We examined how the immune microenvironment molds tumor evolution at different metastatic organs in a longitudinal dataset of colorectal cancer. Through multiplexed analyses, we showed that clonal ...evolution patterns during metastatic progression depend on the immune contexture at the metastatic site. Genetic evidence of neoantigen depletion was observed in the sites with high Immunoscore and spatial proximity between Ki67+ tumor cells and CD3+ cells. The immunoedited tumor clones were eliminated and did not recur, while progressing clones were immune privileged, despite the presence of tumor-infiltrating lymphocytes. Characterization of immune-privileged metastases revealed tumor-intrinsic and tumor-extrinsic mechanisms of escape. The lowest recurrence risk was associated with high Immunoscore, occurrence of immunoediting, and low tumor burden. We propose a parallel selection model of metastatic progression, where branched evolution could be traced back to immune-escaping clones. The findings could inform the understanding of cancer dissemination and the development of immunotherapeutics.
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•Different escape mechanisms delineated by lack of adaptive immunity or immunoediting•Non-recurrent clones are immunoedited; progressing clones are immune privileged•Immunoediting and Immunoscore are predictive factors of metastasis recurrence•Parallel selection model describes clonal immunoediting and tumor evolution
A longitudinal analysis of clonal evolution of tumors across multiple tissues identifies a parallel selection model that explains the role of immune editing in controlling metastatic growth.
This study assesses how the metastatic immune landscape is impacting the response to treatment and the outcome of colorectal cancer (CRC) patients.
Complete curative resection of metastases (n = 441) ...was performed for two patient cohorts (n = 153). Immune densities were quantified in the center and invasive margin of all metastases. Immunoscore and T and B cell (TB) score were analyzed in relation to radiological and pathological responses and patient's disease-free (DFS) and overall survival (OS) using multivariable Cox proportional hazards models. All statistical tests were two-sided.
The spatial distribution of immune cells within metastases was nonuniform. Patients, as well as metastases of the same patient, had variable immune infiltrates and response to therapy. A beneficial response was statistically significantly associated with increased immune densities. Among all metastases, Immunoscore (I) and TB score evaluated in the least immune-infiltrated metastases were the strongest predictors for DFS and OS (five-year follow-up, Immunoscore: I 3-4: DFS rate = 27.9%, 95% CI = 15.2 to 51.3; vs I 0-1-2: DFS rate = 12.3%, 95% CI = 4.9 to 30.6; HR = 0.45, 95% CI = 0.28 to 0.70, P = .02; I 3-4: OS rate = 64.6%, 95% CI = 46.6 to 89.6; vs I 0-1-2: OS rate = 32.5%, 95% CI = 17.2 to 61.4; HR = 0.32, 95% CI = 0.15 to 0.66, P = .001, C-index = 65.9%; five-year follow-up, TB score: TB 3-4: DFS rate = 25.7%, 95% CI = 14.2 to 46.6; vs TB 0-1-2: DFS rate = 5.0%, 95% CI = 0.8 to 32.4; HR = 0.36, 95% CI = 0.22 to 0.57, P < .001; TB 3-4: OS rate = 63.7%, 95% CI = 46.4 to 87.5; vs TB 0-1-2: OS rate: 21.4%, 95% CI = 9.2 to 49.8; HR = 0.25, 95% CI = 0.12 to 0.51, P < .001, C-index = 67.8%). High TB score and Immunoscore patients had a median survival of 70.5 months, while low patients survived only 25.1 to 38.3 months. Nonresponding patients with high-immune infiltrates had prolonged DFS (HR = 0.28, 95% CI = 0.15 to 0.52, P = .001) and OS (HR = 0.25, 95% CI = 0.1 to 0.62, P = .001). The immune parameters remained the only statistically significant prognostic factor associated with DFS and OS in multivariable analysis (P < .001), while response to treatment was not.
Response to treatment and prolonged survival of metastatic CRC patients were statistically significantly associated with high-immune densities quantified into the least immune-infiltrated metastasis.
Treatment of metastatic colorectal cancer is based upon the assumption that metastases are homogeneous within a patient. We quantified immune cell types of 603 whole-slide metastases and primary ...colorectal tumors from 222 patients. Primary lesions, and synchronous and metachronous metastases, had a heterogeneous immune infiltrate and mutational diversity. Small metastases had frequently a low Immunoscore and T and B cell score, while a high Immunoscore was associated with a lower number of metastases. Anti-epidermal growth factor receptor treatment modified immune gene expression and significantly increased T cell densities in the metastasis core. The predictive accuracy of the Immunoscore from a single biopsy was superior to the one of programmed cell death ligand 1 (PD-L1). The immune phenotype of the least-infiltrated metastasis had a stronger association with patient outcome than other metastases.
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•Inter- and intra-metastatic immune infiltrates are heterogeneous in colorectal cancer•T cell densities from metastases increase following anti-EGFR treatment•Immunoscore (IS) outperforms PDL1 staining in metastatic biopsy diagnostic accuracy•IS and TB score from the least-infiltrated metastasis are most survival associated
Van den Eynde et al. quantify immune cell types in metastases and primary colorectal tumors. They show that high Immunoscore (IS) associates with fewer metastases, that anti-EGFR treatment significantly increases T cell density in the core of metastases, and that the predictive accuracy of IS better than PDL1.
Surgical resection of colorectal liver metastases combined with systemic treatment aims to maximize patient survival. However, recurrence rates are very high postsurgery. In order to assess patient ...prognosis after metastasis resection, we evaluated the main patho‐molecular and immune parameters of all surgical specimens. Two hundred twenty‐one patients who underwent, after different preoperative treatment, curative resection of 582 metastases were analyzed. Clinicopathological parameters, RAS tumor mutation, and the consensus Immunoscore (I) were assessed for all patients. Overall survival (OS) and time to relapse (TTR) were estimated using the Kaplan–Meier method and compared by log‐rank tests. Cox proportional hazard models were used for uni‐ and multivariate analysis. Immunoscore and clinicopathological parameters (number of metastases, surgical margin, histopathological growth pattern, and steatohepatitis) were associated with relapse in multivariate analysis. Overall, pathological score (PS) that combines relevant clinicopathological factors for relapse, and I, were prognostic for TTR (2‐year TTR rate PS 0–1: 49.8.% (95% CI: 42.2–58.8) versus PS 2–4: 20.9% (95% CI: 13.4–32.8), hazard ratio (HR) = 2.54 (95% CI: 1.82–3.53), p < 0.0000; and 2‐year TTR rate I 0: 25.7% (95% CI: 16.3–40.5) versus I 3–4: 60% (95% CI: 47.2–76.3), HR = 2.87 (95% CI: 1.73–4.75), p = 0.0000). Immunoscore was also prognostic for OS (HR I 3–4 versus I 0 = 4.25, 95% CI: 1.95–9.23; p = 0.0001). Immunoscore (HR I 3–4 versus I 0 = 0.27, 95% CI: 0.12–0.58; p = 0.0009) and RAS mutation (HR mutated versus WT = 1.66, 95% CI: 1.06–2.58; p = 0.0265) were significant for OS. In conclusion, PS including relevant clinicopathological parameters and Immunoscore permit stratification of stage IV colorectal cancer patient prognosis in terms of TTR and identify patients with higher risk of recurrence. Immunoscore remains the major prognostic factor for OS.
Objective
Combined vascular and pancreatic resection improves long-term survival of patients suffering from ductal adenocarcinoma of the pancreatic head. This study was designed to compare the ...results of surgical resection in patients with pancreatic cancer with or without vascular resection. Late 10-year disease-free survival was considered as an indicator of patients’ disease cure.
Methods
A total of 149 consecutive patients have undergone pancreatoduodenectomy without vascular resection (group 1: 82 patients), with isolated venous resection (group B: 67 patients), or with arterial and/or venous resection (group C: 8 patients).
Results
The duration of surgery and blood losses were significantly more important in groups B and C compared with group A; however, postoperative morbidity and mortality rates were similar. R1 resection was significantly more frequent in groups B (42%) and C (50%) compared with group A (13%;
p
= 0.0002), but there were more advanced tumors in these groups, as demonstrated by a lower Karnowsky index, higher Ca 19-9 plasmatic level, greater tumor size, more advanced stage in the AJCC classification, and more tumor location in the uncinate process of the pancreas. Ten-year overall and disease-free survivals were significantly better in group A (19 and 20%) compared with group B (2.8 and 0%) and group C (0% and 0%). Multivariate analysis proved vascular resection and metastatic nodal status as being independent predictive factors of disease-free survival.
Conclusions
Vascular resection combined to pancreatoduodenectomy for pancreatic cancer increases local resectability without increasing mortality and morbidity rates but does not improve patients’ disease cure rate.
Summary
Neuroendocrine tumor (NET) metastases represent at this moment the only accepted indication of liver transplantation (LT) for liver secondaries. Between 1984–2007, nine (1.1%) of 824 adult ...LTs were performed because of NET. There were five well differentiated functioning NETs (four carcinoids and one gastrinoma), three well differentiated non functioning NETs and one poorly differentiated NET. Indications for LT were an invalidating unresectable tumor (4×), and/or a diffuse tumor localization (3×) and/or a refractory hormonal syndrome (5×). Median post‐LT patient survival is 60.9 months (range 4.8–119). One‐, 3‐ and 5‐year actuarial survival rates are 88%, 77% and 33%; 1, 3 and 5 years disease free survival rates are 67%, 33% and 11%. Due to a more rigorous selection procedure, results improved since 2000; three out of five patients are alive disease‐free at 78, 84 and 96 months. Review of these series together with a review of the literature reveals that results of LT for this oncological condition can be improved using better selection criteria, adapted immunosuppression and neo‐ and adjuvant surgical as well as medical tretament. LT should be considered earlier in the therapeutic algorithm of selected NET patients as it is the only therapy that can offer a cure.
Abstract
Background and study aims
Endoscopic submucosal dissection (ESD) has been developed as an option for treatment of esophageal, gastric and colorectal lesions. However, there is no consensus ...on the role of ESD in duodenal tumors.
Methods
This systematic review and meta-analysis compared ESD and endoscopic mucosal resection (EMR) in sporadic non-ampullary superficial duodenal tumors (NASDTs), including local experience. We conducted a search in PubMed, Scopus and the Cochrane library up to August 2017 to identify studies that compared both techniques reporting at least one main outcome (en-bloc/complete resection, local recurrence). Pooled outcomes were calculated under fixed and random-effect models. Subgroup analyses were conducted.
Results
A total of 753 patients presenting with 784 NASDTs (242 ESD, 542 EMR) in 14 studies were included. Tumor size (MD: 5.88, CI95 %: 2.15, 9.62,
P
= 0.002, I
2
= 79 %) and procedure time (MD: 65.65, CI95 %: 40.39, 90.92,
P
< 0.00001, I
2
= 88 %) were greater in the ESD group. En-bloc resection rate was significantly higher in Asian studies (OR: 2.16 CI95 %: 1.15, 4.08,
P
= 0.02, I
2
: 46 %). ESD provided a higher complete resection rate (OR: 1.63 I95 %: 1.06, 2.50,
P
= 0.03, I
2
: 59 %), but there was no risk difference in the risk of local recurrence (RD: – 0.03 CI95 %: – 0.07, 0.01,
P
= 0.15, I
2
: 0 %) or delayed bleeding. ESD was associated with an increased number of intraoperative perforations RD: 0.12 (CI95 %: 0.04, 0.20),
P
= 0.002, I
2
: 56 % and emergency surgery for delayed perforations. The inclusion of eligible studies was limited to retrospective series with inequalities in comparative groups.
Conclusions
Duodenal ESD for NASDTs may achieve higher en-bloc and complete resections at the expense of a greater perforation rate compared to EMR. The impact on local recurrence remains uncertain.
Retrospective studies reported that preoperative oxaliplatin-based chemotherapy increased pathological response (PR) in patients resected for colorectal liver metastases (CRLM). This multicenter ...prospective randomized (1/1) phase II trial evaluated PR on resected CRLM after preoperative mFOLFOX6 (arm A) or FOLFIRI (arm B) + bevacizumab. The primary endpoint was the major pathological response rate (MPRR), defined as the percentage of patients presenting CRLMs with mean tumor regression grade (TRG) < 3. Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). Out of 65 patients, 57 patients (28 and 29 in arm A/B) were resected for CRLM (one patient with lung metastases). Clinical and treatment characteristics were similar in both arms. One-month postoperative complications were 39.3%/31.0% in arm A/B (p = 0.585). MPRR and complete PR were 32.1%/20.7% (p = 0.379) and 14.3%/0.0% (p = 0.052) in arm A/B, respectively. PFS and OS were not different. Patients with PR among all CRLMs (max TRG ≤ 3; 43.8% of patients) had a lower risk of relapse (PFS: HR = 0.41, 95%CI = 0.204−0.840, p = 0.015) and a tendency towards better survival (OS: HR = 0.34, 95%CI = 0.104−1.114, p = 0.075). The homogeneity of PR was associated with improved PFS/OS. This trial fails to demonstrate a significant increase in MPRR in patients treated with mFOLFOX6-bevacizumab but confirms PR as an important prognostic factor.
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