Exosome Shedding Is Concordant with Objective Treatment Response Rate and Stratifies Time to Progression in Treatment Naïve, Non-Resectable Hepatocellular Carcinoma
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patient Cohort
2.2. Primary Outcome
2.3. Blood Collection
2.4. Exosome Isolation and Identification
2.5. Imaging Flow Cytometry Parameters
2.6. Statistical Analysis
3. Results
3.1. Protocol Setup for Detection of EXs Using Imaging Flow Cytometry
3.2. Patient Demographics
3.3. EX Shedding Following LDT
3.4. Prognostic Factors Associated with EX Shedding Following LDT
3.5. Post-LDT EX Shedding and TTP
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Demographic | Cohort |
---|---|
Patients, n (%) | 43 (100) |
Age at diagnosis, years (IQR) | 61 (58–68) |
Sex, male (%) | 33 (76) |
Race, n (%) | |
Caucasian | 25 (58) |
African American | 12 (28) |
Other | 6 (14) |
Cirrhotic Etiology, n (%) | |
HCV | 20 (47) |
NASH | 10 (23) |
Other | 13 (30) |
Cirrhosis Status at Diagnosis, n (%) | |
Compensated | 35 (81) |
Decompensated | 8 (19) |
Scores and Staging | |
ECOG Performance Status of 0, n (%) | 33 (77) |
Child–Pugh of A, n (%) | 39 (91) |
BCLC Stage A, n (%) | 39 (91) |
Clinical Hepatology Labs | |
Sodium, mM (IQR) | 138 (137–141) |
Creatinine, mg/dL (IQR) | 0.9 (0.8–1.1) |
Bilirubin, mg/dL (IQR) | 0.9 (0.5–1.2) |
Albumin, g/dL (IQR) | 3.5 (3.1–3.8) |
INR, ratio (IQR) | 1.1 (1.0–1.2) |
MELD-Na, score (IQR) | 8 (7–10) |
Tumour Burden and Biomarkers | |
Largest lesion, cm (IQR) | 2.7 (2.2–4.2) |
Cumulative lesion, cm (IQR) | 3.4 (2.4–4.7) |
Milan, within criteria (%) | 38 (88) |
AFP, ng/mL (IQR) | 15 (6.6–44) |
First-Line Liver-Directed Therapy | |
DEE-TACE, (%) | 4 (9) |
90Y, n (%) | 23 (53) |
MWA, n (%) | 16 (37) |
Treatment Response to First-Line LDT | |
ORR | 34 (79) |
Non-ORR | 9 (21) |
Study Endpoint | |
Active, n (%) | 21 (49) |
Tumor progression, n (%) | 8 (19) |
Transplanted, n (%) | 14 (32) |
EXosome Shedding | Baseline | Post-LDT | p Value |
---|---|---|---|
EXs by marker, median (IQR) | |||
CD9+ | 7.2 × 106 (3.8 × 106–17.4 × 106) | 10.7 × 106 (4.3 × 106–20.7 × 106) | 0.545 |
CD63+ | 0.5 × 106 (0.3 × 106–1.1 × 106) | 0.7 × 106 (0.4 × 106–0.9 × 106) | 0.734 |
Double positive, CD9+ CD63+ | 0.08 × 106 (0.03 × 106–0.2 × 106) | 0.1 × 106 (0.05 × 106–0.4 × 106) | 0.632 |
Exosome Shedding Group | |||
CD9+ EXs, n (%) | 0.042 | ||
High | 16 (41) | 20 (50) | |
Low | 23 (59) | 20 (50) | |
CD63+ EXs, n (%) | 0.004 | ||
High | 17 (44) | 20 (50) | |
Low | 22 (56) | 20 (50) | |
Double positive, CD9+ CD63+ EXs, n (%) | 0.015 | ||
High | 17 (44) | 20 (50) | |
Low | 22 (56) | 20 (50) |
CD9+ EXs | |||
---|---|---|---|
Demographic | High | Low | p Value |
Age at diagnosis, median (IQR) | 61 (58–67) | 62 (55–68) | 0.926 |
Sex, male, n (%) | 17 (85) | 14 (70) | 0.252 |
Race, n (%) | 0.180 | ||
Caucasian | 13 (65) | 10 (50) | |
African American | 3 (15) | 8 (40) | |
Other | 4 (20) | 2 (10 | |
Cirrhotic etiology, n (%) | 0.066 | ||
HCV | 11 (55) | 8 (40) | |
NASH | 3 (15) | 7 (35) | |
Other | 6 (30) | 5 (25) | |
Cirrhosis status at diagnosis, n (%) | 0.427 | ||
Compensated | 15 (75) | 17 (85) | |
Decompensated | 5 (25) | 3 (15) | |
Scores and Staging | |||
ECOG performance status 0, n (%) | 15 (75) | 15 (75) | 1.0 |
Child–Pugh A, n (%) | 17 (85) | 19 (95) | 0.282 |
BCLC HCC stage A, n (%) | 20 (100) | 17 (85) | 0.036 |
Clinical Hepatology Labs | |||
Sodium | 138 (137–141) | 139 (136–140) | 0.866 |
Creatinine | 1.0 (0.8–1.1) | 0.9 (0.8–1.2) | 0.219 |
Bilirubin | 0.7 (0.5–1.0) | 1.1 (0.6–1.3) | 0.181 |
Albumin | 3.8 (3.1–4.1) | 3.4 (3.1–3.6) | 0.901 |
INR | 1.1 (1.0–1.3) | 1.1 (1.0–1.2) | 0.184 |
MELD-Na | 8 (7–10) | 9 (7–11) | 0.527 |
Tumor Burden and Biomarkers | |||
Largest lesion | 2.7 (2.3–3.6) | 3.1 (2.2–4.8) | 0.187 |
Cumulative lesion | 3.0 (2.3–4.7) | 3.8 (2.6–4.8) | 0.233 |
Milan criteria | 19 (95) | 17 (85) | 0.282 |
AFP | 7.8 (4.0–38) | 21 (8.2–75) | 0.067 |
First-Line Liver-Directed Therapy | 0.066 | ||
DEE-TACE, n (%) | 2 (10) | 0 (0) | |
90Y, n (%) | 8 (40) | 14 (70) | |
MWA, n (%) | 10 (50) | 6 (30) | |
Treatment Response to First-Cycle LDT | 0.030 | ||
ORR, n (%) | 19 (95) | 14 (70) | |
Non-ORR, n (%) | 1 (5) | 6 (30) | |
Study Endpoint | <0.001 | ||
Tumor progression, n (%) | 0 (0) | 7 (78) | |
Transplanted, n (%) | 10 (100) | 2 (22) |
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Núñez, K.G.; Wyczechowska, D.; Hibino, M.; Sandow, T.; Gimenez, J.; Koksal, A.R.; Aydin, Y.; Dash, S.; Cohen, A.J.; Thevenot, P.T. Exosome Shedding Is Concordant with Objective Treatment Response Rate and Stratifies Time to Progression in Treatment Naïve, Non-Resectable Hepatocellular Carcinoma. Livers 2023, 3, 727-738. https://doi.org/10.3390/livers3040047
Núñez KG, Wyczechowska D, Hibino M, Sandow T, Gimenez J, Koksal AR, Aydin Y, Dash S, Cohen AJ, Thevenot PT. Exosome Shedding Is Concordant with Objective Treatment Response Rate and Stratifies Time to Progression in Treatment Naïve, Non-Resectable Hepatocellular Carcinoma. Livers. 2023; 3(4):727-738. https://doi.org/10.3390/livers3040047
Chicago/Turabian StyleNúñez, Kelley G., Dorota Wyczechowska, Mina Hibino, Tyler Sandow, Juan Gimenez, Ali R. Koksal, Yucel Aydin, Srikanta Dash, Ari J. Cohen, and Paul T. Thevenot. 2023. "Exosome Shedding Is Concordant with Objective Treatment Response Rate and Stratifies Time to Progression in Treatment Naïve, Non-Resectable Hepatocellular Carcinoma" Livers 3, no. 4: 727-738. https://doi.org/10.3390/livers3040047