococcus suis infection, an emerging zoonosis, is an increasing public health problem across South East Asia and the most common cause of acute bacterial meningitis in adults in Vietnam. Little is known of the risk factors underlying the disease.

Methods and Findings

A case-control study with appropriate hospital and matched community controls for each patient was conducted between May 2006 and June 2009. Potential risk factors were assessed using a standardized questionnaire and investigation of throat and rectal S. suis carriage in cases, controls and their pigs, using real-time PCR and culture of swab samples. We recruited 101 cases of S. suis meningitis, 303 hospital controls and 300 community controls. By multivariate analysis, risk factors identified for S. suis infection as compared to either control group included eating “high risk” dishes, including such dishes as undercooked pig blood and pig intestine (OR₁ = 2.22; 95%CI = [1.15–4.28] and OR₂ = 4.44; 95%CI = [2.15–9.15]), occupations related to pigs (OR₁ = 3.84; 95%CI = [1.32–11.11] and OR₂ = 5.52; 95%CI = [1.49–20.39]), and exposures to pigs or pork in the presence of skin injuries (OR₁ = 7.48; 95%CI = [1.97–28.44] and OR₂ = 15.96; 95%CI = [2.97–85.72]). S. suis specific DNA was detected in rectal and throat swabs of 6 patients and was cultured from 2 rectal samples, but was not detected in such samples of 1522 healthy individuals or patients without S. suis infection.

Conclusions

This case control study, the largest prospective epidemiological assessment of this disease, has identified the most important risk factors associated with S. suis bacterial meningitis to be eating ‘high risk’ dishes popular in parts of Asia, occupational exposure to pigs and pig products, and preparation of pork in the presence of skin lesions. These risk factors can be addressed in public health campaigns aimed at preventing S. suis infection.     

Evaluation of the effect of systolic blood pressure and pulse pressure on cognitive function: the Women's Health and Aging Study II

Background

Evidence suggests that elevated systolic blood pressure (SBP) and pulse pressure (PP) in midlife is associated with increased risk for cognitive impairment later in life. There is mixed evidence regarding the effects of late life elevated SBP or PP on cognitive function, and limited information on the role of female gender.

Methods/Principal Findings

Effects of SBPand PPon cognitive abilities at baseline and over a 9-year period were evaluated in 337 non-demented community-dwelling female participants over age 70 in the Women''s Health and Aging Study II using logistic and Cox proportional hazards regression analyses. Participants aged 76–80 years with SBP≥160 mmHg or PP≥84 mmHg showed increased incidence of impairment on Trail Making Test-Part B (TMT, Part B), a measure of executive function, over time when compared to the control group that included participants with normal and pre-hypertensive SBP (<120 and 120–139 mmHg) or participants with low PP (<68 mmHg) (HR = 5.05 [95%CI = 1.42, 18.04], [HR = 5.12 [95%CI = 1.11; 23.62], respectively). Participants aged 70–75 years with PP≥71 mmHg had at least a two-fold higher incidence of impairment on HVLT-I, a measure of verbal learning, over time when compared to participants with low PP (<68 mmHg) (HR = 2.44 [95%CI = 1.11, 5.39]).

Conclusions/Significance

Our data suggest that elevated SBP or PP in older non-demented women increases risk for late-life cognitive impairment and that PP could be used when assessing the risk for impairment in cognitive abilities. These results warrant further, larger studies to evaluate possible effects of elevated blood pressure in normal cognitive aging.     

Survival of civilian and prisoner drug-sensitive, multi- and extensive drug- resistant tuberculosis cohorts prospectively followed in Russia

Objective and Methods

A long-term observational study was conducted in Samara, Russia to assess the survival and risk factors for death of a cohort of non-multidrug resistant tuberculosis (non-MDRTB) and multidrug resistant tuberculosis (MDRTB) civilian and prison patients and a civilian extensive drug-resistant tuberculosis (XDRTB) cohort.

Results

MDRTB and XDRTB rates of 54.8% and 11.1% were identified in the region. Half (50%) of MDRTB patients and the majority of non-MDRTB patients (71%) were still alive at 5 years. Over half (58%) of the patients died within two years of establishing a diagnosis of XDRTB. In the multivariate analysis, retreatment (HR = 1.61, 95%CI 1.04, 2.49) and MDRTB (HR = 1.67, 95%CI 1.17, 2.39) were significantly associated with death within the non-MDR/MDRTB cohort. The effect of age on survival was relatively small (HR = 1.01, 95%CI 1.00, 1.02). No specific factor affected survival of XDRTB patients although median survival time for HIV-infected versus HIV-negative patients from this group was shorter (185 versus 496 days). The majority of MDRTB and XDRTB strains (84% and 92% respectively) strains belonged to the Beijing family. Mutations in the rpoB (codon 531 in 81/92; 88.8%), katG (mutation S315T in 91/92, 98.9%) and inhA genes accounted for most rifampin and isoniazid resistance respectively, mutations in the QRDR region of gyrA for most fluroquinolone resistance (68/92; 73.5%).

Conclusions

Alarmingly high rates of XDRTB exist. Previous TB treatment cycles and MDR were significant risk factors for mortality. XDRTB patients'' survival is short especially for HIV-infected patients. Beijing family strains comprise the majority of drug-resistant strains.     

First efficacy results of capecitabine with anthracycline- and taxane-based adjuvant therapy in high-risk early breast cancer: a meta-analysis

Background

Capecitabine is effective and indicated for the salvage treatment of metastatic breast cancer. Therefore, it is essential to evaluate the efficacy of capecitabine in the adjuvant setting. There have been two large randomized studies to determine whether patients with high-risk early breast cancer benefit from the addition of capecitabine to standard chemotherapy, but they have yielded inconsistent results. We first undertook a meta-analysis to evaluate the efficacy of the addition of capecitabine over standard treatment.

Methods

PubMed, EBSCO, Web of Science, conference proceedings and key trials were searched from 1998 to 2011. The hazard ratio (HR) was used to evaluate the efficacy of a taxane-anthracycline regimen and a taxane-anthracycline-capecitabine regimen in early breast cancer. All of the data from each study use either fixed-effects or random-effects by Stata.

Findings

We found significant improvement in the additional capecitabine arm versus control in disease-free survival (DFS) (HR = 0.83, 95% CI: 0.71–0.98, P = 0.027), overall survival (OS) (HR = 0.71, 95% CI: 0.57–0.88, P = 0.002), distant recurrence (HR = 0.79, 95% CI: 0.66–0.94, P = 0.008) and the death from breast cancer only (HR = 0.65, 95% CI: 0.51–0.83, P = 0.001). Meanwhile, the subgroup analysis revealed that capecitabine improved the DFS in triple negative (HR = 0.71, 95% CI: 0.53–0.96, P = 0.028), hormone receptor negative (HR = 0.73, CI: 0.56–0.94, P = 0.017) and HER2 negative (HR = 0.81, CI: 0.67–0.98, P = 0.034) patients.

Conclusion

Due to the synergistic effect of taxane and capecitabine, taxane-anthracycline-capecitabine regimen may effectively improve the efficacy in the adjuvant setting and may be a novel generation of adjuvant chemotherapy regimen. The results of the current meta-analysis support this hypothesis and indicate that taxane-based regimen with capecitabine may be an effective, convenient, and well tolerated regimen in patients with early breast cancer.     

Genetic polymorphism in a VEGF-independent angiogenesis gene ANGPT1 and overall survival of colorectal cancer patients after surgical resection

Background

The VEGF-independent angiogenic signaling plays an important role in the development of colorectal cancer (CRC). However, its implication in the clinical outcome of CRC has not been reported. This study aimed to investigate the association between genetic variations in several major VEGF-independent signaling pathway genes and the overall survival of CRC patients.

Methods

Seven single nucleotide polymorphisms (SNPs) in four important VEGF-independent angiogenic genes (ANGPT1, AMOT, DLL4 and ENG) were genotyped in a Chinese population with 408 CRC patients.

Results

One SNP, rs1954727 in ANGPT1, was significantly associated with CRC overall survival. Compared to patients with the homozygous wild-type genotype of rs1954727, those with heterozygous and homozygous variant genotypes exhibited a favorable overall survival with a hazard ratio (HR) of 0.89 (95% confidence interval [CI] 0.55–1.43, P = 0.623), and 0.32 (95% CI 0.15–0.71, P = 0.005), respectively (P trend = 0.008). In stratified analysis, this association remained significant in patients receiving chemotherapy (P trend = 0.012), but not in those without chemotherapy. We further evaluated the effects of chemotherapy on CRC survival that was stratified by rs1954727 genotypes. We found that chemotherapy resulted in a significantly better overall survival in the CRC patients (HR = 0.44, 95% CI 0.26–0.75, P = 0.002), which was especially prominent in those patients with the heterozygous genotype of rs1954727 (HR = 0.45, 95%CI 0.22–0.92, P = 0.028).

Conclusion

Our data suggest that rs1954727 in ANGPT1 gene might be a prognostic biomarker for the overall survival of CRC patients, especially in those receiving chemotherapy, a finding that warrants validation in larger independent populations.     

Prognostic value of survivin in patients with non-small cell lung carcinoma: a systematic review with meta-analysis

Purpose

The potential prognostic value of survivin in resected non-small cell lung carcinoma (NSCLC) is variably reported. The objective of this study was to conduct a systematic review of literatures evaluating survivin expression in resected NSCLC as a prognostic indicator.

Methods

Relevant literatures were identified using PubMed, EMBASE and Chinese Biomedicine Databases. We present the results of a meta-analysis of the association between survivin expression and overall survival (OS) in NSCLC patients. Studies were pooled and summary hazard ratios (HR) were calculated. Subgroup analyses and publication bias were also conducted.

Results

We performed a final analysis of 2703 patients from 28 evaluable studies. Combined HRs suggested that survivin overexpression had an unfavorable impact on NSCLC patients'' survival with no evidence of any significant publication bias (HR = 2.03, 95%CI: 1.78–2.33, Egger''s test, P = 0.24) and no severe heterogeneity between studies (I² = 26.9%). Its effect also appeared significant when stratified according to the studies categorized by histological type, HR estimate, patient race, cutoff point (5%, 10%), detection methods and literature written language except for disease stage. Survivin was identified as a prognostic marker of advanced-stage NSCLC (HR = 1.93, 95%CI: 1.49-2.51), but not early-stage NSCLC (HR = 1.97, 95%CI: 0.76-5.14), in spite of the combined data being relatively small.

Conclusion

This study shows that survivin expression appears to be a pejorative prognostic factor in terms of overall survival in surgically treated NSCLC. Large prospective studies are now needed to confirm the clinical utility of survivin as an independent prognostic marker.     

Postoperative fever: the potential relationship with prognosis in node negative breast cancer patients

Background

Postoperative fever may serve as an indirect sign to reflect the alterations of the host milieu caused by surgery. It still remains open to investigation whether postoperative fever has a bearing on prognosis in patients with lymph node negative breast cancers.

Methods

We performed a retrospective study of 883 female unilateral patients with lymph node negative breast cancer. Fever was defined as an oral temperature ≥38 in one week postoperation. Survival curves were performed with Kaplan-Meier method, and annual relapse hazard was estimated by hazard function.

Findings

The fever patients were older than those without fever (P<0.0001). Hypertensive patients had a propensity for fever after surgery (P = 0.011). A statistically significant difference was yielded in the incidence of fever among HR+/ERBB2-, ERBB2+, HR-/ERBB2- subgroups (P = 0.012). In the univariate survival analysis, we observed postoperative fever patients were more likely to recur than those without fever (P = 0.0027). The Cox proportional hazards regression analysis showed that postoperative fever (P = 0.044, RR = 1.89, 95%CI 1.02–3.52) as well as the HR/ERBB2 subgroups (P = 0.013, HR = 1.60, 95%CI 1.09–2.31) was an independent prognostic factor for relapse-free survival.

Conclusion

Postoperative fever may contribute to relapse in node negative breast cancer patients, which suggests that changes in host milieu related to fever might accelerate the growth of micro-metastatic foci. It may be more precise to integrate both tumor- and host-related factors for the evaluation of relapse risk.     

Association between CD209 -336A/G and -871A/G Polymorphisms and Susceptibility of Tuberculosis: A Meta-Analysis

Background

The association between CD209 promoter polymorphisms (-336A/G, -871A/G) and tuberculosis (TB) risk has been widely reported, but results of previous studies remain controversial and ambiguous. To assess the association between CD209 polymorphisms and TB risk, a meta-analysis was performed.

Methods

Based on comprehensive searches of the PubMed, Embase, Web of Science, Weipu, and CBM databases, we identified outcome data from all articles estimating the association between CD209 polymorphisms and TB risk. The pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated.

Results

A total of 14 studies with 3,610 cases and 3,539 controls were identified. There was no significant association between CD209 -336A/G polymorphism and TB risk (OR = 1.04, 95% CI = 0.91–1.19 for G vs. A; OR = 1.13, 95% CI = 0.84–1.53 for GG vs. AA; OR = 1.04, 95% CI = 0.87–1.24 for GG+AG vs. AA; OR = 1.11, 95% CI = 0.88–1.39 for GG vs. AG+AA). However, the significant association was revealed for Asians in GG vs. AA (OR = 2.48, 95% CI = 1.46–4.22, P = 0.0008) and GG vs. AG+AA (OR = 2.10, 95% CI = 1.33–3.32, P = 0.001). For the CD209 -871A/G polymorphism, lack of an association was also found (OR = 0.81, 95% CI = 0.70–0.95 for G vs. A; OR = 1.00, 95% CI = 0.52–1.93 for GG vs. AA; OR = 0.73, 95% CI = 0.60–0.89 for GG+AG vs. AA; OR = 1.09, 95% CI = 0.57–2.10 for GG vs. AG+AA).

Conclusion

The present meta-analysis suggested that CD209 promoter polymorphisms (-336A/G, -871A/G) were unlikely to substantially contribute to TB susceptibility. However, the GG genotype of CD209 -336A/G polymorphism might be a genetic risk factor that increases TB susceptibility for Asians in GG vs. AA and GG vs. AG+AA.     

Television viewing and incident cardiovascular disease: prospective associations and mediation analysis in the EPIC Norfolk Study

Background

Although television viewing time is detrimentally associated with intermediate cardiovascular risk factors, the relationship with incident total (i.e. combined fatal and non-fatal) cardiovascular disease (CVD), non-fatal CVD and coronary heart disease is largely unknown. This study examined whether television viewing time is associated with these three outcomes, independently of physical activity energy expenditure and other confounding variables.

Methodology/Principal Findings

A population-based cohort of 12,608 men and women (aged 61.4±9.0), free from stroke, myocardial infarction and cancer at baseline in 1998–2000 were followed up until 2007 (6.9±1.9 years). Participants self-reported education, smoking, alcohol use, antihypertensive, lipid lowering and antidepressant medication, disease history, total energy intake, sleep duration, physical activity and television viewing. BMI, waist circumference, blood pressure, triglycerides, HDL cholesterol and glycated haemoglobin (HbA_1c) were measured by standardized procedures; a clustered metabolic risk score was constructed. Every one hour/day increase in television viewing was associated with an increased hazard for total (HR = 1.06, 95%CI = 1.03–1.08; 2,620 cases), non-fatal CVD (HR = 1.06, 95%CI = 1.03–1.09; 2,134 cases), and coronary heart disease (HR = 1.08, 95%CI = 1.03–1.13; 940 cases), independent of gender, age, education, smoking, alcohol, medication, diabetes status, CVD family history, sleep duration and physical activity energy expenditure. Energy intake, BMI, waist circumference, blood pressure, triglycerides, HDL cholesterol, HbA_1c and the clustered metabolic risk score only partially mediated these associations.

Conclusions

These results indicate that the most prevalent leisure time (sedentary) behaviour, television viewing, independently contributes to increased CVD risk. Recommendations on reducing television viewing time should be considered.     

Overexpression of the HIF hydroxylases PHD1, PHD2, PHD3 and FIH are individually and collectively unfavorable prognosticators for NSCLC survival

Introduction

Hypoxia induced factors (HIFs) are at the heart of the adaptive mechanisms cancer cells must implement for survival. HIFs are regulated by four hydroxylases; Prolyl hydroxylase (PHD)-1,-2,-3 and factor inhibiting HIF (FIH). We aimed to investigate the prognostic impact of these oxygen sensors in NSCLC.

Methods

Tumor tissue samples from 335 resected stages I to IIIA NSCLC patients was obtained and tissue microarrays (TMAs) were constructed. Hydroxylase expression was evaluated by immunohistochemistry.

Principal Findings

There was scorable expression for all HIF hydroxylases in tumor cells, but not in stroma. In univariate analyses, high tumor cell expression of all the HIF hydroxylases were unfavorable prognosticators for disease-specific survival (DSS); PHD1 (P = 0.023), PHD2 (P = 0.013), PHD3 (P = 0.018) and FIH (P = 0.033). In the multivariate analyses we found high tumor cell expression of PHD2 (HR = 2.03, CI 95% 1.20–3.42, P = 0.008) and PHD1 (HR = 1.45, CI 95% 1.01–2.10, P = 0.047) to be significant independent prognosticators for DSS. Besides, there was an additive prognostic effect by the increasing number of highly expressed HIF hydroxylases. Provided none high expression HIF hydroxylases, the 5-year survival was 80% vs. 23% if all four were highly expressed (HR = 6.48, CI 95% 2.23–18.8, P = 0.001).

Conclusions

HIF hydroxylases are, in general, poor prognosticators for NSCLC survival. PHD1 and PHD2 are independent negative prognostic factors in NSCLC. Moreover, there is an additive poor prognostic impact by an increasing number of highly expressed HIF hydroxylases.     

Minor physical anomalies in patients with schizophrenia, unaffected first-degree relatives, and healthy controls: a meta-analysis

Background

Minor physical anomalies (MPAs) have been found to be more prevalent in schizophrenia than control participants in numerous studies and may index a potential endophenotype for schizophrenia.

Aim

To quantitatively define the magnitude of the difference in total MPA scores between patients with schizophrenia and healthy controls; to determine the degree of manifestation in unaffected first-degree relatives compared to patients and controls; and to investigate the degree of sensitivity among individual MPA items.

Methods

A systematic search was conducted on the literature pertaining to MPAs in patients with schizophrenia and unaffected relatives. Effect sizes (Cohen''s d and odds ratios) and corresponding confidence intervals were combined using the Comprehensive Meta-Analysis software package.

Results

A large difference was found when examining 14 studies comprising 1207 patients with schizophrenia and 1007 healthy controls (d = 0.95, 95% CI = 0.63, 1.27). Six studies involving relatives of individuals with schizophrenia showed a medium effect size (d = 0.45, 95% CI = 0.29,0.62) between patients and relatives, but a small and non-significant effect size (d = 0.32, 95% CI = −0.08, 0.73) between relatives and controls. The majority of MPAs items showed significant odds ratios (1.26–9.86) in comparing patients and controls.

Conclusions

The findings indicate that medium effect size of MPAs have been demonstrated in patients with schizophrenia as compared to healthy controls, and to a lesser extent in unaffected relatives. These findings are consistent with the idea that MPAs may represent a putative endophenotype for schizophrenia. However, more research including first-degree family members is warranted.