Cetuximab Monotherapy and Cetuximab plus Irinotecan in Irinotecan-Refractory Metastatic Colorectal Cancer

Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been reported to predict oncologic outcomes in patients with various types of cancer. However, their prognostic value in patients with esophageal cancer is unclear. In this meta-analysis, we evaluated the prognostic significance of NLR and PLR in esophageal cancer patients. We performed comprehensive searches of electronic databases to identify studies that evaluated the prognostic impact of pretreatment NLR and PLR in esophageal cancer patients. The end points were overall survival (OS), disease-free survival, and clinicopathologic parameters. A meta-analysis using random-effects models was performed to calculate hazard ratios (HRs) or odds ratios with 95 % confidence intervals (CIs). Seven retrospective, observational, cohort studies involving 1540 patients were included. All seven studies evaluated NLR, and four evaluated PLR. Both high NLR (HR 1.40, 95 % CI 1.08–1.81, P = 0.01) and high PLR (HR 1.59, 95 % CI 1.14–2.21, P = 0.006) were significantly predictive of poorer OS. NLR was not a significant predictor of disease-free survival. High PLR (HR 1.85, 95 % CI 1.50–2.28, P < 0.00001) but not NLR was significantly predictive of poorer OS in a subgroup of patients who underwent curative surgery without neoadjuvant chemoradiation. Both high NLR and high PLR were significantly associated with deeper tumor invasion and lymph node metastasis. NLR and PLR are associated with tumor progression and are predictive of poorer survival in patients with esophageal cancer. These ratios may thus help to inform treatment decisions and predict treatment outcomes.

Prognostic Significance of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio in Oncologic Outcomes of Esophageal Cancer: A Systematic Review and Meta-analysis

Gastric cancer (GC) remains an important cause of cancer death worldwide with a high mortality rate due to the fact that the majority of GC cases are diagnosed at an advanced stage when the prognosis is poor and the treatment options are limited. Unfortunately, the existing circulating biomarkers for GC diagnosis and prognosis display low sensitivity and specificity and the GC diagnosis is based only on the invasive procedures such as upper digestive endoscopy. There is a huge need for less invasive or non-invasive tests but also highly specific biomarkers in case of GC. Body fluids such as peripheral blood, urine or saliva, stomach wash/gastric juice could be a source of specific biomarkers, providing important data for screening and diagnosis in GC. This review summarized the recently discovered circulating molecules such as microRNAs, long non-coding RNAs, circular RNAs, which hold the promise to develop new strategies for early diagnosis of GC.

Recent advances in gastric cancer early diagnosis.

Thousands of genes have been well demonstrated to play important roles in cancer progression. As genes do not function in isolation, they can be grouped into “networks” based on their interactions. In this study, we discover a network regulating Claudin-4 in gastric cancer. We observe that Claudin-4 is up-regulated in gastric cancer and is associated with poor prognosis. Claudin-4 reinforce proliferation, invasion, and EMT in AGS, HGC-27, and SGC-7901 cells, which could be reversed by miR-596 and miR-3620-3p. In addition, lncRNA-KRTAP5-AS1 and lncRNA-TUBB2A could act as competing endogenous RNAs to affect the function of Claudin-4. Our results suggest that non-coding RNAs play important roles in the regulatory network of Claudin-4. As such, non-coding RNAs should be considered as potential biomarkers and therapeutic targets against gastric cancer. Non-coding RNAs can modify the expression of proteins in cancer networks. Here the authors reveal a regulatory network in gastric cancer whereby claudin-4 expression is reduced by specific miRNAs, which are in turn bound by specific lncRNAs acting as competing endogenous RNAs (ceRNAs), resulting in increased claudin-4 expression.

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Non-coding RNAs participate in the regulatory network of CLDN4 via ceRNA mediated miRNA evasion

Summary Surgery is an important treatment modality for the majority of solid organ cancers. Unfortunately, cancer recurrence following surgery of curative intent is common, and typically results in refractory disease and patient death. Surgery and other perioperative interventions induce a biological state conducive to the survival and growth of residual cancer cells released from the primary tumour intraoperatively, which may influence the risk of a subsequent metastatic disease. Evidence is accumulating that anaesthetic and analgesic interventions could affect many of these pathophysiological processes, influencing risk of cancer recurrence in either a beneficial or detrimental way. Much of this evidence is from experimental in vitro and in vivo models, with clinical evidence largely limited to retrospective observational studies or post hoc analysis of RCTs originally designed to evaluate non-cancer outcomes. This narrative review summarises the current state of evidence regarding the potential effect of perioperative anaesthetic and analgesic interventions on cancer biology and clinical outcomes. Proving a causal link will require data from prospective RCTs with oncological outcomes as primary endpoints, a number of which will report in the coming years. Until then, there is insufficient evidence to recommend any particular anaesthetic or analgesic technique for patients undergoing tumour resection surgery on the basis that it might alter the risk of recurrence or metastasis.

Influence of perioperative anaesthetic and analgesic interventions on oncological outcomes: a narrative review.

The association between nonsteroidal anti-inflammatory drugs (NSAIDs) and breast cancer survival is still controversial. The aim of our meta-analysis was to assess the survival benefit of NSAIDs. A literature search was conducted in PubMed and EMBASE (to September 2014). A meta-analysis was performed with hazard ratios (HRs) and 95 % confidence intervals (CIs) as the effect measures. Subgroup analyses were based on time of NSAID use (before and after diagnosis), medication type (aspirin and other nonaspirin NSAIDs), and study design (cohort and case–control studies). There were 16 eligible studies. Use of NSAIDs after diagnosis was significantly inversely associated with relapse/metastasis (HR 0.69, 95 % CI 0.59–0.80) and tended toward potentially protective effects on all-cause mortality, although significance was not reached (HR 0.79, 95 % CI 0.61–1.02). In cohort studies, the association between post-diagnostic use of NSAIDs and breast cancer survival was stronger with reduced heterogeneity (breast-cancer-specific mortality: HR 0.65, 95 % CI 0.48–0.89, I
 2 = 65.3 %; all-cause mortality: HR 0.73, 95 % CI 0.57–0.92, I
 2 = 83.2 %; relapse/metastasis: HR 0.73, 95 % CI 0.61–0.86, I
 2 = 48.3 %). Aspirin use after diagnosis was significantly associated with breast-cancer-specific mortality (HR 0.69, 95 % CI 0.50–0.96) and relapse/metastasis (HR 0.75, 95 % CI 0.56–1.00), and tended toward a protective effect on all-cause mortality, although significance was not reached (HR 0.79, 95 % CI 0.60–1.03). Including cohort studies only, we obtained similar results and post-diagnostic use of aspirin was significantly associated with all-cause mortality (HR 0.72, 95 % CI 0.56–0.93). NSAIDs and aspirin after but not before diagnosis were associated with improved breast cancer survival, including breast-cancer-specific mortality, all-cause mortality, and relapse/metastasis.

Aspirin and nonsteroidal anti-inflammatory drugs after but not before diagnosis are associated with improved breast cancer survival: a meta-analysis

Over the last two decades, genome-wide studies have revealed that only a small fraction of the human genome encodes proteins; long noncoding RNAs (lncRNAs) account for 98% of the total genome. These RNA molecules, which are >200 nt in length, play important roles in diverse biological processes, including the immune response, stem cell pluripotency, cell proliferation, apoptosis, differentiation, invasion, and metastasis by regulating gene expression at the epigenetic, transcriptional, and posttranscriptional levels. However, the detailed molecular mechanisms underlying lncRNA function are only partially understood. Recent studies showed that many lncRNAs are aberrantly expressed in gastric cancer (GC) tissues, gastric juice, plasma, and cells, and these alterations are linked to the occurrence, progression, and outcome of GC. Here, we review the current knowledge of the biological functions and clinical aspects of lncRNAs in GC.

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Long noncoding RNAs in gastric cancer: functions and clinical applications

Numerous microRNAs (miRNAs/miRs) are involved in suppressing or promoting the formation of cancer. However, to the best of our knowledge, the role of miRNA-1258 in gastric cancer (GC) has not previously been investigated. Our previous study demonstrated an increased expression of heparanase (HPSE) in GC tissues and HPSE-facilitated invasion and metastasis of GC cells. Consequently, in the present study, the function of miR-1258 in the invasion and metastasis of GC cells was investigated to determine whether miR-1258 is associated with GC through HPSE. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to determine miR-1258 expression in GC cell lines and tissues. A Transwell cell invasion assay and an MTT proliferation assay were used to investigate the effects of miR-1258 on the invasion and proliferation of one of the cell lines, SGC-7901 cells, in vitro. The effect of miR-1258 on SGC-7901 cell metastasis was investigated using an in vivo tumor metastasis formation assay. Western blot analysis and RT-qPCR were used to investigate whether HPSE was a target of miR-1258 in GC. The expression of miR-1258 was significantly downregulated in 3 GC cell lines and 116 GC tissues compared with controls (all P<0.001). An association was identified between decreased miR-1258 expression level and increased age (P=0.042), advanced pathological tumor stage (P=0.027) and positive lymphatic vessel invasion (P=0.044) in patients with GC. Furthermore, the upregulation of miR-1258 expression suppressed SGC-7901 cell invasion in vitro (P<0.001) and inhibited SGC-7901 cell metastasis in vivo (P=0.016). The western blot analysis and RT-qPCR results indicated that miR-1258 downregulated the expression of HPSE at the translational level. The results of the present study indicate that miR-1258 acts as a tumor suppressor to inhibit invasion and metastasis by targeting HPSE. Therefore, miR-1258 may serve as a novel biomarker and therapeutic target in the treatment of GC.

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MicroRNA-1258: An invasion and metastasis regulator that targets heparanase in gastric cancer.

BACKGROUND The prognostic significance of claudin 4 (CLDN4) in patients with gastric cancer (GC) is controversial. This meta-analysis aims to assess the correlation between CLDN4 expression and clinicopathological characteristics and assess the prognostic significance of CLDN4 in GC. METHODS We searched the PubMed and Embase databases. We performed the meta-analysis with odds ratio (OR), hazard ratio (HR), and 95% confidence interval (CI) as effect values. RESULTS Fourteen studies containing 2,106 patients with GC were analyzed. The overall analysis showed that CLDN4 expression was associated with increasing pT category, tumor size, and lymph node metastasis in patients with GC (pT3-T4 vs pT1-T2: OR =1.56, 95% CI =1.13-2.16; P<0.01; large tumor size vs small tumor size: OR =1.64, 95% CI =1.15-2.34; P<0.01; positive lymph node metastasis vs negative lymph node metastasis: OR =1.49, 95% CI =1.12-1.97; P<0.01). CLDN4 expression was associated with histological differentiation (differentiated type vs undifferentiated type: OR =2.90, 95% CI =1.32-6.37; P=0.01; Lauren intestinal type vs diffuse type: OR =3.51, 95% CI =1.48-8.28; P<0.01). CLDN4 expression was also strongly associated with sex and age. This meta-analysis found no significant association between CLDN4 expression and prognosis for overall survival in patients with GC (HR =0.74, 95% CI =0.43-1.27; P=0.28). CONCLUSION Present study indicates that aberrant CLDN4 expression plays an important role in the clinicopathological characteristics of GC.

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Clinicopathological significance of claudin 4 expression in gastric carcinoma: a systematic review and meta-analysis

Numerous studies focusing on genetic variants in order to find cetuximab subpopulation biomarkers have emerged, yet the significance of each biomarker is diverse. Based on these results, we carried out a meta-analysis to assess the correlation between epidermal growth factor (EGF) A61G polymorphism and clinical outcomes of metastatic colorectal cancer (mCRC) patients treated with cetuximab. We aim to prove that EGF polymorphisms may be potential biomarkers for cetuximab therapeutic strategies. We identified 6 previously published studies including 569 patients treated with cetuximab-based regimens. Outcomes included clinical response, progression-free survival (PFS), and overall survival (OS). GG homozygote showed association with better response rates (GG vs. AA+AG, OR = 2.82; 95% CI = 1.58-5.04) and than AA+AG genotypes. This meta-analysis showed that mCRC patients harboring GG genotype of EGF A61G polymorphism inclined to have a better response rate with cetuximab treatment.

Polymorphism in epidermal growth factor is related to clinical outcomes of metastatic colorectal cancer patients treated with cetuximab: a systematic review and meta-analysis.

Ping Chen

Papers

Aspirin and nonsteroidal anti-inflammatory drugs after but not before diagnosis are associated with improved breast cancer survival: a meta-analysis

Long noncoding RNAs in gastric cancer: functions and clinical applications

MicroRNA-1258: An invasion and metastasis regulator that targets heparanase in gastric cancer.

Clinicopathological significance of claudin 4 expression in gastric carcinoma: a systematic review and meta-analysis

Polymorphism in epidermal growth factor is related to clinical outcomes of metastatic colorectal cancer patients treated with cetuximab: a systematic review and meta-analysis.