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Background and aimsDistant metastasis is a major cause of deaths in patients with colorectal cancer (CRC), which is partly due to lack of robust metastasis-predictive biomarkers. In spite of the important function of microRNA (miR)-203 in cancer metastasis, its clinical significance in CRC metastasis remains unknown. Here, we evaluated the potential role of serum miR-203 as a non-invasive biomarker for CRC metastasis.MethodsMiR-203 expression was quantified by quantitative reverse-transcription PCR in 58 pairs of primary CRC (pCRC) and corresponding matched liver metastasis (LM), as well as 186 serum and 154 matched tissue specimens from patients with CRC in cohort 1. Next, we performed validation of miR-203 levels in serum from 144 patients with CRC in an independent cohort (cohort 2). Mouse models of CRC-associated metastases were established to identify the source of circulating miR-203. Expression patterns of miR-203 in tissues were determined by in situ hybridisation.ResultsMiR-203 expression was significantly upregulated in LM compared with matched pCRC tissues. Serum miR-203 levels were significantly upregulated in a stage-dependent manner, and high miR-203 expression was associated with poor survival in patients with CRC in both patient cohorts. Increased miR-203 levels in serum indicated high risk for poor prognosis (HR=2.1), as well as metastasis to lymph nodes (OR=2.5), liver (OR=6.2), peritoneum (OR=7.2) and distant organs (OR=4.4). Serum miR-203 levels were significantly higher in animals with liver or systemic metastasis compared with controls.ConclusionsHigh levels of serum miR-203 associate with poor survival and metastasis, suggesting it to be a promising non-invasive prognostic and metastasis-predictive biomarker in patients with CRC.

Poor prognosis germ-cell tumours are only cured in about half of patients. We aimed to assess whether treatment intensification based on an early tumour marker decline will improve progression-free survival for patients with germ-cell tumours. In this phase 3, multicentre, randomised trial, patients were enrolled from France (20 centres), USA (one centre), and Slovakia (one centre). Patients were eligible if they were older than 16 years, had evidence of testicular, retroperitoneal, or mediastinal non-seminomatous germ cell tumours based on histological findings or clinical evidence and highly elevated serum human chorionic gonadotropin or alfa-fetoprotein concentrations that matched International Germ Cell Cancer Consensus Group poor prognosis criteria. After one cycle of BEP (intravenous cisplatin [20 mg/m2 per day for 5 days], etoposide [100 mg/m2 per day for 5 days], and intramuscular or intravenous bleomycin [30 mg per day on days 1, 8, and 15]), patients' human chorionic gonadotropin and alfa-fetoprotein concentrations were measured at day 18–21. Patients with a favourable decline in human chorionic gonadotropin and alfa-fetoprotein continued BEP (Fav-BEP group) for 3 additonal cycles, whereas patients with an unfavourable decline were randomly assigned (1:1) to receive either BEP (Unfav-BEP group) or a dose-dense regimen (Unfav-dose-dense group), consisting of intravenous paclitaxel (175 mg/m2 over 3 h on day 1) before BEP plus intravenous oxaliplatin (130 mg/m2 over 3 h on day 10; two cycles), followed by intravenous cisplatin (100 mg/m2 over 2 h on day 1), intravenous ifosfamide (2 g/m2 over 3 h on days 10, 12, and 14), plus mesna (500 mg/m2 at 0, 3, 7 and 11 h), and bleomycin (25 units per day, by continuous infusion for 5 days on days 10–14; two cycles), with granulocyte-colony stimulating factor (lenograstim) support. Centrally blocked computer-generated randomisation stratified by centre was used. The primary endpoint was progression-free survival and the efficacy analysis was done in the intention-to-treat population. The planned trial accrual was completed in May, 2012, and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00104676. Between Nov 28, 2003, and May 16, 2012, 263 patients were enrolled and 254 were available for tumour marker assessment. Of these 51 (20%) had a favourable marker assessment, and 203 (80%) had an unfavourable tumour marker decline; 105 were randomly assigned to the Unfav-dose-dense group and 98 to the Unfav-BEP group. 3-year progression-free survival was 59% (95% CI 49–68) in the Unfav-dose-dense group versus 48% (38–59) in the Unfav-BEP group (HR 0·66, 95% CI 0·44–1·00, p=0·05). 3-year progression-free survival was 70% (95% CI 57–81) in the Fav-BEP group (HR 0·66, 95% CI 0·49–0·88, p=0·01 for progression-free survival compared with the Unfav-BEP group). More grade 3–4 neurotoxic events (seven [7%] vs one [1%]) and haematotoxic events occurred in the Unfav-dose-dense group compared with in the Unfav-BEP group; there was no difference in grade 1–2 febrile neutropenia (18 [17%] vs 18 [18%]) or toxic deaths (one [1%] in both groups). Salvage high-dose chemotherapy plus a stem-cell transplant was required in six (6%) patients in the Unfav-dose-dense group and 16 (16%) in the Unfav-BEP group. Personalised treatment with chemotherapy intensification reduces the risk of progression or death in patients with poor prognosis germ-cell tumours and an unfavourable tumour marker decline. Institut National du Cancer (Programme Hospitalier de Recherche Clinique).

BackgroundOccult metastatic tumors, below imaging thresholds, are a limitation of staging systems that rely on cross-sectional imaging alone and are a cause of the routine understaging of pancreatic ductal adenocarcinomas (PDACs). We investigated circulating tumor cells (CTCs) as a preoperative predictor of occult metastatic disease and as a prognostic biomarker for PDAC patients.Experimental DesignA total of 126 patients (100 with cancer, 26 with benign disease) were enrolled in our study and CTCs were identified and enumerated from 4 mL of venous blood using the microfluidic NanoVelcro assay. CTC enumeration was correlated with clinicopathologic variables and outcomes following both surgical and systemic therapies.ResultsCTCs were identified in 78% of PDAC patients and CTC counts correlated with increasing stage (ρ = 0.42, p < 0.001). Of the 53 patients taken for potentially curative surgery, 13 (24.5%) had occult metastatic disease intraoperatively. Patients with occult disease had significantly more CTCs than patients with local disease only (median 7 vs. 1 CTC, p < 0.0001). At a cut-off of three or more CTCs/4 mL, CTCs correctly identified patients with occult metastatic disease preoperatively (area under the receiver operating characteristic curve 0.82, 95% confidence interval (CI) 0.76–0.98, p < 0.0001). CTCs were a univariate predictor of recurrence-free survival following surgery [hazard ratio (HR) 2.36, 95% CI 1.17–4.78, p = 0.017], as well as an independent predictor of overall survival on multivariate analysis (HR 1.38, 95% CI 1.01–1.88, p = 0.040).ConclusionsCTCs show promise as a prognostic biomarker for PDAC patients at all stages of disease being treated both medically and surgically. Furthermore, CTCs demonstrate potential as a preoperative biomarker for identifying patients at high risk of occult metastatic disease.

Anoikis is a type of programmed cell death induced by loss of anchorage to the extracellular matrix (ECM). Anoikis resistance (AR) is crucial for the survival of metastatic cancer cells in blood, lymphatic circulation and distant organs. Compared to ordinary cancer cells, anoikis resistant cancer cells undergo various cellular and molecular alterations, probably characterizing the cells with unique features not limited to anoikis resistance. However, the molecular mechanisms connecting anoikis resistance to other metastatic properties are still poorly understood. Here, the biological interaction between anoikis resistance and angiogenesis as well as their involvement into peritoneal metastasis of gastric cancer (GC) were investigated in vitro and in vivo. The prognostic value of key components involved in this interaction was evaluated in the GC cohort. Compared to ordinary GC cells, GC AR cells exhibited stronger metastatic and pro-angiogenic traits corresponding to elevated PDGFB secretion. Mechanistically, transcription factor C/EBPβ facilitated PDGFB transcription by directly binding to and interacting with PDGFB promoter elements, subsequently increasing PDGFB secretion. Secreted PDGFB promoted the survival of detached GC cells through a C/EBPβ-dependent self-feedback loop. Moreover, secreted PDGFB promoted angiogenesis in metastases via activation of the MAPK/ERK signaling pathway in vascular endothelial cells. Both C/EBPβ activation level and PDGFB expression were significantly elevated in GC and correlated with metastatic progression and poor prognosis of patients with GC. Overall, interaction between GC AR cells and vascular endothelial cells promotes angiogenesis and peritoneal metastasis of GC based on C/EBPβ-mediated PDGFB autocrine and paracrine signaling. C/EBPβ-PDGFB-PDGFRβ-MAPK axis promises to be potential prognostic biomarkers and therapeutic targets for peritoneal metastasis of GC.

Background: This study was intended to determine the clinical significance of circulating tumour cells (CTCs) in patients with advanced gastric cancer (AGC), particularly the potential role of CTCs for dynamic monitoring of the therapeutic response. Methods: A single-centre, prospective study was undertaken in 136 patients with newly diagnosed AGC. The patients’ CTCs were enumerated using CellSearch at baseline and at the first response evaluation. In 15 patients whose clinical condition permitted longitudinal study, CTCs were longitudinally enumerated during treatment. Results: Following 6 weeks of chemotherapy, an unfavourable post-therapy CTC level (⩾3 CTCs per 7.5 ml) was closely correlated with the objective response rate ( P =0.016) and the disease control rate ( P =0.013), and it also independently predicted a shorter progression-free survival and overall survival. Particularly, conversion to a favourable CTC level following therapy improved the prognosis, but patients who changed to an unfavourable CTC level fared significantly worse. Elevated CTCs during therapy may be associated with a poor prognosis. Conclusions: Post-therapy CTC level may help in evaluating therapeutic response in patients with AGC and predicting their prognosis. In addition, changes in CTCs following therapy may be useful in rapidly identifying ineffective treatments and poor prognosis.

BackgroundNext-generation sequencing (NGS) is a useful tool for detecting genomic alterations in circulating tumor DNA (ctDNA). To date, most ctDNA tests have been performed on patients with widely metastatic disease. Patients with peritoneal carcinomatosis (metastases) present unique prognostic and therapeutic challenges. We therefore explored preoperative ctDNA in patients with peritoneal metastases undergoing surgery.MethodsPatients referred for surgical resection of peritoneal metastases underwent preoperative blood-derived ctDNA analysis (clinical-grade NGS [68–73 genes]). ctDNA was quantified as the percentage of altered circulating cell-free DNA (% cfDNA).ResultsEighty patients had ctDNA testing: 46 (57.5%) women; median age 55.5 years. The following diagnoses were included: 59 patients (73.8%), appendix cancer; 11 (13.8%), colorectal; five (6.3%), peritoneal mesothelioma; two (2.5%), small bowel; one (1.3%) each of cholangiocarcinoma, ovarian, and testicular cancer. Thirty-one patients (38.8%) had detectable preoperative ctDNA alterations, most frequently in the following genes: TP53 (25.8% of all alterations detected) and KRAS (11.3%). Among 15 patients with tissue DNA NGS, 33.3% also had ctDNA alterations (overall concordance = 96.7%). Patients with high ctDNA quantities (≥ 0.25% cfDNA, n = 25) had a shorter progression-free survival (PFS) than those with lower ctDNA quantities (n = 55; 7.8 vs. 15.0 months; hazard ratio 3.23, 95% confidence interval 1.43–7.28, p = 0.005 univariate, p = 0.044 multivariate).ConclusionsA significant proportion of patients with peritoneal metastases referred for surgical intervention have detectable ctDNA alterations preoperatively. Patients with high levels of ctDNA have a worse prognosis independent of histologic grade.

Purpose This was a review of circulating tumor DNA (ctDNA) in patients with peritoneal metastases from colorectal cancer. Methods We searched the PubMed database for studies reporting detection of ctDNA in patients with colorectal cancer (CRC) and with peritoneal metastases (PM) from colorectal cancer (CRPM). We extracted data on the population included, number of subjects, study design, type of ctDNA assay used and schedule, and the major findings from these publications. Results We identified 13 studies for review investigating ctDNA, using a variety of ctDNA assays, among 1787 patients with CRC without PM, as well as four eligible published and one unpublished (in press) studies, which included 255 patients with PM from any primary site and 61 patients with CRPM. Among the 13 studies investigating ctDNA among CRC without PM, posttreatment surveillance ctDNA was associated with recurrence and was generally more sensitive than imaging or tumor markers. Among the five studies including patients with PM, ctDNA was not universally able to detect the presence of PM, but when present, ctDNA predicted worse outcomes. Conclusion Circulating-tumor DNA is a potentially useful surveillance tool for patients with CRC. However, the sensitivity of ctDNA to detect CRPM is variable and warrants further inquiry.

Background We evaluated the prognostic value of the preoperative serum carcinoembryonic antigen (CEA) level in patients with colorectal cancer (CRC). Patients and Methods The study group comprised 638 patients. The optimal cutoff value for the preoperative serum CEA level was determined. Predictive factors of recurrence were evaluated using multivariate analyses. The relapse-free time was investigated according to the CEA level. Results All patients underwent potentially curative resection for CRC without distant metastasis, classified as stage I, II, or III. The optimal cutoff value for preoperative serum CEA level was 10 ng/ml. Elevated preoperative serum CEA level was observed in 92 patients. Multivariate analysis identified tumor–node–metastasis (TNM) stage and preoperative serum CEA level as independent predictive factors of recurrence. The relapse-free survival between CEA levels >10 ng/ml and <10 ng/ml significantly differed in patients with stage II and III. However, there was no significant difference in relapse-free survival between CEA levels >10 ng/ml and <10 ng/ml in patients with stage I. Conclusion Preoperative serum CEA is a reliable predictive factor of recurrence after curative surgery in CRC patients and a useful indicator of the optimal treatment after resection, particularly for cases classified as stage II or stage III.

Background We previously demonstrated the potential of circulating tumor DNA (ctDNA) for the amplification of detecting HER2 in patients with gastric cancer (GC). In the present study, we focused on the clinical courses of patients who developed recurrence with GC, and investigated the potential clinical utility of the ddPCR-based HER2 copy number (CN) as a marker for the temporal and/or spatial heterogeneities of GC during treatment progress. Method We enrolled 30 healthy volunteers and 60 patients with GC who underwent surgery, including 17 patients who developed recurrence. Using ribonuclease P RNA component H1 ( RPPH1 ) as a reference gene, plasma HER2 to RPPH1 ratios (the HER2 ratio) were determined using ddPCR. Results The preoperative plasma HER2 ratio correlated with the tumor HER2 status ( p  < 0.001), and sensitivity and specificity were 0.733 and 0.933, respectively. Analyses of plasma samples during the postoperative follow-up periods revealed that high plasma HER2 ratios were detected at the time of recurrence in 7 of 13 cases, which were diagnosed as being HER2 negative at the time of surgery. These results were supported by continuously increasing HER2 ratios thereafter with the progression of recurrent cancer. Conclusion The plasma HER2 ratio determined by ddPCR is a repeatable and noninvasive approach for real-time evaluations of the HER2 status to monitor the effects of treatments for patients with HER2-positive GC and enable treatment options for patients with HER2-negative GC but positive conversion of the HER2 status after recurrence.

Background Malignant peritoneal mesothelioma (MPM) is a rare but aggressive cancer. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) was the preferred choice for selected patients. The purpose of this study was to thoroughly examine the impact of the combined treatment and the prognostic variables, particularly the neutrophil-to-lymphocyte ratio (NLR). Methods Characteristics of MPM patients who underwent CRS combined HIPEC treatment, followed by adjuvant chemotherapy were retrospectively collected. The univariable analysis was performed to identify the decisive influential factor. Using Kaplan-Meier analysis, the cumulative probability of survival was determined. Using Univariate Cox analysis, the prognostic factors—particularly NLR—and its correlation with survival were assessed. In the multivariate Cox proportional hazards model, predictive factors that demonstrated significance in univariate analysis were used. The degree of connection between predictors and survival was evaluated through the use of hazard ratios (HRs) and 95% confidence intervals (95% CIs). Results A total of 64 patients were enrolled in this study. The 1, 3, 5 years survival rates were 70.3%, 65.6%, 59.4%, respectively. According to multivariate Cox analysis, patients’ survival was found to be substantially associated with post-operative NLR (HR 0.180, 0.067–0.531), Ki-67 (HR 0.184, 0.024–0.817), post-operative neutrophil count (HR 0.228, 0.075–0.696), and bidirectional pathological type (HR, 0.375, 0.146–0.964). Conclusions NLR is associated with the patients’ prognosis after CRS combined HIPEC treatment.