Prognostic significance of cyclooxygenase‐2 in cervical cancer: A meta‐analysis

Published data on the prognostic value of cyclooxygenase‐2 (COX‐2) overexpression in cervical cancer are conflicting and heterogeneous. We performed a meta‐analysis to more precisely estimate its prognostic significance. The pooled hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the effects. Twenty‐three studies with 1,477 cervical cancer patients were selected to evaluate the association between COX‐2 and overall survival (OS), disease‐free survival (DFS), response to chemoradiation (RC) and clinicopathological parameters. High COX‐2 expression predicted poor OS (HR: 2.53, 95% CI: 1.54–4.18), DFS (HR: 2.41, 95% CI: 1.58–3.69) and RC (OR: 3.03, 95% CI: 1.97–4.64). Subgroup analyses showed that COX‐2 overexpression was related significantly with poor OS in patients treated by chemoradiation or surgery, and in patients with squamous cell carcinoma, respectively. Besides, COX‐2 overexpression was related significantly with poor DFS in chemoradiation subgroup. Furthermore, COX‐2 overexpression was associated with poor RC in patients who received “FP” regimen or “P” regimen. Additionally, there were significant associations between COX‐2 expression and all clinicopathological parameters except tumor grade. The pooled ORs (95% CI) were as follows: 1.49 (1.09–2.04) for age, 1.77 (1.22–2.56) for lymph node metastasis, 1.04 (0.74–1.47) for tumor grade, 1.71 (1.12–2.64) for tumor size, 2.38 (1.28–4.45) for FIGO stage, 3.96 (2.32–6.77) for histological type, 2.45(1.10–5.42) for parametrical involvement. This meta‐analysis indicated that COX‐2 overexpression might be an unfavorable prognostic and a chemoradiation resistance predictive factor for cervical cancer; it could potentially help to stratify patients further in clinical treatment.     

A preclinical evaluation of a novel multikinase inhibitor,SKLB‐329, as a therapeutic agent against hepatocellular carcinoma

We previously reported that lower post‐diagnostic circulating 25‐hydroxyvitamin D [25(OH)D] concentrations were associated with higher risk of overall mortality and distant disease in stage I–IV postmenopausal breast cancer survivors. This association was now re‐examined in an extended dataset to investigate potential effect modification by tumor characteristics and lifestyle factors. A prospective cohort study was conducted in Germany including 2,177 incident stage I–IV postmenopausal breast cancer patients aged 50–74 years. Patients were diagnosed between 2001 and 2005 and median follow‐up time was 5.3 years. Cox proportional hazards models were stratified by age at diagnosis, study center and season of blood collection and adjusted for other prognostic factors. A meta‐analysis of studies on circulating 25(OH)D and mortality in breast cancer patients was performed to summarize evidence. Lower concentrations of 25(OH)D were significantly associated with higher risk of overall mortality [hazard ratio (HR) lowest vs. highest tertile = 1.86; 95% confidence interval (CI): 1.22, 2.82; p‐trend = 0.002] and distant disease (HR = 1.76; 95% CI: 1.24, 2.49; p‐trend = 0.003) in stage I–IIIa but not in stage IIIb–IV breast cancer patients. No significant interaction by lifestyle factors was observed (all p‐interaction > 0.05). The meta‐analysis yielded significant associations with overall and breast cancer‐specific mortality (lowest vs. highest quantile: HR = 1.52; 95% CI: 1.22, 1.88 and HR = 1.74; 95% CI: 1.23, 2.40, respectively). In conclusion, post‐diagnostic circulating 25(OH)D concentrations were associated with overall mortality and distant disease in stage I–IIIa postmenopausal breast cancer patients. This association was not strongly modified by lifestyle factors.     

Prognostic role of platelet to lymphocyte ratio in non‐small cell lung cancers: A meta‐analysis including 3,720 patients

Platelet to lymphocyte ratio (PLR) was recently reported as a useful index in predicting the prognosis of lung cancer. However, the prognostic role of PLR in lung cancer remains controversial. The aim of this study was to evaluate the association between PLR and clinical outcome of lung cancer patients through a meta‐analysis. Relevant literatures were retrieved from PubMed, Ovid, the Cochrane Library and Web of Science databases. Meta‐analysis was performed using hazard ratio (HR) and 95% confidence intervals (CIs) as effect measures. A total of 5,314 patients from 13 studies were finally enrolled in the meta‐analysis. The summary results showed that elevated PLR predicted poorer overall survival (OS) (HR: 1.526, 95%CI: 1.268–1.836, p < 0.001) in patients with lung cancer and OS (HR: 1.631, 95%CI: 1.447–1.837, p < 0.001) in patients with nonsmall cell lung cancer (NSCLC). Subgroup analysis revealed that increased PLR was also associated with poor OS in NSCLC treated by surgical resection (HR: 1.884, 95%CI: 1.308‐2.714, P < 0.001) and non‐surgery (HR: 1.570, 95%CI: 1.323‐1.863, P < 0.001). In addition, PLR Cut‐off value ≤ 160 (HR: 1.506, 95%CI: 1.292‐1.756, P < 0.001) and PLR Cut‐off value>160 (HR: 1.842, 95%CI: 1.523‐2.228, P < 0.001). In contrast, elevated PLR was not associated with OS (HR: 1.117, 95%CI: 0.796‐1.569, P > 0.05) in patients with small cell lung cancer (SCLC).This meta‐analysis result suggested that elevated PLR might be a predicative factor of poor prognosis for NSCLC patients.     

Pretreatment direct bilirubin and total cholesterol are significant predictors of overall survival in advanced non‐small‐cell lung cancer patients with EGFR mutations

This study was designed to examine the prediction of pretreatment circulating bilirubin and cholesterol for overall survival in 459 advanced non‐small‐cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. Circulating total bilirubin, direct bilirubin (DB), total cholesterol (TC), high‐density lipoprotein cholesterol (HDL‐C) and low‐density lipoprotein cholesterol (LDL‐C) levels were measured at baseline. The mean age (standard deviation) of all study patients was 58.7 (10.5) years, and 42.9% of them was males. Ever smokers accounted for 27.0% and lung adenocarcinoma for 90.4%. The median follow‐up time and survival time were 29.5 and 34.9 months, respectively. Patients with higher DB had a 1.68‐fold increased risk of death compared with patients with lower DB (hazard ratio [HR] = 1.68, 95% confidence interval [CI]: 1.22–2.30, p = 0.001), while patients with higher TC were at a 63% reduced risk of death compared with patients with lower TC (HR = 0.37, 95% CI: 0.20–0.67, p = 0.001). As for HDL‐C, patients with higher levels had the risk of death reduced by 46% (HR = 0.54, 95% CI: 0.29–1.00, p = 0.049) compared with patients with lower levels. After the Bonferroni correction, only DB and TC were significantly associated with NSCLC survival. Our findings demonstrate for the first time that pretreatment DB was identified as a significant risk factor, yet TC as a protective factor, for overall survival in NSCLC patients with EGFR mutations.     

Genome‐wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patients

Survival rates for osteosarcoma, the most common primary bone cancer, have changed little over the past three decades and are particularly low for patients with metastatic disease. We conducted a multi‐institutional genome‐wide association study (GWAS) to identify germline genetic variants associated with overall survival in 632 patients with osteosarcoma, including 523 patients of European ancestry and 109 from Brazil. We conducted a time‐to‐event analysis and estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models, with and without adjustment for metastatic disease. The results were combined across the European and Brazilian case sets using a random‐effects meta‐analysis. The strongest association after meta‐analysis was for rs3765555 at 9p24.1, which was inversely associated with overall survival (HR = 1.76; 95% CI 1.41–2.18, p = 4.84 × 10^?7). After imputation across this region, the combined analysis identified two SNPs that reached genome‐wide significance. The strongest single association was with rs55933544 (HR = 1.9; 95% CI 1.5–2.4; p = 1.3 × 10^?8), which localizes to the GLDC gene, adjacent to the IL33 gene and was consistent across both the European and Brazilian case sets. Using publicly available data, the risk allele was associated with lower expression of IL33 and low expression of IL33 was associated with poor survival in an independent set of patients with osteosarcoma. In conclusion, we have identified the GLDC/IL33 locus on chromosome 9p24.1 as associated with overall survival in patients with osteosarcoma. Further studies are needed to confirm this association and shed light on the biological underpinnings of this susceptibility locus.     

Overall survival benefits for irinotecan‐containing regimens as first‐line treatment for advanced gastric cancer: An updated meta‐analysis of ten randomized controlled trials

The standard treatment for patients with advanced gastric cancer (AGC) is still debated, and the available data on the benefit of irinotecan‐containing regimen as first‐line treatment for those patients are controversial. We performed a systematic review and meta‐analysis of randomized controlled trials to determine the survival benefits of irinotecan‐containing regimens in this setting. A total of 1,837 patients from ten trials were included in the analysis. Our results showed that irinotecan‐containing regimens significantly improved overall survival [OS: hazard ratio (HR) 0.86, 95% CI = 0.78–0.94, p = 0.002] and progression‐free survival [HR = 0.82, 95% CI = 0.69–0.97, p = 0.026); however, the improvement of time to failure (HR = 0.90; 95% CI = 0.77–1.04, p = 0.15), 1‐year survival rate [1‐year SR: relative risk (RR) 1.10, 95% CI = 0.97–1.24, p = 0.13] and overall response rate (RR = 1.16, 95% CI = 0.91–1.49, p = 0.24] were nonsignificant. Equivalent frequencies of toxicities were found between the two groups excluding more Grade 3 or 4 fatigue (p = 0.001) in irinotecan‐containing regimens. This updated meta‐analysis provided strong evidence for a survival benefit of irinotecan‐containing regimen as first‐line treatment for AGC. A clear advantage of irinotecan‐containing over nonirinotecan‐containing regimen had not been established. These results should help to inform decisions about patient management and design of future trials.     

Lifetime alcohol intake and risk of non‐Hodgkin lymphoma: Findings from the Melbourne Collaborative Cohort Study

Cohort studies have reported inconsistent evidence regarding alcohol intake and risk of non‐Hodgkin lymphoma (NHL), mostly based on alcohol intake assessed close to study enrolment. We examined this association using alcohol intake measured from age 20 onwards. We calculated usual alcohol intake for 10‐year periods from age 20 using recalled frequency and quantity of beverage‐specific consumption for 37,990 participants aged 40–69 years from the Melbourne Collaborative Cohort Study. Cox regression was performed to derive hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between alcohol intake (g/day) and NHL risk. After a mean follow‐up of 19.3 years, 538 NHL cases were diagnosed. Approximately 80% of participants were either lifetime abstainers or consumed below 20 g of ethanol/day. All categories of lifetime alcohol intake were associated with about 20% lower incidence of NHL compared with lifetime abstention, but there was no evidence of a trend by amount consumed (HR = 0.97 per 10 g/day increment in intake, 95% CI: 0.92–1.03; p value = 0.3). HRs for beer, wine and spirits were 0.91 (95% CI: 0.83–1.00; p value = 0.05), 1.03 (95% CI: 0.94–1.12; p value = 0.6), and 1.06 (95% CI: 0.83–1.37; p value = 0.6), respectively, per 10 g/day increment in lifetime intake. There were no significant differences in associations between NHL subtypes. In this low‐drinking cohort, we did not detect a dose‐dependent association between lifetime alcohol intake and NHL risk.     

The clinical value of combination of immune checkpoint inhibitors in cancer patients: A meta‐analysis of efficacy and safety

The use of immune checkpoint inhibitors (ICIs) in combination therapy is an emerging trend in tumor immunology. However, the value of combination immunotherapy remains controversial, because of the toxic effects induced by combination. The added benefit of each additional drug has not been assessed against the added toxicity. We searched for clinical trials that evaluated ICI monotherapies and combination therapies in lung cancer and melanoma patients. The overall response rate (ORR), grade 3/4 treatment‐related adverse event rate, overall survival (OS), and progression‐free survival (PFS) were extracted from the most recently published studies to determine the relative risk (RR), hazard ratios (HRs), and 95% confidence intervals (CIs). Seven randomized controlled trials and one open‐label study were identified (n = 3,097). Treatments included combinations of several ICIs, a combination of an ICI and dacarbazine, two combinations of an ICI, paclitaxel and carboplatin, and a combination of an ICI and gp100 vaccine. Higher ORR (RR: 1.51, 95% CI: 1.03–2.20, p = 0.034), OS (HR: 0.86, 95% CI: 0.78–0.95, p = 0.000), and PFS (HR: 0.93, 95% CI: 0.72–1.14, p = 0.000) values were observed in combination therapy than in monotherapy. In addition, the toxicity of combination ICI immunotherapy was higher (RR: 1.50, 95% CI: 1.03–2.19, p = 0.036) than that of monotherapy. This meta‐analysis showed that the addition of nivolumab to ipilimumab better benefits PFS and ORR. Adding sargramostim was associated with better OS and safety. The efficacy and safety of a nivolumab‐ipilimumab‐sargramostim combination should be investigated further.     

Promising biomarkers for predicting the outcomes of patients with KRAS wild‐type metastatic colorectal cancer treated with anti‐epidermal growth factor receptor monoclonal antibodies: A systematic review with meta‐analysis

KRAS mutations have been established as a major predictive biomarker for resistance to the treatment of metastatic colorectal cancer (mCRC) with anti‐epidermal growth factor receptor monoclonal antibodies (anti‐EGFR MoAbs). However, many patients with KRAS wild‐type tumors still do not respond to the treatment. We conducted a systematic review with meta‐analysis to assess whether BRAF mutations, PIK3CA mutations and PTEN loss can predict the outcomes of patients with KRAS wild‐type mCRC treated with anti‐EGFR MoAbs. Studies that explored the association of one or more of the three biomarkers with progression‐free survival (PFS), overall survival (OS) and/or objective response rate (ORR) were identified through August 2012. Summary hazard ratios (HRs) and rate differences (RDs) and corresponding 95% confidence intervals (CIs) were calculated by using the random‐effects model. BRAF mutations, PIK3CA exon 20 mutations and PTEN loss were all associated with shorter PFS (HR = 2.59, 95% CI 1.67–4.03; HR = 2.52, 95% CI 1.33–4.78 and HR = 1.75, 95% CI 1.19–2.56, respectively), shorter OS (HR = 2.74, 95% CI 1.79–4.19; HR = 3.29, 95% CI 1.60–6.75 and HR = 1.85, 95% CI 1.30–2.64, respectively) and lower ORR (RD = ?36%, 95% CI ?44 to ?28%; RD = ?38%, 95% CI ?51 to ?24% and RD = ?41%, 95% CI ?68 to ?14%, respectively). PIK3CA exon 9 mutations were associated with none of the outcomes. Studies with relevant data consistently demonstrated a stronger predictive power of combined multiple biomarkers as compared to one alteration alone. These results suggest that BRAF mutations, PIK3CA exon 20 mutations and PTEN loss are predictive of better outcomes in KRAS wild‐type mCRC treated with anti‐EGFR MoAbs. However, the quality of included studies varied, and some of the meta‐analyses were limited by significant between‐study heterogeneity. In the future, well‐designed large randomized controlled trials conducted in KRAS wild‐type mCRC patients with subgroup analysis according to BRAF, PIK3CA exon 20 and PTEN status are essential to fully assess the clinical relevance of these biomarkers.     

Targeting SLC1a5‐mediated glutamine dependence in non‐small cell lung cancer

We previously elucidated the pleotropic role of solute carrier family A1 member 5 (SLC1A5) as the primary transporter of glutamine (Gln), a modulator of cell growth and oxidative stress in non‐small cell lung cancer (NSCLC). The aim of our study was to evaluate SLC1A5 as a potential new therapeutic target and candidate biomarker predictive of survival and response to therapy. SLC1A5 targeting was examined in a panel of NSCLC and human bronchial cell lines by RNA interference and by a small molecular inhibitor, gamma‐l ‐glutamyl‐p‐nitroanilide (GPNA). The effects of targeting SLC1A5 on cell growth, Gln uptake, ATP level, autophagy and cell death were examined. Inactivation of SLC1A5 genetically or pharmacologically decreased Gln consumption, inhibited cell growth, induced autophagy and apoptosis in a subgroup of NSCLC cell lines that overexpress SLC1A5. Targeting SLC1A5 function decreased tumor growth in NSCLC xenografts. A multivariate Cox proportional hazards analysis indicates that patients with increased SLC1A5 mRNA expression have significantly shorter overall survival (p = 0.01, HR = 1.24, 95% CI: 1.05–1.46), adjusted for age, gender, smoking history and disease stage. In an immunohistochemistry study on 207 NSCLC patients, SLC1A5 protein expression remained highly significant prognostic value in both univariate (p < 0.0001, HR = 1.45, 95% CI: 1.15–1.50) and multivariate analyses (p = 0.04, HR = 1.22, 95% CI: 1.01–1.31). These results position SLC1A5 as a new candidate prognostic biomarker for selective targeting of Gln‐dependent NSCLC.     

Correlation between sex and efficacy of immune checkpoint inhibitors (PD‐1 and CTLA‐4 inhibitors)

Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on immune response, which is affected by sex difference, where both biological and sociological factors are involved. The role of sex in ICI trials has been overlooked. How sex correlates with ICI efficacy is incompletely understood. Clinical trials evaluating ICI versus other therapies in male and female patients were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS) and progression‐free survival (PFS) were used. Six thousand and ninety‐six patients from 11 trials were included. More improvement of OS was observed in males (HR, 0.62; 95% CI, 0.53–0.71; p < 0.001) treated with ICI versus controls than females (HR, 0.74; 95% CI, 0.65–0.84; p < 0.001). ICIs improved PFS more in males (HR, 0.57; 95% CI, 0.43–0.71; p < 0.001) than females (HR, 0.71; 95% CI, 0.52–0.91; p < 0.001). The sex difference had more effect on the overall survival in melanoma patients versus NSCLC patients. Overall survival of patients treated with CTLA‐4 inhibitor was more influenced by sex variable compared with PD‐1 inhibitors. A significant sex‐related efficacy difference was observed between female and male melanoma patients. Although male patients had longer OS and PFS than females when treated with ICIs versus controls, the difference was not significant. Sex difference should be more considered in future clinical trials, guidelines and clinical practice.     

Diagnostic value of fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography for the detection of metastases in non–small‐cell lung cancer patients

In the recent years, fluorine 18 fluorodeoxyglucose (¹⁸F‐FDG) positron emission tomography (PET)/computed tomography (CT) has emerged as a new modality for staging non–small‐cell lung cancer (NSCLC) patients. The aim of this meta‐analysis was to assess the diagnostic value of ¹⁸F‐FDG PET/CT in detecting metastatic lesions in NSCLC patients. Meta‐analysis methods were used to pool sensitivity, specificity, positive and negative likehood ratios, diagnostic odd ratios and to construct a summary receiver‐operating characteristic curve. Data from included studies were pooled to compare the diagnostic accuracy between PET/CT and PET or CT alone in nodal staging. Totally, 56 studies involving 8,699 patients met the inclusion criteria. The pooled sensitivities and specificities of ¹⁸F‐FDG PET/CT were 0.72 [95% confidence interval (CI): 0.65–0.78] and 0.91 (95% CI: 0.86–0.94) in determining mediastinal nodal staging; 0.71 (95% CI: 0.60–0.80) and 0.83 (95% CI: 0.77–0.88) in intrathoracic staging; 0.78 (95% CI: 0.64–0.87) and 0.90 (95% CI: 0.84–0.94) in intrathoracic staging on a per‐node basis. For detecting extrathoracic metastases, the pooled sensitivities and specificities of ¹⁸F‐FDG PET/CT were 0.77 (95% CI: 0.47–0.93) and 0.95 (95% CI: 0.92–0.97) for all extrathoracic metastases; 0.91 (95% CI: 0.80–0.97) and 0.98 (95% CI: 0.94–0.99) for bone metastases. ¹⁸F‐FDG PET/CT is beneficial in detecting lymph node metastases and extrathoracic metastases although PET/CT showed low sensitivity in detecting brain metastases. ¹⁸F‐FDG PET/CT confers significantly higher sensitivity and specificity than contrast‐enhanced CT (both p < 0.01) and higher sensitivity than ¹⁸F‐FDG PET in staging NSCLC (p < 0.05).     

The prognostic value of E‐cadherin in gastric cancer: A meta‐analysis

The prognostic impact of E‐cadherin downregulation in gastric cancer has been assessed for years while the results are controversial and heterogeneous. We thus comprehensively reviewed the evidence for evaluation of E‐cadherin expression in gastric cancer to determine this effect. We searched PubMed and Embase to identify eligible studies, and 26 studies comprising 4,383 gastric cancer patients were included to assess the association between E‐cadherin immunohistochemical expression and overall survival (OS) and clinicopathological characteristics. Summary hazard ratios (HRs) or odds ratios (ORs) with 95% confidence interval (95% CI) were calculated to estimate the effect. We also performed meta‐regression and subgroup analysis according to study location, publication year, number of patients, quality score of studies and cut‐off value. Reduced E‐cadherin expression was significantly correlated with poor OS of gastric cancer patients (HR 1.62, 95% CI 1.34–1.96). Subgroup analysis indicated that E‐cadherin low‐expression had an unfavorable impact on OS in Asian patients (HR 1.87, 95% CI 1.45–2.41). Moreover, downregulation of E‐cadherin was significantly associated with TNM stage (OR 2.52, 95% CI 1.85–3.43), the depth of invasion (OR 2.01, 95% CI 1.39–2.90), lymph node metastasis (OR 2.39, 95% CI 1.68–3.40), distant metastasis (OR 2.23, 95% CI 1.21–4.11), grade of differentiation (OR 2.26, 95% CI 1.60–3.21), vascular invasion (OR 1.86, 95% CI 1.10–3.13) and histological type of gastric cancer (OR 4.22, 95% CI 2.96–6.02). This meta‐analysis revealed that E‐cadherin expression might be a predicative factor of poor prognosis for gastric cancer particularly in Asia.     

Reduced disease‐specific survival following a diagnosis of multiple primary cutaneous malignant melanomas—a nationwide,population‐based study

Outcome data comparing patients with multiple primary invasive cutaneous malignant melanomas (MPMs) to single primary invasive cutaneous malignant melanomas (SPMs) show conflicting results. We have analyzed differences in disease‐specific survival between these patients in a nationwide population‐based setting. From the Swedish Melanoma Register, 27,235 patients were identified with a first invasive cutaneous malignant melanoma (CMM) between 1990 and 2007, followed‐up through 2013. Of these, 700 patients developed MPMs. Cox proportional hazard regression was used for adjusted cause‐specific hazard ratios (HRs). An interval of ≤5 years between CMM diagnoses was significantly correlated to a decreased CMM‐specific survival in Stage I–II MPM‐ vs. SPM‐patients (HR 1.32; 95% CI 1.04–1.67; p = 0.02). MPM‐patients with longer time interval between diagnoses experienced similar risk of CMM‐death as SPM‐patients. The risk of CMM‐death increased by almost 50% above the expected outcome according to stage of the index CMM by the diagnosis of a second CMM (HR 1.48; 95% CI 1.19–1.85; p < 0.001). MPM vs. SPM‐patients had a worse outcome (HR 1.38; 95% CI 1.05–1.83; p = 0.001). This emphasizes the importance of prevention efforts in SPM‐patients to decrease the risk of subsequent CMMs and has implications for more vigilant follow‐up in MPM‐patients.     

Body mass index and survival in patients with renal cell carcinoma: A clinical‐based cohort and meta‐analysis

Growing evidence suggests that obesity, an established cause of renal cell cancer (RCC), may also be associated with a better prognosis. To evaluate the association between RCC survival and obesity, we analyzed a large cohort of patients with RCC and undertook a meta‐analysis of the published evidence. We collected clinical and pathologic data from 1,543 patients who underwent nephrectomy for RCC between 1994 and 2008 with complete follow‐up through 2008. Patients were grouped according to BMI (kg/m²): underweight <18.5, normal weight 18.5 to <23, overweight 23 to <25 and obese ≥25. We estimated survival using the Kaplan–Meier method and Cox proportional hazard models to examine the impact of BMI on overall survival (OS) and cancer‐specific survival (CSS) with adjustment for covariates. We performed a meta‐analysis of BMI and OS, CSS and recurrence‐free survival (RFS) from all relevant studies using a random‐effects model. The 5‐year CSS increased from 76.1% in the lowest to 92.7% in the highest BMI category. A multivariate analysis showed higher OS [hazard ratio (HR) = 0.45; 95% CI: 0.29–0.68) and CSS (HR = 0.47; 95% CI: 0.29–0.77] in obese patients than in normal weight patients. The meta‐analysis further corroborated that high BMI significantly improved OS (HR = 0.57; 95% CI: 0.43–0.76), CSS (HR = 0.59; 95% CI: 0.48–0.74) and RFS (HR = 0.49; 95% CI: 0.30–0.81). Our study shows that preoperative BMI is an independent prognostic indicator for survival among patients with RCC.     

Impact of statin use on cancer recurrence and mortality in breast cancer: A systematic review and meta‐analysis

Statins have shown antineoplastic properties in preclinical studies with breast cancer cells. They inhibit the enzyme “HMG CoA reductase” and the expression of this enzyme in cancer cells has been implicated as a favorable prognostic factor in patients with breast cancer. After a search of MEDLINE and Embase from inception through November 2015, 817 abstracts were reviewed to identify studies that described an association between statin use and outcomes in breast cancer. A total of 14 studies which included 75,684 women were identified. In a meta‐analysis of 10 studies, statin use was associated with improved recurrence‐free survival (RFS; HR 0.64; 95% CI 0.53–0.79, I² = 44%). Furthermore, this RFS benefit appeared to be confined to use of lipophilic statins (HR 0.72; 95% CI 0.59–0.89) as hydrophilic statin use was not associated with improvement in RFS (HR 0.80; 95% CI 0.44–1.46). Statin users similarly showed improved overall survival in a meta‐analysis with substantial heterogeneity (8 studies, HR 0.66; 95% CI 0.44–0.99, I² = 89%). Statin users also had improved cancer‐specific survival, although this relationship was measured with less precision (six studies, HR 0.70; 95% CI 0.46–1.06, I² = 86%). In conclusion, breast cancer patients who use statins, or specifically, lipophilic statins show improved recurrence‐free survival. Statin users also had improved overall survival and cancer‐specific survival. These findings should be assessed in a prospective randomized cohort and the choice of statin, dose and biomarkers that may predict the efficacy of these drugs should be identified.     

Obstructive sleep apnoea and the incidence and mortality of cancer: a meta‐analysis

As there are conflicting reports regarding the association between obstructive sleep apnoea (OSA) and cancer incidence and mortality, a meta‐analysis was performed to evaluate whether OSA is independently associated with cancer incidence and mortality. Pubmed, EMBASE and Web of Science were searched up until November 2014. Studies that assessed OSA and the future risk of cancer incidence or mortality were included. Pooled hazard ratios (HR) and corresponding 95% confidence intervals (CI) were calculated. Subgroup analysis was conducted based on the polysomnographic variable, apnoea–hypopnoea index. Six studies, which involved 114 105 participants, were pooled in this meta‐analysis. Fixed‐effects analysis showed the pooled adjusted HR of cancer incidence as 0.91 (95% CI, 0.74–1.13; P = 0.408) for mild OSA, 1.07 (95% CI, 0.86–1.33; P = 0.552) for moderate OSA and 1.03 (95% CI, 0.85–1.26; P = 0.743) for severe OSA. Random‐effects analysis demonstrated neither mild OSA (adjusted HR, 0.79; 95% CI, 0.46–1.34; P = 0.381), moderate OSA (adjusted HR, 1.92; 95% CI, 0.63–5.88; P = 0.251) nor severe OSA (adjusted HR, 2.09; 95% CI, 0.45–9.81; P = 0.349) correlated with cancer mortality. This meta‐analysis indicates that OSA is not independently associated with cancer incidence and mortality according to currently available data. Additional experimental and human research is required to determine the exact association between OSA and cancer.     

TP53 Arg72Pro polymorphism and lung cancer risk: A meta‐analysis

No clear consensus has been reached on the TP53 Arg72Pro polymorphism (G12139C) and lung cancer risk. Thus, a meta‐analysis was conducted to summarize the possible association. There was no statistical association between 12139C (Pro allele) and lung cancer risk in Caucasians compared with 12139G allele. However, the association was observed in all subjects (9,387 patients and 9,922 controls, p = 0.04, OR = 1.08, 95% CI 1.00–1.17), as well as in Asians (p = 0.0004, OR = 1.14, 95% CI 1.06–1.22). The association was also found in Asians under recessive genetic model (p < 0.00001, OR = 1.37, 95% CI 1.20–1.57) and homozygote comparison (CC vs. GG) (p < 0.0001, OR = 1.34, 95% CI 1.16–1.56). 12139C allele might increase the lung adenocarcinoma risk compared with 12139G allele (p = 0.01, OR = 1.11, 95% CI 1.02–1.21), and the effect was also found under recessive genetic model (p = 0.003, OR = 1.28, 95% CI 1.09–1.50) and homozygote comparison (CC vs. GG) (p = 0.007, OR = 1.28, 95% CI 1.07–1.52). There was an elevated association between the 12139C and the stage I lung cancer under dominant genetic model (p = 0.04, OR = 1.48, 95% CI 1.02–2.16), but no association was observed in other stages. No association of smoking was found between 12139C allele and lung cancer under recessive genetic model. Our result indicated that 12139C might increase the risk of lung cancer under recessive genetic model in adenocarcinoma, in Asians, and in lung cancer stage I. More studies stratified for lung cancer stage‐genotyping interaction should be performed to clarify the role of TP53 Arg72Pro polymorphism in the development of lung cancer. © 2009 UICC     

Adolescent and mid‐life diet and subsequent risk of thyroid cancer in the NIH‐AARP diet and health study

Although thyroid cancer is suspected to have a nutritional etiology, prospective studies examining the relationship between diet and thyroid cancer are lacking. During 1996–1997, NIH‐AARP Diet and Health Study participants, ages 51–72 years, completed a 37‐item food frequency questionnaire about diet at ages 12–13 years (adolescence) and 10 years before baseline (mid‐life). Over a median 10 years of follow‐up, 325 individuals (143 men and 182 women) were diagnosed with thyroid cancer. Multivariable‐adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for intakes of foods and food groups comparing the highest to the lowest quartiles. Adolescent intakes of chicken/turkey (HR = 1.59, 95% CI: 0.97–2.60; p_trend < 0.01) and sweet baked goods (HR = 1.59, 95% CI: 1.09–2.34; p_trend = 0.04) were positively associated with thyroid cancer risk, while intake of butter/margarine was inversely associated with risk (HR = 0.64, 95% CI: 0.44–0.91; p_trend < 0.02). Similar to adolescent diet, mid‐life intake of sweet baked goods was nonsignificantly associated with an increased risk of thyroid cancer (HR = 1.39, 95% CI: 0.96–2.00; p_trend = 0.11), but intake of butter/margarine was inversely associated with risk (HR = 0.66, 95% CI: 0.46–0.95; p_trend = 0.03). Among men, higher adolescent consumption of canned tuna was positively associated with risk of thyroid cancer (HR = 1.69, 95% CI: 1.01–2.83; p_trend = 0.03), and greater mid‐life intake of broccoli was associated with a twofold increased risk (HR = 2.13, 95% CI: 1.13–3.99; p_trend < 0.01). This large prospective study suggests that several components of the adolescent and mid‐life diet, including iodine‐rich foods and goitrogens, may influence thyroid cancer risk.     

Hematologic toxicity assessment in solid tumor patients treated with cetuximab: A pooled analysis of 18 randomized controlled trials

The role of cetuximab in treatment‐related hematologic toxicity is not clear. We performed a meta‐analysis of published randomized controlled trials (RCTs) to determine the overall risk of ≥grade 3 hematologic toxicity events (HTEs) associated with cetuximab. PubMed, EMBASE, and Web of Knowledge databases as well as abstracts presented at American Society of Clinical Oncology conferences and ClinicalTrials.gov were searched to identify relevant studies. Eligible studies included RCTs in which cetuximab in combination with chemotherapy or chemoradiotherapy was compared with chemotherapy or chemoradiotherapy alone. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using fixed‐ or random‐effects models. A total of 11,234 patients with a variety of advanced solid tumors from 18 RCTs were included in the meta‐analysis. Compared with chemotherapy alone, the addition of cetuximab was associated with increased risks of ≥grade 3 leucopenia/neutropenia and anemia events in colorectal cancer, with RRs of 1.16 (95% CI 1.05–1.27, p = 0.002; incidence, 21.0 vs. 18.0%) and 2.67 (95% CI 1.53–4.65, p = 0.01; incidence, 4.0 vs. 2.0%), respectively. Cetuximab was also associated with an increased risk of leucopenia/neutropenia in nonsmall cell lung cancer (NSCLC) (RR: 1.15; 95% CI 1.08–1.22, p < 0.01). Additionally, K‐ras wild type in the case of colorectal cancer patients was more vulnerable to ≥grade 3 leucopenia or neutropenia events in cetuximab group (RR: 1.31; 95% CI 1.11–1.54, p = 0.001). With present evidence, cetuximab in conjunction with chemotherapy or chemoradiotherapy, compared with chemotherapy or chemoradiotherapy alone, was associated with increased slight risk of ≥grade 3 HTEs, especially in colorectal cancer and NSCLC.