Seasonal variation in effect of anti-PD-1 initiation on overall survival among patients with advanced melanoma

Melanoma is a highly immunogenic cancer, and circannual rhythms influence the activity of the immune system. We retrospectively collected information on all cases with metastatic melanoma (ocular melanoma excluded) that initiated treatment with BRAF-inhibitor-based therapy (BRAFi) or anti-PD-1 monotherapy (PD-1). Cases were divided in two groups based on treatment initiation in the summer half-year (April to September) or winter half-year (October to March). We collected a total of 1054 (BRAF-i) and 1205 (PD-1) patient cases. Median follow-up was 39.7 (BRAFi) and 47.5 (PD-1) months. We did not observe differences in outcomes across patients who were treated in summer versus winter in the BRAFi cohort. Furthermore, we did not observe significant differences in ORR, CRR, and PFS in the PD-1 cohort. However, in patients with BRAF wild-type disease of the PD-1 cohort, treatment initiation in summer was associated with an improved OS (mOS 39.7 months [summer] versus 21.3 months [winter]; HR 0.70, 95% CI 0.57–0.86, p = .0007). This result remained robust to multivariable proportional hazards adjustment (HR 0.70, 95% CI 0.57–0.87, p = .001). Initiation of immunotherapy in summer is associated with prolonged survival in patients with BRAF wild-type melanoma living in Denmark.     

The prognostic value of circulating tumor DNA in patients with melanoma: A systematic review and meta-analysis

BackgroundCirculating tumor DNA (ctDNA) has been investigated as a potential prognostic biomarker to evaluate the therapeutic efficacy and disease progression in melanoma patients, yet results remain inconclusive. The purpose of this study was to illustrate the prognostic value of ctDNA in melanoma.ObjectivesTo describe the clinical prognostic value of ctDNA for melanoma patients.MethodsSearched for eligible articles from Pubmed, Web of Science and Embase. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate the association between ctDNA at baseline or during treatment and overall survival (OS) and progression-free survival (PFS).ResultsA total of 9 articles were obtained, involving 617 melanoma patients. The pooled HRs revealed that compared with baseline undetectable ctDNA patients, detectable ctDNA was highly correlated with poor OS (HR 2.91, 95% CI: 2.22–3.82; p < 0.001) and PFS (HR 2.75, 95% CI: 1.98–3.83; p < 0.001). A meta-analysis of these adjusted HRs was performed and confirmed that ctDNA collected at baseline was associated with poorer OS/PFS (OS: HR 3.00, 95% CI 2.19–4.11, p < 0.001/PFS: HR 2.68, 95% CI 1.77–4.06, p < 0.001). During treatment, a significant association was shown between ctDNA and poorer OS/PFS (OS: HR 6.26, 95% CI 2.48–15.80, p < 0.001; PFS: HR 4.93, 95% CI 2.36–10.33, p < 0.001).ConclusionInvestigation and application of ctDNA will improve "liquid biopsy" and play a role in early prediction, monitoring disease progression and precise adjusting treatment strategies in melanoma patients.     

Beyond the 5-year milestone: Long-term survivorship of melanoma patients treated off-trial with anti-PD-1

Little is known about the long-term outcomes of anti-PD-1 treated patients with melanoma beyond 5 years, especially for patients treated off clinical trials. This retrospective cohort study includes patients with unresectable stage III/IV nonuveal melanoma treated with anti-PD-1 off-trial at Memorial Sloan Kettering Cancer Center between 2014 and 2017 who survived at least 5 years following their first anti-PD-1 dose (N = 139). We characterized overall survival (OS), melanoma-specific survival (MSS) estimates, treatment-free survival rates, and subsequent treatment courses. Median follow-up among 5-plus year survivors (N = 125) was 78.4 months (range 60.0–96.3). OS at year 7 (2 years post 5-year landmark) was 90.1% (95% CI: 83.0%–94.3%). Fourteen deaths occurred, seven due to melanoma. MSS at year 7 (2 years post 5-year landmark) was 95.0% (95% CI: 33.5%–95.2%). In patients who completed anti-PD-1 based therapy and did not require subsequent treatment by 5 years (N = 80), the probability of not requiring additional treatment for an additional 2 years was 95.7% (95% CI: 91.0%–100%). Patients treated with anti-PD-1 regimens off clinical trials who survive at least 5 years from initial anti-PD-1 treatment can be reassured of their excellent long-term prognosis, particularly if they did not require additional melanoma treatment during the first 5 years.     

Association of programmed death ligand‐1 (PD‐L1) expression with treatment outcomes in patients with BRAF mutation‐positive melanoma treated with vemurafenib or cobimetinib combined with vemurafenib

The prognostic significance of programmed death ligand‐1 (PD ‐L1) on treatment outcomes in patients receiving BRAF with or without MEK inhibitors is not well understood. This retrospective exploratory analysis evaluated the association of tumour PD ‐L1 expression with progression‐free survival (PFS ) and overall survival (OS ) among 210 patients in the coBRIM trial treated with cobimetinib plus vemurafenib or placebo plus vemurafenib. In the vemurafenib cohort, there was a trend of increased PFS and OS in those with PD ‐L1⁺ melanoma, with hazard ratios (HR s; PD ‐L1⁺ vs. PD ‐L1^?) of 0.70 (95% CI , 0.46–1.07) and 0.69 (95% CI , 0.42–1.13) for PFS and OS , respectively. However, in patients treated with cobimetinib plus vemurafenib, a similar trend was not observed with HR s (PD ‐L1⁺ versus PD ‐L1^?) of 1.04 (95% CI , 0.66–1.68) and 0.94 (95% CI , 0.57–1.57) for PFS and OS , respectively. The combination cobimetinib plus vemurafenib appears to overcome the poor prognosis associated with low PD ‐L1 expression.     

Promoter methylation as biomarkers for diagnosis of melanoma: A systematic review and meta-analysis

Melanoma is one of the most common skin cancer that is characterized by rapid growth, early metastasis, high malignant, and mortality. Accumulating evidence demonstrated that promoter methylation of tumor-suppressor genes is implicated in the pathogenesis of melanoma. In the current study, we performed a meta-analysis to identify promising methylation biomarkers in the diagnosis of melanoma. We carried out a systematic literature search using Pubmed, Embase, and ISI web knowledge database and found that gene promoter methylation of 50 genes was reported to be associated with the risk of melanoma. Meta-analysis revealed that hypermethylation of claudin 11 (CLDN11; odds ratio [OR], 16.82; 95% confidence interval [CI], 1.97–143.29; p = 0.010), O-6-methylguanine-DNA methyltransferase (MGMT; OR, 5.59; 95% CI, 2.51–12.47; p < 0.0001), cyclin-dependent kinase inhibitor 2A (p16; OR, 6.57; 95% CI, 2.19–19.75; p = 0.0008), retinoic acid receptor β (RAR-β2; OR, 24.31; 95% CI, 4.58–129.01; p = 0.0002), and Ras association domain family member (RASSF1A; OR, 9.35; 95% CI, 4.73–18.45; p < 0.00001) was significantly higher in melanoma patients compared with controls. CLDN11 (OR, 14.52; 95% CI, 1.84–114.55; p = 0.01), MGMT (OR, 8.08; 95% CI, 1.84–35.46; p = 0.006), p16 (OR, 9.44; 95% CI, 2.68–33.29; p = 0.0005), and RASSF1A (OR, 7.72; 95% CI, 1.05–56.50; p = 0.04) hypermethylation was significantly increased in primary melanoma compared with controls. Methylation frequency of CLDN11 (OR, 25.56; 95% CI, 2.32–281.66; p = 0.008), MGMT (OR, 4.64; 95% CI, 1.98–10.90; p = 0.0004), p16 (OR, 4.31; 95% CI, 1.33–13.96; p = 0.01), and RASSF1A (OR, 10.10; 95% CI, 2.87–35.54; p = 0.0003) was significantly higher in metastasis melanoma compared with controls. These findings indicated that CLDN11, MGMT, p16, RAR-β2, and RASSF1A hypermethylation is a risk factor and a potential biomarker for melanoma. CLDN11, MGMT, p16, and RASSF1A promoter methylation may take part in the development of melanoma and become useful biomarkers in the early diagnosis of the disease.     

Effect of early adverse events on response and survival outcomes of advanced melanoma patients treated with vemurafenib or vemurafenib plus cobimetinib: A pooled analysis of clinical trial data

This study aimed to evaluate the impact of early adverse events on overall survival (OS), progression‐free survival (PFS) and objective response within a pooled secondary analysis of participants treated with first‐line vemurafenib or vemurafenib plus cobimetinib in the clinical trials BRIM3 and coBRIM. The study included 583 participants who received vemurafenib monotherapy and 247 who received vemurafenib plus cobimetinib. Adverse events requiring vemurafenib/cobimetinib dose adjustment within the first 28 days of therapy were significantly associated with OS (hazard ratio (HR) [95% CI]: dose reduced/interrupted = 0.79 [0.65–0.96]; drug withdrawn = 1.18 [0.71–1.96]; p = 0.032), PFS (HR [95% CI]: dose reduced/interrupted = 0.82 [0.67–0.99]; drug withdrawn = 1.58 [0.97–2.58]; p = 0.017) and objective response (odds ratio (OR) [95% CI]: dose reduced/interrupted = 1.35 [0.99–1.85]; drug withdrawn = 0.17 [0.06–0.43]; p = <0.001). Arthralgia occurring within the first 28 days of vemurafenib or vemurafenib plus cobimetinib therapy was also significantly associated with favourable OS (p = 0.026), PFS (p = 0.042) and objective response (p = 0.047).     

The predictive efficacy of tumor mutation burden in immunotherapy across multiple cancer types: A meta-analysis and bioinformatics analysis

PurposeTo explore the predictive efficacy of tumor mutation burden (TMB) as a potential biomarker for cancer patients treated with Immune checkpoint inhibitors (ICIs).MethodsWe systematically searched PubMed, Cochrane Library, Embase and Web of Science for clinical studies (published between Jan 1, 2014 and Aug 30, 2021) comparing immunotherapy patients with high TMB to patients with low TMB. Our main endpoints were objective response rate (ORR), durable clinical benefit (DCB), overall survival (OS) and progress-free Survival (PFS). Moreover, we downloaded simple nucleotide variation (SNV) data of 33 major cancer types from the TCGA database as non-ICIs group, and compared the high TMB patients’ OS between the non-ICIs group and meta-analysis results.ResultsOf 10,450 identified studies, 41 were eligible and were included in our analysis (7713 participants). Compared with low TMB patients receiving ICIs, high TMB yielded a better ORR (RR = 2.73; 95% CI: 2.31–3.22; P = 0.043) and DCB (RR = 1.93; 95% CI: 1.64–2.28; P = 0.356), and a significantly increased OS (HR =0.24; 95% CI: 0.21–0.28; P < 0.001) and PFS (HR = 0.38; 95% CI: 0.34–0.42; P < 0.001). Furthermore, compared with non-ICIs group from the TCGA database, immunotherapy can improve OS in some cancer types with high TMB and better prognosis, including colorectal cancer, gastric cancer, lung cancer, melanoma and pan-cancer.ConclusionTMB is a promising therapeutic and prognostic biomarker for immunotherapy, which indicates a better ORR, DCB, OS and PFS. If there is a standard for TMB assessment and cut-off, it could improve the management of different cancers.     

Pre-treatment prognostic nutritional index may serve as a potential biomarker in urinary cancers: a systematic review and meta-analysis

Background

To investigate the potential prognostic role of pre-treatment prognostic nutritional index (PNI) in urinary cancers.

Methods

Relevant articles were searched comprehensively from PubMed, Embase and Web of Science, up to November 2018. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted to evaluate their associations.

Result

A total of 12 related articles including 6561 patients were ultimately enrolled. Our results indicated that a relatively lower level of pre-treatment PNI was associated with decreased OS, CSS/DSS and DFS/RFS/PFS (pooled HR?=?1.68, 95% CI 1.45–1.95; pooled HR?=?1.57, 95% CI 1.33–1.86; pooled HR?=?1.75, 95% CI 1.53–1.99, respectively). Subsequent stratified analysis by cancer type for OS showed that PNI could also be a predictor no matter in renal cell cancer (RCC) or bladder cancer (BC) (pooled HR?=?1.65, 95% CI 1.37–1.97 and pooled HR?=?1.67, 95% CI 1.20–2.33). Similar results could be found in DFS/RFS/PFS (RCC: HR?=?1.81, 95% CI 1.54–2.13 and BC: HR?=?1.68, 95% CI 1.32–2.12) and in CSS/DSS (RCC: HR?=?1.50, 95% CI 1.23–1.82 and upper tract urothelial carcinoma: HR?=?1.61, 95% CI 1.13–2.28). As for the treatment subgroup, a relatively lower level of PNI could also be a positive predictor for OS (surgery: HR?=?1.64, 95% CI 1.40–1.93; target therapy: HR?=?1.88, 95% CI 1.34–2.63) and DFS/RFS/PFS (surgery: HR?=?1.69, 95% CI 1.47–1.95; target therapy: HR?=?2.14, 95% CI 1.50–3.05).

Conclusion

The outcomes of us shed light on that elevated pre-treatment PNI was positively associated with OS, CSS/DSS and DFS/RFS/PFS, indicating that it could be an independent prognostic factor in urinary cancers.

     

Pooling analysis reveals that galectin-1 is a reliable prognostic biomarker in various cancers

Galectin-1 is reported to be upregulated in various human cancers. However, the relationship between galectin-1 expression and cancer prognosis has not been systematically assessed. In this study, we searched PubMed, Web of Science, and Embase to collect all relevant studies and a meta-analysis was performed. We found that increased galectin-1 expression was associated with tumor size (odds ratio [OR] = 1.75; 95% confidence interval [CI]: 1.06–2.89; p = 0.029), clinical stage (OR = 3.89; 95% CI: 2.40–6.31; p < 0.001), and poorer differentiation (OR = 1.39; 95% CI: 1.14–1.69; p = 0.001), but not with age (OR = 1.07; 95% CI: 0.82–1.39; p = 0.597), sex (OR = 0.89; 95% CI: 0.74–1.07; p = 0.202), or lymph node metastasis (OR = 2.57; 95% CI: 0.98–6.78; p = 0.056). In addition, we found that high galectin-1 expression levels were associated with poor overall survival (HR = 2.12; 95% CI: 1.71–2.64; p < 0.001). The results were further validated using The Cancer Genome Atlas data set. Moreover, high galectin-1 expression was significantly associated with disease-free survival (hazard ratio [HR] = 1.60; 95% CI: 1.17–2.19; p = 0.003), progression-free survival (HR = 1.93; 95% CI: 1.65–2.25; p < 0.001), and cancer-specific survival (HR = 1.82; 95% CI: 1.30–2.55; p < 0.001). Our meta-analysis demonstrated that galectin-1 might be a useful common biomarker for predicting prognosis in patients with cancer.     

The Role of a Single Angiogenesis Inhibitor in the Treatment of Recurrent Glioblastoma Multiforme: A Meta-Analysis and Systematic Review

Background

Currently, the standard treatment for newly diagnosed glioblastoma multiforme (GBM) is maximal safe surgical resection followed by radiation therapy with concurrent and adjuvant temozolomide. However, disease recurs in almost all patients, and the optimal salvage treatment for recurrent GBM remains unclear. We conducted a systematic review and meta-analysis of published clinical trials to assess the efficacy and toxicities of angiogenesis inhibitors alone as salvage treatment in these patients.

Methods

Trials published between 1994 and 2015 were identified by an electronic search of public databases (MEDLINE, EMBASE, Cochrane library). Demographic data, treatment regimens, objective response rate (ORR), median progression-free survival (PFS), median overall survival (OS), 6-months PFS rate, 1-year OS and grade 3/4 toxicities were extracted. We also compared the main outcomes of interest between bevacizumab and other angiogenesis inhibitors. All analyses were performed using Comprehensive Meta Analysis software (Version 2.0).

Results

A total of 842 patients were included for analysis: 343 patients were treated with bevacizumab, 386 with other angiogenesis inhibitors and 81 with thalidomide. The pooled ORR, 6-months PFS, and 1-year OS for recurrent GBM patients receiving angiogenesis inhibitors was 20.1%, 19.5% and 29.3%, respectively. The use of single agent bevacizumab in recurrent GBM significantly improved ORR and 6-months PFS when compared to other angiogenesis inhibitors [relative risk (RR) 2.93, 95% CI 1.38–6.21; p = 0.025; and RR 2.36 95% CI 1.46–3.82; p<0.001, respectively], while no significant difference in 1-year OS was found between the two groups (p = 0.07). when compared to thalidomide, bevacizumab treatment in recurrent GBM significantly improved ORR (RR 6.8, 95%CI: 2.64–17.6, p<0.001), but not for 6-months PFS (p = 0.07) and 1-year OS (p = 0.31). As for grade 3/4 toxicities, the common toxicity was hypertension with pooled incidence of 12.1%, while high-grade thromboembolic events (2.2%), hemorrhage (5.1%) and GI perforation (2.8%) associated with angiogenesis inhibitors were relatively low.

Conclusions

In comparison with other angiogenesis inhibitors and thalidomide, the use of single agent bevacizumab as salvage treatment for recurrent GBM patients improve ORR and 6-months PFS, but not for 1-year OS.     

Effects of metastasectomy and other factors on survival of patients with ovarian metastases from gastric cancer: a systematic review and meta-analysis

Ovarian metastasis from gastric cancer (Krukenberg tumor [KT]) has no consensus treatment and the role of surgical treatment is still controversial. Identifying prognostic factors for KT could help guide the management of this tumor. We used a meta-analysis to evaluate the prognostic value of metastasectomy and other factors in patients with KT to develop a treatment plan. We searched literature in PubMed, Cochrane library and EMBASE. We analyzed hazard ratios (HR) and 95% confidence intervals (CI) with respect to overall survival (OS). The meta-analysis included 12 cohort studies with 1,031 patients associated with longer OS following metastasectomy (HR = 0.41; 95% CI = 0.32–0.53; P < 0.001), R0 resection (HR = 0.37; 95% CI = 0.26–0.53; P < 0.001), metachronous ovarian metastasis (HR = 0.74; 95% CI = 0.58–0.93; P = 0.012), size of KT (<5 cm) (HR = 0.74; 95% CI = 0.58–0.95; P = 0.019), ECOG PS (Eastern Cooperative Oncology Group performance status) 0 to 1 (HR = 0.48; 95% CI = 0.29–0.80; P = 0.004), tumor confined to ovary (HR = 0.40; 95% CI = 0.16–0.99; P = 0.047), and tumor confined to pelvic cavity (HR = 0.36; 95% CI = 0.14–0.92; P = 0.033). Shorter OS was associated with peritoneal carcinomatosis (HR = 2.00; 95% CI = 1.25–3.21; P = 0.004), ascites (HR = 1.66; 95% CI = 1.19–2.31; P = 0.003) and positive CEA (HR = 1.41; 95% CI = 1.10–1.82; P = 0.007). Gastrectomy led to a slight improvement in OS, but without statistical significance (HR = 0.69; 95% CI = 0.47–1.02; P = 0.061). No significant difference in OS was observed in patients with signet-ring cells (HR = 1.17; 95% CI = 0.91–1.51; P = 0.226), bilateral ovarian metastasis (HR = 0.87; 95% CI = 0.70–1.08; P = 0.212), age ≥ 50 years (HR = 0.93; 95% CI = 0.71–1.22; P = 0.619), positive CA19-9 (HR = 1.01; 95% CI = 0.75–1.35; P = 0.960), and positive CA-125 (HR = 0.98; 95% CI = 0.73–1.33; P = 0.915). Various factors affect OS in patients with KT.     

Baseline blood volume identified by dynamic contrast-enhanced computed tomography as a new independent prognostic factor in metastatic renal cell carcinoma

BackgroundPreliminary data showed prognostic impact of contrast-enhanced computed tomography (DCE-CT) identified Blood Volume (BV) in patients with metastatic renal cell carcinoma (mRCC). BV as an independent prognostic factor remains to be assessed.Materials and MethodsDCE-CT identified BV was prospectively quantified in patients with mRCC receiving first line therapies, adjusted for International mRCC Database Consortium (IMDC) individual features and treatments, and associated with overall survival (OS), progression-free survival (PFS) and objective response (ORR), using Cox and logistic regression, respectively.Results105 patients with mRCC were included. Median baseline BV was 32.87 mL × 100 g⁻¹ (range 9.52 to 92.87 mL × 100 g⁻¹). BV above median was associated with IMDC favorable risk category (P = 0.004), metastasis free interval ≥ 1 year (P = 0.007), male gender (P = 0.032), normal hemoglobin (P = 0.040) and normal neutrophils (P = 0.007), whereas low BV was associated with poor risk IMDC features (P < 0.05). Patients with high vs. low baseline BV had longer PFS (12.5 vs. 5.6 months, P = 0.015) and longer OS (42.2 vs. 22.4 months, P = 0.001), respectively. In multivariate analysis high baseline BV remained independent favorable for OS (HR 0.49, 95% CI 0.30–0.78, P = 0.003) and PFS (HR 0.64; 95% CI 0.42–0.97, P = 0.036). BV as a continuous variable was also associated with OS in the multivariate analysis (HR 0.98, 95% CI 0.96–1.00, P = 0.017). The estimated concordance index (c-index) was 0.688 using IMDC score and 0.701 when BV was added.ConclusionsDCE-CT identified Blood Volume is a new, independent prognostic factor in mRCC, which may improve the prognostic accuracy of IMDC.     

The Pan-Immune-Inflammation Value predicts the survival of patients with anaplastic lymphoma kinase-positive non-small cell lung cancer treated with first-line ALK inhibitor

BackgroundAnaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have significantly improved the clinical outcomes of patients with ALK-positive non-small cell lung cancer (NSCLC). However, reliable biomarkers to predict the prognostic role of this treatment are lacking. The Pan-Immune-Inflammation Value (PIV) has recently been demonstrated as a novel comprehensive biomarker to predict survival of patients with solid tumors. Our study aimed to evaluate the prognostic power of PIV in this group of patients.Patients and methods94 patients with advanced ALK-positive NSCLC who received first-line ALK inhibitors were enrolled in this study. PIV was calculated as the product of peripheral blood neutrophil, monocyte, and platelet counts divided by lymphocyte count. Kaplan-Meier method and Cox hazard regression models were used for survival analyses.ResultsThe 1-year progression-free survival (PFS) was 63.5%, and the 5-year overall survival (OS) rate was 55.1%. Patients with higher PIV, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune inflammation index (SII) had worse PFS in univariate analysis, but only the PIV (hazard ratio [HR] = 2.90, 95% confidence interval [CI]: 1.79–4.70, p < 0.001) was an independent prognostic factor in multivariate analysis. Similarly, patients with higher PIV, NLR, PLR, and SII had a worse OS in the univariate analysis, but only the PIV (HR = 4.70, 95% CI: 2.00–11.02, p < 0.001) was significantly associated with worse OS in multivariate analysis.ConclusionPIV is a comprehensive and convenient predictor of both PFS and OS in patients with ALK-positive advanced NSCLC who received first-line ALK TKIs. Prospective clinical trials are required to validate the value of this new parameter.     

Prognostic Significance of the Metabolic Marker Hexokinase-2 in Various Solid Tumors: A Meta-Analysis

ObjectiveRecently, numerous studies have reported that hexokinase-2 (HK2) is aberrantly expressed in cancer, indicating that HK2 plays a pivotal role in the development and progression of cancer. However, its prognostic significance in solid tumor remains unclear. Accordingly, we performed a meta-analysis to assess the prognostic value of HK2 in solid tumor.MethodsEligible studies were identified using PubMed, Embase, and Web of Science databases. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) or progression-free survival (PFS)/disease-free survival (DFS)/relapse-free survival (RFS) were estimated with random effects or fixed effects models, respectively. Subgroup analysis was also performed according to patients’ ethnicities, tumor types, detection methods, and analysis types.ResultsData from 21 included studies with 2532 patients were summarized. HK2 overexpression was significantly associated with worse OS (pooled HR = 1.90, 95% CI = 1.51–2.38, p < 0.001) and PFS (pooled HR = 2.91, 95% CI = 2.02–4.22, p < 0.001) in solid tumor. As to a specific form of cancer, the negative effect of HK2 on OS was observed in hepatocellular carcinoma (pooled HR = 2.06, 95% CI = 1.67–2.54, p < 0.001), gastric cancer (pooled HR = 1.72, 95% CI = 1.09–2.71, p = 0.020), colorectal cancer (pooled HR = 2.89, 95% CI = 1.62–5.16, p < 0.001), but not in pancreatic cancer (pooled HR = 1.13, 95% CI = 0.28–4.66, p = 0.864). No publication bias was found in the included studies for OS (Begg’s test, p = 0.325; Egger’s test, p = 0.441).ConclusionIn this meta-analysis, we identified that elevated HK2 expression was significantly associated with shorter OS and PFS in patients with solid tumor, but the association varies according to cancer type.     

An inherited variant in the gene coding for vitamin D‐binding protein and survival from cutaneous melanoma: a BioGenoMEL study

An association between low serum vitamin D levels and poorer melanoma survival has been reported. We have studied inheritance of a polymorphism of the GC gene, rs2282679, coding for the vitamin D‐binding protein, which is associated with lower serum levels of vitamin D, in a meta‐analysis of 3137 melanoma patients. The aim was to investigate evidence for a causal relationship between vitamin D and outcome (Mendelian randomization). The variant was not associated with reduced overall survival (OS) in the UK cohort, per‐allele hazard ratio (HR) for death 1.23 (95% confidence interval (CI) 0.93, 1.64). In the smaller cohorts, HR in OS analysis was 1.07 (95% CI 0.88, 1.3) and for all cohorts combined, HR for OS was 1.09 (95% CI 0.93, 1.29). There was evidence of increased melanoma‐specific deaths in the seven cohorts for which these data were available. The lack of unequivocal findings despite the large sample size illustrates the difficulties of implementing Mendelian randomization.     

Clinical Profile of Cyclooxygenase-2 Inhibitors in Treating Non-Small Cell Lung Cancer: A Meta-Analysis of Nine Randomized Clinical Trials

Background

Evidence on the benefits of combining cyclooxygenase-2 inhibitor (COX-2) in treating non-small cell lung cancer (NSCLC) is still controversial. We investigated the efficacy and safety profile of cyclooxygenase-2 inhibitors in treating NSCLC.

Methods

The first meta-analysis of eligible studies was performed to assess the effect of COX-2 inhibitors for patients with NSCLC on the overall response rate (ORR), overall survival (OS), progression-free survival (PFS), one-year survival, and toxicities. The fixed-effects model was used to calculate the pooled RR and HR and between-study heterogeneity was assessed. Subgroup analyses were conducted according to the type of COX-2 inhibitors, treatment pattern, and treatment line.

Results

Nine randomized clinical trials, comprising 1679 patents with NSCLC, were included in the final meta-analysis. The pooled ORR of patients who have NSCLC with COX-2 inhibitors was significantly higher than that without COX-2 inhibitors. In subgroup analysis, significantly increased ORR results were found on celecoxib (RR = 1.29, 95% CI: 1.09, 1.51), rofecoxib (RR = 1.61, 95% CI: 1.14, 2.28), chemotherapy (RR = 1.40, 95% CI: 1.20, 1.63), and first-line treatment (RR = 1.39, 95% CI: 1.19, 1.63). However, COX-2 inhibitors had no effect on the one-year survival, OS, and PFS. Increased RR of leucopenia (RR = 1.21, 95% CI: 1.01, 1.45) and thrombocytopenia (RR = 1.36, 95% CI: 1.06, 1.76) suggested that COX-2 inhibitors increased hematologic toxicities (grade ≥ 3) of chemotherapy

Conclusions

COX-2 inhibitors increased ORR of advanced NSCLC and had no impact on survival indices, but it may increase the risk of hematologic toxicities associated with chemotherapy.     

The Efficacy of Synchronous Combination of Chemotherapy and EGFR TKIs for the First-Line Treatment of NSCLC: A Systematic Analysis

Background

The combination of chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) currently has become the hotspot issue in the treatment of non-small lung cancer (NSCLC). This systematic review was conducted to compare the efficacy and safety of the synchronous combination of these two treatments with EGFR TKIs or chemotherapy alone in advanced NSCLC.

Methods

EMBASE, PubMed, the Central Registry of Controlled Trials in the Cochrane Library (CENTRAL), Chinese biomedical literature database (CNKI) and meeting summaries were searched. The Phase II/III randomized controlled trials were selected by which patients with advanced NSCLC were randomized to receive a combination of EGFR TKIs and chemotherapy by synchronous mode vs. EGFR TKIs or chemotherapy alone.

Results

A total of six randomized controlled trials (RCTs) including 4675 patients were enrolled in the systematic review. The meta-analysis demonstrated that the synchronous combination group of chemotherapy and EGFR TKIs did not reach satisfactory results; there was no significant difference in overall survival (OS), time to progression (TTP) and objective response rate (ORR), compared with monotherapy (OS: HR = 1.05, 95%CI = 0.98–1.12; TTP: HR = 0.94, 95%CI = 0.89–1.00; ORR: RR = 1.07, 95%CI = 0.98–1.17), and no significant difference in OS and progression-free survival (PFS), compared with EGFR TKIs alone (OS: HR = 1.10, 95% CI = 0.83–1.46; PFS: HR = 0.86, 95% CI = 0.67–1.10). The patients who received synchronous combined therapy presented with increased incidences of grade 3/4 anemia (RR = 1.40, 95% CI = 1.10–1.79) and rash (RR = 7.43, 95% CI = 4.56–12.09), compared with chemotherapy, grade 3/4 anemia (RR = 6.71, 95% CI = 1.25–35.93) and fatigue (RR = 9.60, 95% CI = 2.28–40.86) compared with EGFR TKI monotherapy.

Conclusions

The synchronous combination of chemotherapy and TKIs is not superior to chemotherapy or EGFR TKIs alone for the first-line treatment of NSCLC.     

A systematic review and meta-analysis of higher expression of folate receptor alpha (FOLR1) predicts poor cancer prognosis

Abstract

Folate receptor alpha (FOLR1), a glycosylphosphatidylinositol-linked protein, is a well characterized folate transporter. However, the prognostic power of FOLR1 in cancer remains controversial. We conducted a meta-analysis to assess the prognostic roles of FOLR1 on different cancers. Twelve studies involving 4471 patients were included in this meta-analysis. The pooled analysis indicated that high FOLR1 significantly predicted poor overall survival (OS) (pooled hazard ratio (HR)?=?0.78, 95% confidence interval (CI)?=?0.64–0.94, p?=?0.009) and the disease-free survival (DFS) (HR?=?1.25, 95% CI?=?1.07–1.47, p?=?0.005). Subgroup analyses based on tumour type found that high FOLR1 level was associated with poor OS in breast cancer (HR?=?2.66, 95% CI?=?1.54–4.59, p?=?0.0005) and endometrial carcinoma (HR?=?1.30, 95% CI?=?1.05–1.61, p?=?0.02). However, FOLR1 has relatively weakly correlation with gender, tumour size and chemotherapy. Additionally, overexpression of FOLR1 was correlated with grade, FIGO stage, vital status and nodule status. The present meta-analysis indicated that the high expression of FOLR1 is associated with the poor survival of cancer patients, which is helpful for the clinical decision-making process.     

Prognostic value of periostin in multiple solid cancers: A systematic review with meta-analysis

Previous studies have shown that the expression of periostin (POSTN) is significantly correlated with prognosis in multiple solid cancers. However, the function of POSTN in tumorigenesis and its relationship with clinical outcomes have not been systematically summarized and analyzed. Thus, a meta-analysis was performed to evaluate the prognostic pertinence of POSTN in solid cancer. We conducted a systematic search in the PubMed, EMBASE, Web of Science, and Cochrane library databases, and a total of 10 studies were used to assess the association of POSTN expression and patients’ overall survival (OS) and disease-free survival (DFS). The hazard ratio (HR) or odds ratio (OR) and their corresponding 95% confidence intervals (95% CIs) were further calculated to estimate the association between POSTN and relevant clinical parameters of solid cancer patients. The pooled results indicated that POSTN overexpression was associated with poor OS (HR = 2.35, 95% CI = 1.88–2.93, p < .00001) and DFS (HR = 2.70, 95% CI = 2.00–3.65, p < .00001) in a cohort of 993 patients with cancer. Subsequent analyses showed that the positive expression ratio of POSTN was evidently higher in cancer tissues than in normal tissues (OR = 7.44, 95% CI = 3.66–13.95, p < .00001). In addition, subgroup analysis showed that POSTN was related to microvascular invasion (OR = 5.09, 95% CI = 3.07–8.44, p < .00001), tumor differentiation (OR = 2.03, 95% CI = 1.41–2.91, p = .0001), and lymph node metastasis (OR = 3.05, 95% CI = 2.01–4.64, p < .00001). These data showed that POSTN could be a credible prognostic biomarker and a potential therapeutic target in human solid cancer.     

Clinical significance of preoperative neutrophil-lymphocyte versus platelet-lymphocyte ratio in patients with operable colorectal cancer

The objective of this study was to clarify whether the neutrophil-lymphocyte ratio (NLR) and the platelet-lymphocyte ratio (PLR) are significant prognostic markers in patients with resectable colorectal cancer (CRC). A total of 200 patients who underwent curative resection for CRC were enrolled. The NLR and PLR were positively correlated (p?<?0.001). Both the NLR and PLR were shown to be good prognostic biomarkers of overall survival (OS) (p?=?0.002 and p?=?0.001, respectively). The PLR was an independent prognostic factor of OS based on multivariate analysis (hazard ratio, 1.971; 95% confidence interval, 1.102–3.335; p?=?0.021).