The portal venous circulation provides a conduit for pancreatic ductal adenocarcinoma (PDAC) tumor cells to the liver parenchyma sinusoids, a frequent site of metastasis. Turbulent flow in the portal circulation promotes retention of PDAC shed circulating tumor cells (CTC) and myeloid-derived immunosuppressor cells (MDSC). Excessive colony stimulating factor-1 receptor (CSF1R) signaling can induce myeloid differentiation to MDSC and transformation of MDSC to myeloid-derived fibroblasts (M-FB). Interactions between PDAC CTC and M-FB in the portal blood promotes the formation of immunoresistant clusters that enhance CTC proliferation, migration, and survival. Analysis of portal and peripheral blood samples collected intraoperatively from 30 PDAC patients undergoing pancreatico-duodenectomy showed that PDAC patient plasma contained high levels of macrophage colony stimulating factor (M-CSF/CSF1), granulocyte-macrophage colony stimulating factor (GM-CSF/CSF2), interleukin-8 (IL-8), and interleukin-34 (IL-34) compared to healthy control levels. Moreover, the level of M-CSF in portal blood was significantly higher than that detected in the peripheral blood of PDAC patients. PDAC CTC aseptically isolated by fluorescence activated cell sorting (FACS) out of freshly collected patient portal blood mononuclear cells (PortalBMC) had elevated RNA expression of IL34 (IL-34 gene) and CSF1 (M-CSF/CSF1 gene) which both signal through CSF1R. PDAC CTC also had high levels of RNA expression for CXCL8, the gene encoding chemokine interleukin-8 (IL-8) which can attract myeloid cells through their CXCR2 receptors. FACS-isolated portal PDAC CTC and M-FB co-cultured ex vivo had increased CTC proliferation, motility, and cluster formation compared to CTC cultured alone. CSF1R and CXCR2 cell surface expression were found on PDAC portal blood CTC and M-FB, suggesting that both cell types may respond to M-CSF, IL-34, and IL-8-mediated signaling. Portal PDAC CTC displayed enhanced RNA expression of CSF1 and IL34, while CTC+M-FB+ clusters formed in vivo had increased RNA expression of CSF2 and IL34. Portal M-FB were found to have high CSF1R RNA expression. CTC isolated from ex vivo 7-day cultures of PDAC patient portal blood mononuclear cells (PortalBMC) expressed elevated CSF1, IL34, and IL8 RNA, and CSF1 expression was elevated in M-FB. Treatment with rabbit anti-CSF1R antibodies decreased CTC proliferation. Treatment of PortalBMC cultures with humanized anti-CSF1R, humanized anti-IL-8, or anti-IL-34 antibodies disrupted CTC cluster formation and increased CTC apoptosis. U937 myeloid precursor cell line cultures treated with conditioned media from PortalBMC ex vivo cultures without treatment or treated with anti-IL-8 and/or anti-CSF1R did not prevent myeloid differentiation in the myeloid precursor cell line U937 to macrophage, dendritic cell, MDSC, and M-FB phenotypes; whereas, U937 cultures treated with conditioned media from PortalBMC ex vivo cultures exposed to anti-IL-34 were significantly inhibited in their myeloid differentiation to all but the M-FB phenotype. PDAC patient T cells that were found phenotypically anergic (CD3+CD25+CTLA4+PD1L1+) in PortalBMC could be re-activated (CD3+CD25+CTLA4-PD1L1-), and displayed increased interferon gamma (IFNγ) production when PortalBMC ex vivo cultures were treated with anti-CSF1R, anti-IL-8, and anti-IL-34 antibodies alone or in combination. These findings suggest that PDAC CTC have the potential to influence myeloid differentiation and/or antigen presenting cell activation in the PDAC portal blood microenvironment, and that disruption of CTC/M-FB interactions may be potential targets for reversing the immunosuppression supporting CTC survival in the portal blood.
Introduction. Previous research suggests the presence of a spouse may considerably affect melanoma detection rates through more frequent examinations, better access to healthcare, and improved social support. Yet, the role of marital status on melanoma survival is currently unknown. The aim of this study is to assess whether marital status is associated with survival following melanoma diagnosis. Methods. We performed secondary analysis of data from all participants of the Florida Cancer Data System (FCDS) and included adult melanoma patients diagnosed between 2001 and 2009 with follow-up information available until 2015. Marital status was categorized as single, married, divorced, or widowed. The primary outcome was survival interval after melanoma diagnosis, which was assessed according to the time from the date of diagnosis to the time of death or last contact. Cox proportional hazard models were used to assess the independent association between marital status and survival. Results. We assessed data from 36,578 melanoma patients. Married patients were significantly more likely to survive than single patients (Hazard ratio (HR) = 0.65; 99% Confidence Interval (CI): 0.57–0.74; P<0.001) after adjusting for age, sex, race, ethnicity, geographic location, insurance status, tobacco use, primary site, stage, and histology. There was no evidence of effect modification by gender (P=0.189). Conclusions. Married patients, including both men and women, had a 35% reduction in the risk of death after melanoma diagnosis compared with single patients, and mechanisms independent of earlier detection, such as social support, may play a role in survival in patients with melanoma.
690 Background: Downstaging of pancreatic adenocarcinoma in patients presenting with nonmetastatic, unresectable disease has proven to be associated with improved clinical outcomes. Efforts at rescuing these patients to become surgical candidates are commonly attempted with a combination of systemic and radiation strategies. In this study, we aimed to determine tumor downsizing in patients that underwent neoadjuvant systemic therapy followed by a curative-intended surgical resection. Methods: A retrospective review of consecutive patients that underwent surgical resection for pancreatic adenocarcinoma following a course of neoadjuvant therapy was performed. Basic demographics, endoscopic ultrasound (EUS) findings, chemotherapy regimens and duration, rates of radiotherapy, type of surgical procedure and pathologic results were recorded. Tumor response to neoadjuvant therapy was established by correlating EUS- to pathologic tumor dimensions. Analysis of the data was done using Mann-Whitney U test, Pearson correlation and Chi-square when indicated. Results: A total of 97 patients were analyzed; 40 underwent neoadjuvant chemotherapy (13 patients also received concurrent radiation therapy). In those 57 patients that were resected upfront, EUS tended to underestimate tumor sizes significantly compared to pathologic dimensions, with an average difference between dimensions of 0.66 cm (p = 0.0004). Within the group treated with neoadjuvant chemotherapy, 90% of patients had downsizing at an average of 8% of tumor size. There were no differences in rates of tumor downsizing between FOLFIRINOX or Gemcitabine/Nac-paclitaxel treated patients. In addition, there were no correlations in margin status (R0) based on chemotherapy used, with both regimens achieving a similar rate of R0 resections (mean 61%). The type of chemotherapy regimen used did not affect the ratio of positive lymph nodes harvested. Conclusions: In patients that present with borderline resectable pancreatic adenocarcinoma, a course of neoadjuvant therapy results in tumor downsizing in a significant number allowing for margin negative resections. These results were seen regardless of the chemotherapeutic regimens utilized.
cancer. Based on our results, determination of tumor sizing based on EUS has the potential to under-stage patients with pancreatic cancer.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.