In the West, more than one third of newly diagnosed subjects show metastatic disease in gastric cancer (mGC) with few care options available. Gastrectomy has recently become a subject of debate, with ...some evidence showing advantages in survival beyond the sole purpose of treatment tumor-related complications. We investigated the survival benefit of different strategies in mGC patients, focusing on the role and timing of gastrectomy. Data were extracted from the SEER database. Groups were determined according to whether patients received gastrectomy, chemotherapy, supportive care. Patients receiving a multimodality treatment were further divided according to timing of surgery, whether performed before (primary gastrectomy, PG) or after chemotherapy (secondary gastrectomy, SG). 16,596 patients were included. Median OS was significantly higher (p < 0.001) in the SG (15 months) than in the PG (13 months), gastrectomy alone (6 months), and chemotherapy (7 months) groups. In the multivariate analysis, SG showed better OS (HR = 0.22, 95%CI = 0.18-0.26, p < 0.001) than PG (HR = 0.25, 95%CI = 0.23-0.28, p < 0.001), gastrectomy (HR = 0.40, 95%CI = 0.36-0.44, p < 0.001), and chemotherapy (HR = 0.42, 95%CI = 0.4-0.44, p < 0.001). The survival benefits persisted even after the PSM analysis. This study shows survival advantages of gastrectomy as multimodality strategy after chemotherapy. In selected patients, SG can be proposed to improve the management of stage IV disease.
Solid tumors such as pancreatic ductal adenocarcinoma (PDAC) comprise not just tumor cells but also a microenvironment with which the tumor cells constantly interact. Detailed characterization of the ...cellular composition of the tumor microenvironment is critical to the understanding of the disease and treatment of the patient. Single-cell transcriptomics has been used to study the cellular composition of different solid tumor types including PDAC. However, almost all of those studies used primary tumor tissues.
In this study, we employed a single-cell RNA sequencing technology to profile the transcriptomes of individual cells from dissociated primary tumors or metastatic biopsies obtained from patients with PDAC. Unsupervised clustering analysis as well as a new supervised classification algorithm, SuperCT, was used to identify the different cell types within the tumor tissues. The expression signatures of the different cell types were then compared between primary tumors and metastatic biopsies. The expressions of the cell type-specific signature genes were also correlated with patient survival using public datasets.
Our single-cell RNA sequencing analysis revealed distinct cell types in primary and metastatic PDAC tissues including tumor cells, endothelial cells, cancer-associated fibroblasts (CAFs), and immune cells. The cancer cells showed high inter-patient heterogeneity, whereas the stromal cells were more homogenous across patients. Immune infiltration varies significantly from patient to patient with majority of the immune cells being macrophages and exhausted lymphocytes. We found that the tumor cellular composition was an important factor in defining the PDAC subtypes. Furthermore, the expression levels of cell type-specific markers for EMT
cancer cells, activated CAFs, and endothelial cells significantly associated with patient survival.
Taken together, our work identifies significant heterogeneity in cellular compositions of PDAC tumors and between primary tumors and metastatic lesions. Furthermore, the cellular composition was an important factor in defining PDAC subtypes and significantly correlated with patient outcome. These findings provide valuable insights on the PDAC microenvironment and could potentially inform the management of PDAC patients.
Background Gastric adenocarcinoma is an aggressive disease with frequent lymph node (LN) metastases for which lymphadenectomy results in a survival benefit. In the US, the National Comprehensive ...Cancer Network guidelines recommend D2 lymphadenectomy or a minimum of 15 LNs retrieved. However, retrieval of only 15 LNs is considered by most international guidelines as inadequate. We sought to evaluate the survival benefits associated with a more complete lymphadenectomy. Study Design An international database was constructed by combining gastric cancer cases from the Surveillance, Epidemiology, and End Results program database (n = 13,932) and the Yonsei University Gastric Cancer database (n = 11,358) (total n = 25,289). Kaplan-Meier survival analysis was performed along with Joinpoint analysis to obtain the optimal number of LNs to retrieve based on survival. Prognostic significance of number of nodes retrieved was then confirmed with univariate and multivariate analyses. Results Analysis for both mean and median survival yielded 29 LNs removed as the Joinpoint. This was confirmed with multivariate analysis, where 15 retrieved LNs cutoff fell out of the model and 29 retrieved LNs remained intact, with a hazard ratio of 0.799 (95% CI 0.759 to 0.842; p < 0.001). Stage-stratified Kaplan-Meier analysis for a cutoff point of 29 LNs also demonstrated a statistically significant improvement in survival. Conclusions Joinpoint analysis has allowed for the creation of a model demonstrating the point at which additional dissection would not provide additional benefit. This large international dataset analysis demonstrates that the maximal survival advantage is seen by performing a lymphadenectomy with a minimum of 29 LNs retrieved.
Background
No international consensus on the treatment of advanced gastric cancer (AGC) exists. In the absence of well-designed, comparative studies between neoadjuvant versus adjuvant strategies, ...concerns about increased risk of postoperative complications remain barriers to neoadjuvant chemotherapy (NAC) for AGC. We evaluated surgical outcomes of AGC patients who received minimally invasive radical gastrectomy with D2 lymphadenectomy after NAC.
Methods
We collected data from two high-volume gastric cancer programs in the United States and China between January 2015 and December 2019 with the last follow-up in February 2020. AGC patients undergoing minimally invasive radical surgery were included. After propensity score-matching, surgical outcomes were analyzed. Risk-factor of complications was analyzed in the whole cohort.
Results
After 1:1 propensity score-matching, 97 patients were included in each cohort. NAC + surgery cohort was younger (58.2 ± 10.3 vs. 61.3 ± 9.6,
P
= 0.036) with lower preoperative WBC count (5.7 ± 2.8 vs. 6.9 ± 2.1 × 10
9
/ml) than the surgery upfront cohort. NAC was not a risk-factor for postoperative complications (odds ratio OR, 0.859; 95% confidence interval CI, 0.46–1.60;
P
= 0.633). Overall risk-factors of postoperative complications included age ≥ 60 years (OR, 21.338; 95% CI, 5.00–91.05;
P
< 0.001), tumor size ≥ 5 cm (OR, 1.24; 95% CI, 1.08–1.83;
P
< 0.001), operation time ≥ 240 min (OR, 5.53; 95% CI, 1.26–24.26;
P
= 0.012), and ASA classification ≥ II (OR, 13.14; 95% CI, 4.12–24.73;
P
< 0.001).
Conclusions
NAC before minimally invasive radical gastrectomy with D2 lymphadenectomy does not increase postoperative complications, and these findings support broader application of NAC and MIS for AGC. Additional studies are required to determine the effect of NAC on long-term survival.
Oncolytic viruses have shown excellent safety profiles in preclinical and clinical studies; however, in most cases therapeutic benefits have been modest. We have previously reported the generation of ...a chimeric poxvirus (CF33), with significantly improved oncolytic characteristics, through chimerization among different poxviruses. Here we report the sequence analysis of CF33 and oncolytic potential of a GFP-encoding CF33 virus (CF33-GFP) with a J2R deletion in lung cancer models. Replication of CF33-GFP and the resulting cytotoxicity were higher in cancer cell lines compared to a normal cell line, in vitro. After infection with virus, cancer cells expressed markers for immunogenic cell death in vitro. Furthermore, CF33-GFP was safe and exerted potent anti-tumor effects at a dose as low as 1000 plaque forming units in both virus-injected and un-injected distant tumors in A549 tumor xenograft model in mice. Likewise, in a syngeneic model of lung cancer in mice, the virus showed significant anti-tumor effect and was found to increase tumor infiltration by CD8+ T cells. Collectively, these data warrant further investigation of this novel chimeric poxvirus for its potential use as a cancer bio-therapeutic.
Background
How the oncologic outcomes after robotic distal pancreatectomy (RDP) compare to those after laparoscopic distal pancreatectomy (LDP) remains unknown.
Methods
Using the National Cancer ...Database (NCDB), we analyzed all patients undergoing LDP or RDP for resectable pancreatic adenocarcinoma over a 4‐year period (2010‐2013).
Results
Of the 704 eligible patients, 605 (86%) underwent LDP and 99 (14%) underwent RDP. The median follow‐up for patients was 25 months. There were no differences in the two groups with respect to sociodemographic, clinicopathologic, or treatment characteristics. On comparing LDP versus RDP, there was no difference in the margin‐positive rate (15% vs 16%; P = 0.84); lymph nodes examined (12 vs 11; P = 0.67); overall survival (hazard ratio HR, 1.1, 95% confidence intervals CI, 0.7 to 1.7; 28 vs 25 months; P = 0.71); hospital stay (6 vs 5 days; P = 0.14); time to chemotherapy (50 vs 52 days; P = 0.65); 30‐day readmission (9.4% vs 9.1%; P = 0.92); and mortality (1% vs 0%; P = 0.28). Patients undergoing LDP had a significantly higher conversion rate to open or minimally invasive pancreatic cancer resections compared with RDP (27% vs 10%; P < 0.001).
Conclusion
The early national experience with RDP demonstrates similar oncologic outcomes to LDP, with a significantly lower conversion rate.
We studied the immunotherapeutic potential of CF33-hNIS-antiPDL1 oncolytic virus (OV) against gastric cancer with peritoneal metastasis (GCPM). We collected fresh malignant ascites (MA) or peritoneal ...washings (PW) during routine paracenteses and diagnostic laparoscopies from GC patients (n = 27). Cells were analyzed for cancer cell markers and T cells, or treated with PBS, CF33-GFP, or CF33-hNIS-antiPDL1 (MOI = 3). We analyzed infectivity, replication, cytotoxicity, CD107α upregulation of CD8+ and CD4+ T cells, CD274 (PD-L1) blockade of cancer cells by virus-encoded anti-PD-L1 scFv, and the release of growth factors and cytokines. We observed higher CD45−/large-size cells and lower CD8+ T cell percentages in MA than PW. CD45−/large-size cells were morphologically malignant and expressed CD274 (PD-L1), CD252 (OX40L), and EGFR. CD4+ and CD8+ T cells did not express cell surface exhaustion markers. Virus infection and replication increased cancer cell death at 15 h and 48 h. CF33-hNIS-antiPDL1 treatment produced functional anti-PD-L1 scFv, which blocked surface PD-L1 binding of live cancer cells and increased CD8+CD107α+ and CD4+CD107α+ T cell percentages while decreasing EGF, PDGF, soluble anti-PD-L1, and IL-10. CF33-OVs infect, replicate in, express functional proteins, and kill ex vivo GCPM cells with immune-activating effects. CF33-hNIS-antiPDL1 displays real potential for intraperitoneal GCPM therapy.
Chimeric antigen receptor (CAR) T cell therapeutic responses are hampered by limited T cell trafficking, persistence, and durable anti-tumor activity in solid tumors. However, these challenges can be ...largely overcome by relatively unconstrained synthetic engineering strategies. Here, we describe CAR T cells targeting tumor-associated glycoprotein-72 (TAG72), utilizing the CD28 transmembrane domain upstream of the 4-1BB co-stimulatory domain as a driver of potent anti-tumor activity and IFNγ secretion. CAR T cell-mediated IFNγ production facilitated by IL-12 signaling is required for tumor cell killing, which is recapitulated by engineering an optimized membrane-bound IL-12 (mbIL12) molecule in CAR T cells. These T cells show improved antigen-dependent T cell proliferation and recursive tumor cell killing in vitro, with robust in vivo efficacy in human ovarian cancer xenograft models. Locoregional administration of mbIL12-engineered CAR T cells promotes durable anti-tumor responses against both regional and systemic disease in mice. Safety and efficacy of mbIL12-engineered CAR T cells is demonstrated using an immunocompetent mouse model, with beneficial effects on the immunosuppressive tumor microenvironment. Collectively, our study features a clinically-applicable strategy to improve the efficacy of locoregionally-delivered CAR T cells engineered with antigen-dependent immune-modulating cytokines in targeting regional and systemic disease.
Background
Peritoneal metastases (PM) from ovarian, gastric, appendiceal, or colorectal origin can be treated via cytoreductive surgery with or without the addition of hyperthermic intraperitoneal ...chemotherapy (HIPEC) for selected patients. Unfortunately, not all patients are candidates for aggressive surgical debulking. For these patients, pressurized intraperitoneal aerosolized chemotherapy (PIPAC) has emerged as an alternative method for intraperitoneal (IP) chemotherapy administration. This report presents the design and implementation of the first phase 1 trial to evaluate the safety and efficacy of PIPAC in the United States.
Methods
This is an ongoing prospective phase 1 clinical trial of PIPAC for patients who have histologically confirmed ovarian, uterine, gastric, appendiceal, or colorectal cancer with PM and have progressed to at least one evidence-based chemotherapeutic regimen. The trial has two clinical arms. The patients in arm 1 have gynecologic and gastric malignancies treated with IP cisplatin and doxorubicin, and the arm 2 patients have colorectal and appendiceal malignancies treated with intravenous fluorouracil and leucovorin followed by IP oxaliplatin. All the patients are monitored for dose-limiting toxicities and adverse events.
Results
Practical and technical considerations for the phase 1 PIPAC trial are presented. These considerations include patient selection, operating room setup, and technical details for successful aerosolized chemotherapy delivery. The phase 1 study results will be reported separately at completion of the trial.
Conclusions
The PIPAC treatment is a feasible, minimally invasive approach that permits IP delivery of chemotherapy. Once completed, the ongoing phase 1 trial will help to provide safety and initial efficacy data.
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