scholarly journals Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis

Gut ◽  
2022 ◽  
pp. gutjnl-2021-325272
Author(s):  
Gaia Bellomo ◽  
Carolyn Rainer ◽  
Valeria Quaranta ◽  
Yuliana Astuti ◽  
Meirion Raymant ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Liver Metastases ◽  
Disease Progression ◽  
Metastatic Disease ◽  
Ex Vivo ◽  
Receptor Activation ◽  
Tumour Cells ◽  
Metastatic Pancreatic Cancer ◽  
Metastatic Tumour ◽  
Metastatic Liver

ObjectivePancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease and cytotoxic chemotherapy is the standard of care treatment for patients with advanced disease. Here, we investigate how the microenvironment in PDAC liver metastases reacts to chemotherapy and its role in metastatic disease progression post-treatment, an area which is poorly understood.DesignThe impact of chemotherapy on metastatic disease progression and immune cell infiltrates was characterised using flow and mass cytometry combined with transcriptional and histopathological analysis in experimental PDAC liver metastases mouse models. Findings were validated in patient derived liver metastases and in an autochthonous PDAC mouse model. Human and murine primary cell cocultures and ex vivo patient-derived liver explants were deployed to gain mechanistical insights on whether and how chemotherapy affects the metastatic tumour microenvironment.ResultsWe show that in vivo, chemotherapy induces an initial infiltration of proinflammatory macrophages into the liver and activates cytotoxic T cells, leading only to a temporary restraining of metastatic disease progression. However, after stopping treatment, neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth. Disruption of neutrophil infiltration or inhibition of the Gas6/AXL signalling axis in combination with chemotherapy inhibits metastatic growth. Chemotherapy increases Gas6 expression in circulating neutrophils from patients with metastatic pancreatic cancer and recombinant Gas6 is sufficient to promote tumour cell proliferation ex vivo, in patient-derived metastatic liver explants.ConclusionCombining chemotherapy with Gas6/AXL or neutrophil targeted therapy could provide a therapeutic benefit for patients with metastatic pancreatic cancer.

A phase II study of S-1 in gemcitabine-refractory metastatic pancreatic cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4115-4115 ◽  
Author(s):  
C. Morizane ◽  
T. Okusaka ◽  
J. Furuse ◽  
H. Ishii ◽  
H. Ueno ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Disease Progression ◽  
Phase Ii ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Objective Response ◽  
Advanced Pancreatic Cancer ◽  
Metastatic Pancreatic Cancer ◽  
Primary Study ◽  
Standard Regimen

4115 Background: Gemcitabine (Gem) monotherapy or Gem-containing chemotherapy is the standard first line therapy for advanced pancreatic cancer. After disease progression, there is no standard regimen available. In a previous phase II trial (J. Furuse et al, Proc ASCO 2005: # 4104), S-1 has been reported to show considerable efficacy, achieving a response rate of 37.5% in chemo-naïve patients with pancreatic cancer. This study evaluated the efficacy and toxicity of S-1 in patients with Gem-refractory metastatic pancreatic cancer. Methods: Eligibility criteria were pathologically-proven pancreatic cancer with confirmation of progressive disease while receiving Gem-based chemotherapy, Karnofsky performance status 80 to 100%, age 20 to 74 years, with measurable metastatic lesions, adequate hematological, renal and liver functions, and written informed consent. S-1 was administered orally at 40 mg/m2 twice daily for 28 days with a rest period of 14 days as one course. Administration was repeated until the appearance of disease progression or unacceptable toxicity. The primary study end point was objective response, secondary end points included toxicity, progression-free survival (PFS) and overall survival, as well as clinical benefit response in symptomatic patients. Results: Forty patients (pts) from two institutions were enrolled between September 2004 and November 2005. Thirty-three pts are currently evaluable for response in this ongoing trial. There have been 5 confirmed partial responses (12.5%), and 14 pts (35%) with stable disease. Median survival has not been reached. Median PFS was 2.1 months. Toxicity data were available for 28 patients. Grade 3 and 4 toxicities were anemia (1 pts), appetite loss (2 pts), and fatigue (2 pts). Conclusions: Preliminary results demonstrated the safety and activity of S-1 in Gem-refractory metastatic pancreatic cancer. Efficacy and toxicity analysis are ongoing. Final results will be presented at the meeting. No significant financial relationships to disclose.

Ki67 and P53 in Relation to Disease Progression in Metastatic Pancreatic Cancer: a Single Institution Analysis

2018 ◽  
Vol 25 (3) ◽  
pp. 1059-1066 ◽  
Author(s):  
Sally Temraz ◽  
Ali Shamseddine ◽  
Deborah Mukherji ◽  
Maya Charafeddine ◽  
Arafat Tfayli ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Disease Progression ◽  
Metastatic Pancreatic Cancer ◽  
Single Institution

scholarly journals Folfirinox versus gemcitabine/nab-paclitaxel as first-line therapy in patients with metastatic pancreatic cancer: a comparative propensity score study

2019 ◽  
Vol 12 ◽  
pp. 175628481987866 ◽  
Author(s):  
Nicolas Williet ◽  
Angélique Saint ◽  
Anne-Laure Pointet ◽  
David Tougeron ◽  
Simon Pernot ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Propensity Score ◽  
Liver Metastases ◽  
Performance Status ◽  
Progression Free Survival ◽  
Metastatic Pancreatic Cancer ◽  
First Line ◽  
First Line Therapy ◽  
Reverse Sequence ◽  
Metastatic Sites

Background: Folfirinox (FFX) and gemcitabine/nab-paclitaxel (GN) are both standard first-line treatments in patients with metastatic pancreatic cancer (mPC). However, data comparing these two chemotherapeutic regimens and their sequential use remain scarce. Methods: Data from two independent cohorts enrolling patients treated with FFX ( n = 107) or GN ( n = 109) were retrospectively pooled. Primary endpoint was overall survival (OS). Progression-free survival (PFS) was the secondary endpoint. A propensity score based on age, gender, performance status (PS), and presence of liver metastases was used to make groups comparable. Results: In the whole study population, OS was significantly higher in FFX (14 months; 95% CI: 10–21) than in GN groups (9 months; 95% CI: 8–12) before ( p = 0.008) and after ( p = 0.021) adjusting for age, number of metastatic sites, liver metastases, peritoneal carcinomatosis and CA19.9 level at baseline. PFS tends to be higher in FFX (6 months) than GN groups (5 months; p = 0.053). After matching ( n = 49/group), patients were comparable for all baseline characteristics including PS. In the matched population, there was a trend toward greater OS in patients treated with FFX (HR = 0.67; p = 0.097). However, survival in each group was not solely a result of the first-line regimen. The proportion of patients who were fit for GN after FFX failure (FFX–GN sequence) was higher (46.9%) than the reverse sequence (20.4%; p = 0.01), which suggests a higher feasibility for the FFX–GN sequence. Corresponding median OS were 19 months versus 9.5 months, respectively ( p = 0.094). Conclusion: This study shows greater OS with FFX than with GN in patients with mPC. GN after FFX failure appears more feasible than the reverse sequence.

Growth patterns of liver metastases as compared to resected tumors of the same colorectal cancer patients.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 519-519
Author(s):  
Rikke Loevendahl Eefsen ◽  
Gert G. Van den Eynden ◽  
Pnina Brodt ◽  
Julia V. Burnier ◽  
Gunilla Hoyer-Hansen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Metastatic Disease ◽  
Growth Pattern ◽  
Biological Diversity ◽  
Hepatic Metastases ◽  
Tnm Staging ◽  
Growth Patterns ◽  
Laboratory Evaluation ◽  
Metastatic Tumour

519 Background: Colorectal cancer (CRC) affects one million people a year. 25% of the patients have metastatic disease at the time of diagnosis. Metastatic disease is one of the major challenges in the treatment of cancer. Even though the TNM staging system is a good prognostic marker, tumours have a biological diversity that cannot be evaluated by the TNM system. Recently three different growth patterns of CRC liver metastases were identified. The aim of this study was to determine the growth patterns of CRC liver metastases from patients with more than one metastasis. Methods: A pilot study was conducted including 34 patients resected for CRC liver metastases, 28 patients selected from a database of 200 patients, operated in Copenhagen between 2007-2010 and 6 patients, operated in Montreal. From these 34 patients, 15 patients were resected for two or more liver metastases. All paraffin embedded tissue sections were stained for reticulin and haematoxylin and eosin at the Finsen Laboratory. Evaluation of the growth pattern was done by three different observers from Antwerp and Copenhagen. Reproducibility was >90%. Results: In the fifteen patients, 9 from Copenhagen and 6 from Montreal, that had multiple hepatic metastases, there was uniformity in the growth pattern of the individual metastases. 40% had a desmoplastic, 33% a pushing and 20% a replacement growth pattern and 7% had a mix pattern. Of the 9 patients from Copenhagen 33% were synchronous and 67% metachronous metastases. Within patients, all patterns were identical. Conclusions: The uniformity of growth patterns seen in each patient suggests that these patterns are not random. The identical growth pattern may be determined by specific interactions between the tumor and the host microenvironment, as postulated by Paget’s seed and soil theory. This could represent three different stromal and cytokine responses or oncogenic pathway responses and could represent metastatic tumour growth in different microenvironments.

A phase II study of capecitabine in combination with erlotinib as first-line therapy in patients with metastatic pancreatic cancer (stage IV).

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 277-277
Author(s):  
S. Candamio Folgar ◽  
C. Méndez Méndez ◽  
M. Jorge Fernández ◽  
C. Romero Reinoso ◽  
G. Quintero-Aldana ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Disease Progression ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Metastatic Pancreatic Cancer ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy

277 Background: Patients with metastatic pancreatic cancer (mPC) have poor prognosis. Given the activity of both capecitabine and erlotinib in pancreatic cancer, we hypothesized that combination use of two drugs in first-line therapy would improve clinical outcomes in these patients. Methods: A prospective, single arm, open-label, phase II study. Patients received capecitabine 1,000mg/m2 twice daily on days 1-14 in 3-week cycles combined with erlotinib 150 mg po daily for 18 weeks, until disease progression, unacceptable toxicity or withdrawal, with a follow-up visit performed at 30-days post-treatment. The primary endpoint was objective response rate measured with RECIST criteria. Results: A total of 32 patients were evaluated. Baseline characteristics: median age was 64 years (56-70), male: 50%, Karnofsky PS ≥ 80%: 94%, tumor histology: 93.5% adenocarcinoma, 49% moderately differentiated. 11 (34%) patients had surgery, 2 (6%) had prior radiotherapy and 3 (9%) prior chemotherapy. Median treatment duration was 61 days (6-156). 3 (9%) patients required dose reduction of capecitabine and 8 (25%) of erlotinib. Of the 32 patients, 6 completed the treatment period, 22 discontinued the study prematurely due to disease progression and 4 due to AEs. Disease control rate (confirmed complete response [CR], partial response [PR] and stable disease [SD] according to RECIST criteria) was 28.2%. 2 (6.3%) patients achieved PR and 7 (21.9%) had SD. After a mean follow-up of 6.3 months, the median progression-free (PFS) and overall survival (OS) was 2.10 and 4.3 months, respectively, with a 6-months survival rate of 43.8%. Safety analysis revealed that the main grade 1/2 toxicities were rash (34%), asthenia (31%), diarrhea (31%), stomatitis (22%) and emesis (22%). Three cases of grade 3 hand-foot syndrome and 1 case of infection due to biliary stent were detected. No toxicity grade 4 occurred. Conclusions: Capecitabine administered in combination with erlotinib is an active regimen in patients with metastatic pancreatic cancer with a favourable safety profile. These results suggest that this regimen could represent a first-line treatment option for these patients. No significant financial relationships to disclose.

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