Table 1.
All studies and biomarkers included with modified REMARK score. Prognostic significance is described as N = not significant, U = significant upon univariable analysis, or M = significant upon multivariable analysis. OS, overall survival. RFS, recurrence-free survival. IHC, immunohistochemistry. CA19-9, carbohydrate antigen 19-9. CEA, carcinoembryonic antigen. TAM, tumour-associated macrophages. TEM, Tie2-expressing monocytes. qPCR, quantitative polymerase chain reaction. MLR, monocyte-to-lymphocyte ratio. NLR, neutrophil-to-lymphocyte ratio. PIWIL2, Piwi-like RNA-mediated gene silencing 2. TLR, thrombocyte-to-lymphocyte ratio. P-4E-BP1, phosphor 4E-BP1. ARID1B, AT-Rich interaction domain 1B. RBM10, RNA binding motif protein 10. CYFRA21-1, cytokeratin 19 fragment. MUC5A, mucin 5A. MUC6, mucin 6. OLFM4, olfactomedin 4. PD-L1, programmed death ligand 1. MMP9, matrix metalloproteinase 9. TCF7, transcription factor 7. VEGF, vascular endothelial growth factor. HDGF, hepatoma-derived growth factor. NGAL, neutrophil-gelatinase-associated lipocalin. TROP2, trophoblast cell surface antigen 2. mGPS, modified Glasgow prognostic score. PLR, platelet-to-lymphocyte ratio. PNI, prognostic nutritional index. EGFR, epidermal growth factor. ERCC1, excision repair cross-complementing group 1. TP, thymidine phosphorylase. TP53, tumour protein 53. LMRc, change in lymphocyte-to-monocyte ratio. RPL34, ribosomal protein L34. ALK, anaplastic lymphoma kinase. BRAF, b-raf protein. IDH, isocitrate dehydrogenase. PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha. PBRM1, polybromo 1. CRP, C reactive protein. Gal-3, galectin-3. ALT, alanine transaminase. AST, aspartate transaminase. IL8, interleukin 8. ANXA10, annexin A10. GGT, gamma glutamyl transferase. HMGA2, high mobility group AT-hook 2. CA125, cancer antigen 125. MSLN, mesothelin. NGF, nerve growth factor. CONUT, controlling nutritional status. ALP, alkaline phosphatase.
| Authors | Biomarker | Cutoff | Detection Site | Detection Method | Total Participants with pCCA | Participants with Positive Biomarker | REMARK Score | Prognostic Significance (N/U/M) |
|---|---|---|---|---|---|---|---|---|
| Abdel Wahab et al., 2016 [11] | Albumin | not specified | Serum | not specified | 234 | not specified | 3/6 | N |
| Bilirubin | not specified | Serum | not specified | 234 | not specified | N | ||
| CA19-9 | not specified | Serum | not specified | 234 | not specified | M (OS) | ||
| Atanasov et al., 2016 [12] | TAM | >25% cell density | Tumour | IHC | 45 | 12 | 6/6 | U (OS) M (RFS) |
| Atanasov et al., 2016 [13] | TEM | expression score 2 | Tumour | IHC | 45 | 11 | 6/6 | M (OS) |
| Atanasov et al. 2018 [14] | miR-126 | not specified | Tumour | qPCR | 45 | 18 | 5/6 | U (OS) |
| Bird et al., 2019 [15] | CA19-9 | >46 U/ml | Serum | not specified | 56 | 22 | 5/6 | M (OS) |
| MLR | ≥3 | Serum | not specified | 56 | 31 | N | ||
| NLR | ≥3 | Serum | not specified | 56 | 23 | N | ||
| Cai et al., 2014 [16] | CA19-9 | >150 U/ml | Serum | not specified | 168 | 74 | 5/6 | M (OS) |
| Bilirubin | >10 mg/dL | Serum | not specified | 168 | 96 | N | ||
| Chen P et al., 2016 [17] | CA19-9 | 73.5–325 U/mL | Serum | not specified | 235 | 78 | 5/6 | M (OS) |
| CA19-9 | >325 U/ml | Serum | not specified | 235 | 79 | M (OS) | ||
| Chen W et al., 2015 [18] | Complete vs. partial Wnt pathway activation | Wnt2+/3+ and b-catenin + and TCF4+ vs. Wnt2+/3+ and b-catenin + or TCF4+ |
Tumour | IHC | 129 | 101 | 4/6 | M (OS) |
| Chen YJ et al., 2015 [19] | PIWIL2 | expression score ≥ 4 | Tumour | IHC | 41 | 33 | 5/6 | M (OS + RFS) |
| Cheng et al., 2007 [20] | Bilirubin | >10 mg/dL | Serum | not specified | 75 | not specified | 5/6 | M (OS) |
| Dumitrascu et al., 2013 [21] | Albumin | >4 g/dL | Serum | not specified | 90 | not specified | 4/6 | U (OS + RFS) |
| Bilirubin | >10.4 mg/dl | Serum | not specified | 90 | not specified | U (OS + RFS) | ||
| CA19-9 | >200 U/mL | Serum | not specified | 90 | not specified | U (OS + RFS) | ||
| Haemoglobin | >12.5 mg/dL | Serum | not specified | 90 | not specified | U (OS + RFS) | ||
| Leukocyte count | >8000/mmc | Serum | not specified | 90 | not specified | U (OS + RFS) | ||
| NLR | >3.3 | Serum | not specified | 90 | not specified | U (OS) M (RFS) |
||
| TLR | >184 | Serum | not specified | 90 | not specified | U (OS + RFS) | ||
| Platelets | >312,000/mmc | Serum | not specified | 90 | not specified | U (OS + RFS) | ||
| Fang et al., 2014 [22] | P-4E-BP1 | >25% positive cells | Tumour | IHC | 61 | 31 | 5/6 | U (OS + RFS) |
| Feng et al., 2021 [23] | ARID1B | n/a | Tumour | NGS | 63 | 58 | 5/6 | M (RFS) |
| RBM10 | n/a | Tumour | NGS | 63 | 58 | N | ||
| Hu et al., 2016 [24] | CA19-9 | >100 U/mL | Serum | Not specified | 381 | not specified | 5/6 | U (OS + RFS) |
| Huang et al., 2015 [25] | CYFRA21-1 | >2.27 ng/mL | Serum | ECL | 31 | 22 | 5/6 | U (OS + RFS) |
| Ishida et al., 2019 [26] | MUC5A and MUC6 | <25% expression | Tumour | IHC | 30 | 13 | 6/6 | M (OS) |
| Jun et al., 2020 [27] | OLFM4 | Tumour | IHC | 54 | 14 | 5/6 | N | |
| Kamphues et al., 2015 [28] | DNA index | >1.5 | Tumour | Image cytometry | 154 | 71 | 5/6 | M (OS) |
| Kriegsmann et al., 2019 [29] | PD-L1 | >5% positive cells | Tumour | IHC | 57 | 3 | 5/6 | N |
| Kuriyama et al., 2020 [30] | CA19-9 | ≥25 U/ml | Serum | not specified | 49 | 35 | 6/6 | N |
| CEA | ≥8.5 ng/mL | Serum | not specified | 49 | 7 | M (OS) | ||
| Li et al., 2020 [31] | Albumin | >35 g/L | Blood | not specified | 292 | not specified | 5/6 | U (OS) |
| Mean Platelet Volume | >13 | Blood | not specified | 292 | not specified | U (OS) | ||
| Platelet Distribution Width | >16.55 | Blood | not specified | 292 | 121 | M (OS) | ||
| Platelets | >300 × 109 | Blood | not specified | 292 | not specified | N | ||
| Li et al., 2019 [32] | Bilirubin | >100 mg/L | Blood | not specified | 181 | not specified | 5/6 | N |
| MMP9 | >201.93 ng/mL | Blood | ELISA | 181 | not specified | M (OS) | ||
| Liu et al., 2019 [33] | TCF7 | not specified. Comparison of low vs. high | Tumour | IHC | 160 | 76 | 5/6 | M (OS) |
| Liu et al., 2011 [34] | VEGF | >25% staining | Tumour | IHC | 58 | 42 | 5/6 | M (OS) |
| HDFG | HDGF labelling index > 166.91 | Tumour | IHC | 58 | 27 | U (OS) | ||
| Nair et al., 2018 [35] | NGAL | >345 Histoscore | Tumour | IHC | 54 | not specified | 5/6 | N |
| Ning et al., 2013 [36] | TROP2 | Score > 4 | Tumour | IHC | 70 | 43 | 6/6 | M (OS) |
| Okuno et al., 2016 [37] | mGPS | mGPS ≥ 1 | Serum | not specified | 534 | 112 | 5/6 | M (OS) |
| NLR | ≥3 | Serum | not specified | 534 | 158 | N | ||
| PLR | ≥150 | Serum | not specified | 534 | 359 | N | ||
| PNI | ≥40 | Serum | not specified | 534 | 362 | N | ||
| Park et al., 2015 [38] | C-met | Staining ≥ 30% | Tumour | IHC | 53 | 19 | 5/6 | N |
| EGFR | Staining ≥ 30% | Tumour | IHC | 53 | not specified | N | ||
| VEGF | Staining ≥ 30% | Tumour | IHC | 53 | not specified | N | ||
| Park et al., 2013 [39] | ERCC1 | Staining > 10% | Tumour | IHC | 41 | 9 | 5/6 | N |
| Survivin | Staining > 10% | Tumour | IHC | 41 | 14 | U (OS) | ||
| TP | Staining > 10% | Tumour | IHC | 41 | 25 | N | ||
| TP53 | Staining > 10% | Tumour | IHC | 41 | 18 | N | ||
| Cyclin D1 | Staining > 10% | Tumour | IHC | 41 | 8 | N | ||
| Peng et al., 2020 [40] | LMRc | Postop LMR > preop LMR | Serum | not specified | 254 | 125 | 6/6 | U (OS) M (RFS) |
| Qian et al., 2020 [41] | RPL34 | Expression ≥ 75 | Tumour | IHC | 121 | 94 | 5/6 | M (OS + RFS) |
| Ramacciato et al., 2010 [42] | Albumin | Low < 3 g/dL | Serum | not specified | 30 | 21 | 4/6 | N |
| Bilirubin | >3 mg/dL | Serum | not specified | 30 | 11 | N | ||
| CA19-9 | >400 ng/mL | Serum | not specified | 30 | 17 | N | ||
| CEA | >2 U/L | Serum | not specified | 30 | 18 | N | ||
| Ruzzenente et al., 2016 [43] | ALK | n/a | Tumour | NGS | 18 | 1 | 5/6 | U (OS) |
| BRAF | n/a | Tumour | NGS | 18 | 1 | N | ||
| IDH | n/a | Tumour | NGS | 18 | 2 | M (OS) | ||
| KRAS | n/a | Tumour | NGS | 18 | 12 | N | ||
| PIK3CA | n/a | Tumour | NGS | 18 | 3 | N | ||
| PBRM1 | n/a | Tumour | NGS | 18 | 3 | N | ||
| TP53 | n/a | Tumour | NGS | 18 | 11 | M (OS) | ||
| Saito et al., 2016 [44] | Albumin | <3.5 mg/dL | Serum | not specified | 121 | 26 | 6/6 | M (OS) |
| CRP | >0.5 mg/dL | Tumour | not specified | 121 | 56 | M (OS) | ||
| CA19-9 | >300 U/mL | Tumour | not specified | 121 | 17 | U (OS) | ||
| CEA | >7 ng/mL | Tumour | not specified | 121 | 14 | M (OS) | ||
| PLR | >150 | Tumour | not specified | 121 | 53 | U (OS) | ||
| Shimura et al., 2017 [45] | Gal-3 | >50% staining | Tumour | IHC | 21 | 11 | 6/6 | N |
| Intranuclear Gal-3 | >5% intranuclear staining | Tumour | IHC | 21 | not specified | N | ||
| Su et al., 1996 [46] | ALT | >120 U/L | Serum | not specified | 44 | 13 | 5/6 | N |
| Albumin | <30 mg/L | Serum | not specified | 44 | 45 | N | ||
| AST | >135 U/L | Serum | not specified | 44 | 6 | N | ||
| Bilirubin | >10 mg/dL | Serum | not specified | 44 | 17 | M (OS) | ||
| Sun et al., 2014 [47] | MMP9 | >50% staining | Tumour | IHC | 58 | 27 | 6/6 | M (OS) |
| Sun Q et al., 2015 [48] | IL8 | median score—not specified | Tumour | IHC | 62 | 35 | 6/6 | M (OS) |
| MMP9 | >50% staining | Tumour | IHC | 62 | 29 | M (OS) | ||
| Sun Q et al., 2018 [49] | Pontin | >5% staining | Tumour | IHC | 86 | 34 | 5/6 | M (OS) |
| Sun R et al., 2019 [50] | ANXA10 | >5% staining | Tumour | IHC | 128 | not specified | 5/6 | M (OS) |
| Sun Z et al., 2020 [51] | Albumin | <35 g/L | Serum | not specified | 110 | 173 | 5/6 | M (OS) |
| ALT | ≥80 U/L | Serum | not specified | 110 | 225 | N | ||
| AST | ≥70 U/L | Serum | not specified | 110 | 202 | N | ||
| GGT | ≥90 U/L | Serum | not specified | 110 | 288 | N | ||
| Bilirubin | ≥4 mg/Dl | Serum | not specified | 110 | 242 | M (OS) | ||
| CRP | ≥5 mg/L | Serum | not specified | 110 | 189 | N | ||
| CA19-9 | >0.001 U/mL | Serum | not specified | 110 | not specified | N | ||
| CEA | ≥5 ng/mL | Serum | not specified | 110 | 71 | N | ||
| Takahashi et al., 2021 [52] | HMGA2 | >50% staining | Tumour | IHC | 41 | 21 | 6/6 | M (OS) |
| Takihata et al., 2021 [53] | CA125 and MSLN coexpression | >50% staining | Tumour | IHC | 31 | 15 | 5/6 | U (OS) |
| Thelen et al., 2008 [54] | CD31 | Average count > 20 | Tumour | IHC | 60 | 38 | 5/6 | M (OS) U (RFS) |
| Urabe et al., 2016 [55] | NGF | >30% | Tumour | IHC | 59 | 35 | 5/6 | N |
| Wang et al., 2020 [56] | CA19-9 | >37 ng/ml | Serum | not specified | 94 | not specified | 5/6 | U (OS) |
| CEA | >5 ng/mL | Serum | not specified | 94 | not specified | N | ||
| NLR | >3.6 | Serum | not specified | 94 | 51 | M (OS + RFS) | ||
| PNI | >43.7 | Serum | not specified | 94 | 50 | M (OS + RFS) | ||
| CONUT Score | >3 | Serum | not specified | 94 | 31 | M (OS + RFS) | ||
| Yoo et al., 2021 [57] | ALT | >40 U/L | Serum | not specified | 196 | not specified | 5/6 | N |
| AST | ≥40 U/L | Serum | not specified | 196 | not specified | N | ||
| ALP | >115 U/L | Serum | not specified | 196 | not specified | N | ||
| CA19-9 | >37 U/mL | Serum | not specified | 196 | not specified | M (OS) | ||
| CEA | >5 ng/ml | Serum | not specified | 196 | not specified | N | ||
| Zhao et al., 2020 [58] | Bilirubin | ≥142.4 µmol/L | Serum | not specified | 335 | 168 | 4/6 | M (OS) |
| CA19-9 | ≥1000 U/mL | Serum | not specified | 335 | 68 | U (OS) M (RFS) |
||
| CEA | ≥3.0 ng/mL | Serum | not specified | 335 | 168 | U (RFS) |