Regarding the comparison between primary debulking surgery (PDS) and neoadjuvant chemotherapy (NACT) for stage III/IV ovarian, tubal and peritoneal cancers, EORTC55971 and CHORUS studies demonstrated ...noninferiority of NACT. Previously, we reported reduced invasiveness of NACT in JCOG0602. This is a final analysis including the primary endpoint of overall survival (OS).
Patients were randomised to PDS (PDS followed by 8x paclitaxel and carboplatin, i.e. TC regimen) or NACT (4x TC, interval debulking surgery IDS, 4x TC). The primary endpoint was OS. The noninferiority hazard ratio (HR) margin for NACT compared with PDS was 1·161. The planned sample size was 300.
Between 2006 and 2011, 301 patients were randomised, 149 to PDS and 152 to NACT. The median OS was 49·0 and 44·3 months in the PDS and NACT. HR for NACT was 1·052 90·8% confidence interval (CI) 0·835–1·326, and one-sided noninferiority p-value was 0·24. Median progression-free survival was 15·1 and 16·4 months in the PDS and NACT (HR: 0·96 95%CI 0·75–1·23). In the PDS arm, 147/149 underwent PDS and 49/147 underwent IDS. In the NACT arm 130/152 underwent IDS. Complete resection was achieved in 12% (17/147) of PDS and 31% (45/147) of PDS ± IDS in the PDS arm and in 64% (83/130) of IDS in the NACT arm. Optimal surgery (residual tumour <1 cm) was achieved in 37% (55/147), 63% (92/147), and 82% (107/130 respectively. In the NACT, PS 2/3, serum albumin ≤2·5, CA125 > 2000 an institution with low study activity was advantageous, whereas clear/mucinous histology was disadvantageous for OS.
The noninferiority of NACT was not confirmed. NACT may not always be a substitute for PDS. However, as our study had smaller numbers, the noninferiority of the previous studies cannot be denied.
Ministry of Health, Labour and Welfare, Japan and the National Cancer Center, Japan.
UMIN000000523.
•Survival noninferiority of NACT compared to PDS was not confirmed in this study.•Noninferiority of the previous studies cannot be denied because of smaller numbers.•There seems to be diversity in the efficacy of PDS/NACT among subgroups of patients.
Abstract
Background
Helicobacter pylori infection is a major cause of non-cardia gastric cancer (NCGC), but uncertainty remains about the associations between sero-positivity to different H. pylori ...antigens and risk of NCGC and cardia gastric cancer (CGC) in different populations.
Methods
A case-cohort study in China included ∼500 each of incident NCGC and CGC cases and ∼2000 subcohort participants. Sero-positivity to 12 H. pylori antigens was measured in baseline plasma samples using a multiplex assay. Hazard ratios (HRs) of NCGC and CGC for each marker were estimated using Cox regression. These were further meta-analysed with studies using same assay.
Results
In the subcohort, sero-positivity for 12 H. pylori antigens varied from 11.4% (HpaA) to 70.8% (CagA). Overall, 10 antigens showed significant associations with risk of NCGC (adjusted HRs: 1.33 to 4.15), and four antigens with CGC (HRs: 1.50 to 2.34). After simultaneous adjustment for other antigens, positive associations remained significant for NCGC (CagA, HP1564, HP0305) and CGC (CagA, HP1564, HyuA). Compared with CagA sero-positive only individuals, those who were positive for all three antigens had an adjusted HR of 5.59 (95% CI 4.68–6.66) for NCGC and 2.17 (95% CI 1.54–3.05) for CGC. In the meta-analysis of NCGC, the pooled relative risk for CagA was 2.96 (95% CI 2.58–3.41) Europeans: 5.32 (95% CI 4.05–6.99); Asians: 2.41 (95% CI 2.05–2.83); Pheterogeneity<0.0001. Similar pronounced population differences were also evident for GroEL, HP1564, HcpC and HP0305. In meta-analyses of CGC, two antigens (CagA, HP1564) were significantly associated with a higher risk in Asians but not Europeans.
Conclusions
Sero-positivity to several H. pylori antigens was significantly associated with an increased risk of NCGC and CGC, with varying effects between Asian and European populations.
Background
This is the final report evaluating the long-term outcomes of a single-arm phase II clinical trial that demonstrated the short-term efficacy of laparoscopic gastrectomy (LG) for highly ...advanced gastric cancer (AGC) KUGC04.
Patients and Methods
Seventy-three patients with histologically confirmed gastric adenocarcinoma and diagnosed with clinical stage II or higher, who potentially underwent curative resection between August 2009 and November 2014, were prospectively enrolled. Long-term outcomes with 5-year progression-free survival (PFS) and 5-year overall survival (OS) were evaluated according to clinical or pathological stages. Recurrence and progression patterns were also investigated. These outcomes were compared with those of previous reports to assess the applicability of LG for highly advanced gastric cancer (HAGC).
Results
The median observation period of all surviving patients was 75.1 months. The 5-year PFS and 5-year OS of all patients was 47.4% and 54.4%, respectively. Clinical stage-specific 5-year PFS and 5-year OS was 75.0, 69.1, 53.9, 39.4, 40.0 and 9.1, and 75.0, 68.8, 61.5, 45.0, 60.0 and 27.3, respectively, in stages IIA, IIB, IIIA, IIIB, IIIC, and IV, respectively. Pathological stage-specific 5-year PFS and 5-year OS, including ypStage with preoperative chemotherapy, was 100, 80.0, 100, 62.5, 80.0, 51.3, 16.7, 22.2 and 12.5, and 100, 80.0, 100, 75.0, 80.0, 64.2, 25.0, 33.3 and 12.5, respectively, in stage X (no residual tumor with preoperative chemotherapy), IA, IB, IIA, IIB, IIIA, IIIB, IIIC, and IV, respectively. Recurrence or progression was observed in 30 patients (41.1%).
Conclusion
LG for HAGC performed by experienced surgeons is safe and oncologically acceptable.
Pyroptosis, a type of inflammatory programmed cell death, is mediated by multiple inflammasomes which can recognize danger signals and activate the secretion of pro-inflammatory cytokines like ...IL-1811Interleukin (IL) -18. and IL-1β22Interleukin (IL) -1β.. It can induce cancer cell death within the gastrointestinal tract. NLRs33NOD-like receptors, AIM244absent in melanoma 2-like receptors, GSDM55gasdermin family play important roles in pyroptosis signaling pathways in intestinal cancer such as gastric cancer, colitis-associated colorectal cancer and esophageal cancer, etc. Furthermore, several inflammasomes are elucidated to be involved in mucosal innate immune responses and modulate specific enteric pathogens infection. Precise modulation of inflammasome activation and exploration of potential diagnostic markers can contribute to the diagnosis, prevention and treatment of intestinal tumors and inflammatory or infectious disorders in human patients in the near future.
Long non-coding RNA signature in gastric cancer Ghafouri-Fard, Soudeh; Taheri, Mohammad
Experimental and molecular pathology,
April 2020, 2020-Apr, 2020-04-00, 20200401, Letnik:
113
Journal Article
Recenzirano
Gastric cancer as a common human malignancy has been associated with aberrant expressions of several coding and non-coding genes. Long non-coding RNAs (lncRNAs) as regulators of gene expressions at ...different genomic, transcriptomic and post-transcriptomic levels are among putative biomarkers and therapeutic targets in gastric cancer. In the present study, we have searched available literature and listed lncRNAs that are involved in the pathogenesis of gastric cancer. In addition, we discuss associations between expressions of these lncRNAs and tumoral features or risk factors for gastric cancer. Based on the established role of lncRNAs in regulation of genomic stability, cell cycle, apoptosis, angiogenesis and other aspects of cell physiology, the potential of these transcripts as therapeutic targets in gastric cancer should be evaluated in future studies.
Most patients with ovarian cancer will relapse after receiving frontline platinum-based chemotherapy and eventually develop platinum-resistant or platinum-refractory disease. We report results of ...avelumab alone or avelumab plus pegylated liposomal doxorubicin (PLD) compared with PLD alone in patients with platinum-resistant or platinum-refractory ovarian cancer.
JAVELIN Ovarian 200 was an open-label, parallel-group, three-arm, randomised, phase 3 trial, done at 149 hospitals and cancer treatment centres in 24 countries. Eligible patients were aged 18 years or older with epithelial ovarian, fallopian tube, or peritoneal cancer (maximum of three previous lines for platinum-sensitive disease, none for platinum-resistant disease) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to avelumab (10 mg/kg intravenously every 2 weeks), avelumab plus PLD (40 mg/m2 intravenously every 4 weeks), or PLD and stratified by disease platinum status, number of previous anticancer regimens, and bulky disease. Primary endpoints were progression-free survival by blinded independent central review and overall survival in all randomly assigned patients, with the objective to show whether avelumab alone or avelumab plus PLD is superior to PLD. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02580058. The trial is no longer enrolling patients and this is the final analysis of both primary endpoints.
Between Jan 5, 2016, and May 16, 2017, 566 patients were enrolled and randomly assigned (combination n=188; PLD n=190, avelumab n=188). At data cutoff (Sept 19, 2018), median duration of follow-up for overall survival was 18·4 months (IQR 15·6–21·9) for the combination group, 17·4 months (15·2–21·3) for the PLD group, and 18·2 months (15·8–21·2) for the avelumab group. Median progression-free survival by blinded independent central review was 3·7 months (95% CI 3·3–5·1) in the combination group, 3·5 months (2·1–4·0) in the PLD group, and 1·9 months (1·8–1·9) in the avelumab group (combination vs PLD: stratified HR 0·78 repeated 93·1% CI 0·59–1·24, one-sided p=0·030; avelumab vs PLD: 1·68 1·32–2·60, one-sided p>0·99). Median overall survival was 15·7 months (95% CI 12·7–18·7) in the combination group, 13·1 months (11·8–15·5) in the PLD group, and 11·8 months (8·9–14·1) in the avelumab group (combination vs PLD: stratified HR 0·89 repeated 88·85% CI 0·74–1·24, one-sided p=0·21; avelumab vs PLD: 1·14 0·95–1·58, one-sided p=0·83). The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysesthesia syndrome (18 10% in the combination group vs nine 5% in the PLD group vs none in the avelumab group), rash (11 6% vs three 2% vs none), fatigue (ten 5% vs three 2% vs none), stomatitis (ten 5% vs five 3% vs none), anaemia (six 3% vs nine 5% vs three 2%), neutropenia (nine 5% vs nine 5% vs none), and neutrophil count decreased (eight 5% vs seven 4% vs none). Serious treatment-related adverse events occurred in 32 (18%) patients in the combination group, 19 (11%) in the PLD group, and 14 (7%) in the avelumab group. Treatment-related adverse events resulted in death in one patient each in the PLD group (sepsis) and avelumab group (intestinal obstruction).
Neither avelumab plus PLD nor avelumab alone significantly improved progression-free survival or overall survival versus PLD. These results provide insights for patient selection in future studies of immune checkpoint inhibitors in platinum-resistant or platinum-refractory ovarian cancer.
Pfizer and Merck KGaA, Darmstadt, Germany.
In the phase III KEYNOTE-061 trial (NCT02370498), pembrolizumab did not significantly improve overall survival versus paclitaxel as second-line therapy for gastric/gastroesophageal junction (GEJ) ...adenocarcinoma with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors. The association of tissue tumor mutational burden (tTMB) status and clinical outcomes was determined, including the relationship with CPS and microsatellite instability-high (MSI-H) status.
In patients with whole exome sequencing (WES) data 420/592 (71%); pembrolizumab, 218; paclitaxel, 202, the association of tTMB with objective response rate (ORR; logistic regression), progression-free survival (PFS; Cox proportional hazards regression), and overall survival (OS; Cox proportional hazards regression) were measured using one-sided (pembrolizumab) and two-sided paclitaxel P values. tTMB was also evaluated using FoundationOne®CDx 205/592 (35%). Prespecified equivalent cut-offs of 175 mut/exome for WES and 10 mut/Mb for FoundationOne®CDx were used.
WES-tTMB was significantly associated with ORR, PFS, and OS in pembrolizumab-treated (all P < 0.001) but not paclitaxel-treated patients (all P > 0.6) in univariate analysis. The area under the receiver operating characteristics curve for WES-tTMB and response was 0.68 95% confidence interval (CI) 0.56-0.81 for pembrolizumab and 0.51 (95% CI 0.39-0.63) for paclitaxel in univariate analysis. There was low correlation between WES-tTMB and CPS in both treatment groups (r ≤ 0.16). WES-tTMB remained significantly associated with all clinical endpoints with pembrolizumab after adjusting for CPS and with PFS and OS after excluding known MSI-H tumors (n = 26). FoundationOne®CDx-tTMB demonstrated a positive association with ORR, PFS, and OS in pembrolizumab-treated patients (all P ≤ 0.003) but not PFS or OS in paclitaxel-treated patients (P > 0.1).
This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and efficacy with pembrolizumab but not paclitaxel in patients with gastric/GEJ adenocarcinoma in a randomized setting. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status.
•Second-line pembrolizumab showed a strong association between tTMB and efficacy in gastric and gastroesophageal cancer.•There was low correlation between WES-tTMB and PD-L1 CPS.•WES-tTMB was associated significantly with pembrolizumab PFS and OS after excluding known MSI-H tumors.•Findings with FoundationOne®CDx-tTMB were similar to those with WES-tTMB.
Objective
The aim of this study was to investigate the prognostic value of preoperative sarcopenia and systemic inflammation for patients with resectable gastric cancer (GC) and develop a novel and ...powerful prognostic score based on these factors.
Materials and Methods
Patients with GC who underwent radical gastrectomy between December 2009 and December 2013 were included. A multivariate Cox regression analysis was performed to identify the prognostic factors. A novel prognostic score (SLMR) was developed based on preoperative sarcopenia and the lymphocyte‐monocyte ratio (LMR), and its prognostic value was evaluated.
Results
In total, 1,167 patients with resectable GC were included in the study. On multivariate analysis, preoperative sarcopenia and the LMR were shown to be independent prognostic factors (both p < .001). A low LMR was an independent predictor from sarcopenia (p < .001). Based on preoperative sarcopenia and the LMR, we established the SLMR. An elevated SLMR was associated with older age, higher ASA scores, larger tumor size, advanced stages, and vascular invasion (all p < .05). Multivariate analysis revealed that the SLMR was a significant independent predictor (p < .001). We incorporated the SLMR into a prognostic model that included tumor size and TNM stage and generated a nomogram, which accurately predicted 3‐ and 5‐year survival for GC patients.
Conclusion
Preoperative systemic inflammation is significantly associated with sarcopenia. The LMR combined with sarcopenia could enhance prognostication for patients with GC who underwent radical gastrectomy.
Implications for Practice
Increasing evidence shows that sarcopenia and systemic inflammation are closely associated with the prognosis of malignant tumors, and it is essential for clinicians to understand the relationship and combined prognostic effects of these factors for gastric cancer (GC). Based on a large data set, this study found that preoperative systemic inflammation was significantly associated with sarcopenia in GC, and combining these two predictors could effectively predict the prognosis and complement the prognostic value of the TNM staging system. These findings may lead to the development of new therapeutic avenues to improve cancer outcomes.
摘要
目标。本研究的目的在于调查可切除性胃癌 (GC) 患者出现术前肌肉减少症和全身炎症的预后价值，并根据这些因素建立新的有效预后评分。
材料和方法。我们招募了 2009 年 12 月至 2013 年 12 月接受胃癌根治术的GC患者。采用多变量 Cox 回归分析确定了预后因素。我们根据术前肌肉减少症和淋巴细胞与单核细胞比率 (LMR) 建立了新的预后评分 (SLMR)，并评估了其预后价值。
结果。本研究共招募了 1 167 名可切除性GC患者。多变量分析显示，术前肌肉减少症和LMR属于独立预后因素(两者的 p < 0.001)。LMR低是肌肉减少症的独立预测因子 (p < 0.001)。根据术前肌肉减少症和LMR，我们确立了SLMR。SLMR升高与年龄较大、ASA 评分较高、肿瘤尺寸较大、晚期胃癌和血管浸润(所有的 p < 0.05)有关。多变量分析表明，SLMR是重要的独立预测因子 (p < 0.001)。我们将SLMR纳入包括肿瘤尺寸和 TNM 分期的预后模型中，并生成了列线图，准确预测胃癌患者的 3 年和 5 年生存率。
结论。术前全身炎症与肌肉减少症显著相关。LMR结合肌肉减少症可加强对接受过胃癌根治术的GC患者的预后。
实践意义:越来越多的证据表明，肌肉减少症和全身炎症与恶性肿瘤的预后密切相关，临床医生必须了解这些因素与胃癌 (GC) 的关系及综合预后效果。基于大量的数据集，本研究发现，术前全身炎症与GC肌肉减少症显著相关，将这两种预测因子相结合，可有效预测预后并补强 TNM 分期系统的预后价值。上述结果让我们可以开发新的治疗途径，进而改善癌症预后。
Evidence shows that sarcopenia and systemic inflammation are closely associated with poor prognosis from malignant tumors. This article assesses the prognostic efficacy of preoperative sarcopenia and systemic inflammation and reports a novel prognostic score based on these factors to predict long‐term outcomes for patients with resectable gastric cancer.
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