Immune checkpoint blockade has demonstrated remarkable efficacy in hepatocellular carcinoma (HCC) but is also commonly accompanied by immune‐related adverse events (irAEs). However, the association ...between irAEs and antitumor efficacy in HCC patients remains unknown. All patients with HCC treated with anti‐PD‐1 antibodies from July 2018 to November 2019 were analyzed and divided into different groups according to their irAEs' status. In total, 101 HCC patients, including 21 (20.8%) patients who presented with irAEs (irAEs+), were enrolled. Among the adverse events, rash (n = 9, 8.9%) was the most frequent irAE, followed by mucositis (n = 3, 3.0%) and thyroiditis (n = 3, 3.0%). Patients in the irAEs+ group showed a higher tumor response rate than those in the irAEs− group (overall response rate: 28.6% vs 6.3%, P = .011; disease control rate: 85.7% vs 60.0%, P = .028). The median progression‐free survival (PFS) times were 14.8 months in the irAEs+ group and 4.1 months in the irAEs− group (P < .001). Further analysis based on the presence or absence of rash showed that the PFS of the patients in the irAEs+/rash+ group was better than that of those in the irAEs+/rash− or irAEs− group (all P < .05). Multivariate analysis showed that irAEs were an independent prognostic factor for PFS (hazard ratio HR: 0.22, P = .002). Thus, the occurrence of irAEs, especially rash, was associated with markedly improved PFS. Awareness of irAEs may help classify the subtype of HCC patients with an unprecedented survival benefit from anti‐PD‐1 antibodies.
What's new?
While anti‐program death receptor‐1 (anti‐PD‐1) antibodies produce clinical responses in patients with hepatocellular carcinoma (HCC), variations in efficacy and in the occurrence of adverse events present significant challenges in the clinical management of HCC. In the present study, the authors show that in HCC patients treated with anti‐PD‐1 antibodies, the development of immune‐related adverse events (irAEs), notably rash, is associated with improved progression‐free survival. The marked association between irAEs and treatment response suggests that irAEs could be used to predict survival in anti‐PD‐1 antibody‐treated HCC patients and could facilitate HCC subtype classification in patients who experience striking survival benefits.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
Microvascular invasion (MVI) is a risk factor for tumor recurrence after hepatectomy in hepatocellular carcinoma (HCC) patients.
Objective
This study aimed to investigate the efficacy and ...safety of postoperative adjuvant transarterial infusion chemotherapy (TAI) with the FOLFOX regimen for HCC patients with MVI.
Methods
In this prospective, phase III, randomized, open-label, controlled clinical trial, HCC patients with histologically confirmed MVI were randomly assigned (1:1) after hepatectomy to receive either one to two cycles of adjuvant TAI (AT group) or follow-up without any adjuvant treatment (FU group). The primary endpoint was disease-free survival (DFS), while secondary endpoints were overall survival (OS) and safety.
Results
Between June 2016 and April 2019, 127 patients were randomly assigned to the AT group (
n
= 63) or FU group (
n
= 64). Clinicopathological characteristics of the two groups were well-balanced. The 6-, 12-, and 18-month OS rates for the AT group were 100.0%, 97.7%, and 97.7%, respectively, and 94.5%, 89.6%, and 78.5% for the FU group, respectively. The 6-, 12-, and 18-month DFS rates for the AT and FU groups were 84.7%, 61.8%, and 58.7%, and 62.9%, 48.1%, and 38.6%, respectively. OS and DFS were significantly better in the AT group than in the FU group (
p
= 0.037 and 0.023, respectively). No patients in the AT group experienced grade 3 or more severe adverse events.
Conclusions
Adjuvant TAI after hepatectomy may bring survival benefits to HCC patients with MVI.
Trial registration
Trial number: NCT03192618.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Long non-coding RNAs (lncRNA) have an essential role in progression and chemoresistance of hepatocellular carcinoma (HCC). In-depth study of specific regulatory mechanisms is of great value in ...providing potential therapeutic targets. The present study aimed to explore the regulatory functions and mechanisms of lncRNA TINCR in HCC progression and oxaliplatin response.
The expression of TINCR in HCC tissues and cell lines was detected by quantitative reverse transcription PCR (qRT-PCR). Cell proliferation, migration, invasion, and chemosensitivity were evaluated by cell counting kit 8 (CCK8), colony formation, transwell, and apoptosis assays. Luciferase reporter assays and RNA pulldown were used to identify the interaction between TINCR and ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) via miR-195-3p. The corresponding functions were verified in the complementation test and in vivo animal experiment.
TINCR was upregulated in HCC and associated with poor patient prognosis. Silencing TINCR inhibited HCC proliferation, migration, invasion, and oxaliplatin resistance while overexpressing TINCR showed opposite above-mentioned functions. Mechanistically, TINCR acted as a competing endogenous (ceRNA) to sponge miR-195-3p, relieving its repression on ST6GAL1, and activated nuclear factor kappa B (NF-κB) signaling. The mouse xenograft experiment further verified that knockdown TINCR attenuated tumor progression and oxaliplatin resistance in vivo.
Our finding indicated that there existed a TINCR/miR-195-3p/ST6GAL1/NF-κB signaling regulatory axis that regulated tumor progression and oxaliplatin resistance, which might be exploited for anticancer therapy in HCC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Serum C-reactive protein (CRP) is a biomarker of an acute inflammatory response and has been successfully used as a prognostic predictor for several malignancies. However, the clinicopathological ...significance of CRP levels in hepatocellular carcinoma (HCC) patients being treated with PD-1 inhibitors remains unclear.
Serum CRP levels were measured for a total of 101 HCC patients that had been treated with PD-1 inhibitors from July 2018 to November 2019. The clinicopathological data was retrospectively analyzed to identify any clinical implications between CRP levels and responses to PD-1 inhibitors and patients' progression-free survival (PFS).
The median PFS was 8.87 months in the CRP-low subgroup and 3.67 months in the CRP-high subgroup (
0.009). Univariate and multivariate Cox regression analysis demonstrated that both serum CRP and AFP levels were independent risk factors for the PFS of HCC patients treated with PD-1 inhibitors (
< 0.05). Moreover, Cox regression analysis after Propensity Score Matching showed the similar results. A prognostic model combining CRP and AFP levels could significantly stratify HCC patients receiving PD-1 inhibitors into low-, intermediate-, and high-risk subgroups (
< 0.001). Patients in the risk subgroups reported similar overall response rates (
0.625) and significantly different disease control rates (low- vs. intermediate- vs. high-risk groups: 81.6% vs. 65.1% vs. 35%, respectively,
0.002).
The results of this study support the association between high serum CRP levels with the response and PFS for HCC patients receiving PD-1 inhibitors. Furthermore, the levels of both CRP and AFP in an HCC patient before treatment initiation show great potential for determining the efficacy of PD-1 inhibitors.
Background
Vessels that encapsulate tumor clusters (VETC) is a novel described vascular pattern different from microvascular invasion (MVI) for patients with hepatocellular carcinoma (HCC). The ...prognostic value of integrating VETC and MVI (VETC-MVI model) in HCC patients after resection remains unclear.
Methods
From January 2013 to December 2016, 498 HCC patients who underwent curative resection were enrolled from five academic centers and stratified into different groups according to their VETC and MVI statuses. Overall survival (OS), disease-free survival (DFS), and early and late recurrence rates were evaluated.
Results
The patients were divided into four subgroups: VETC
−
/MVI
−
(
n
= 277, 55.6%), VETC
−
/MVI
+
(
n
= 110, 22.1%), VETC
+
/MVI
−
(
n
= 53, 10.6%), and VETC
+
/MVI
+
(
n
= 58, 11.6%). The patients in the VETC
+
/MVI
−
and VETC
−
/MVI
+
groups had similar long-term outcomes (OS:
p
= 0.402; DFS:
p
= 0.990), VETC
−
/MVI
−
patients showed the best prognosis, and VETC
+
/MVI
+
patients had the worst prognosis. Further analysis revealed that the VETC-MVI model showed a similar stratification ability for early recurrence but not for late recurrence. The area under the curve values for early recurrence was 0.70, 0.63 and 0.64 for the VETC-MVI model, VETC, and MVI, respectively (VETC-MVI model
vs
VETC:
p
< 0.001; VETC-MVI model
vs
MVI:
p
= 0.004; VETC
vs
MVI:
p
= 0.539). Multivariate Cox regression analysis showed that the VETC-MVI model successfully predicted OS, DFS and early recurrence.
Conclusions
VETC status provides additional discriminative information for patients with either MVI
−
or MVI
+
. A combination of VETC and MVI may help classify subtypes and predict the prognosis of HCC patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Vessels that encapsulate tumor cluster (VETC) is associated with poor prognosis in hepatocellular carcinoma (HCC). Vessels that encapsulate tumor cluster estimation before initial ...treatment is helpful for clinical doctors. We aimed to construct a novel predictive model for VETC, using preoperatively accessible clinical parameters and imagine features.
Methods
Totally, 365 HCC patients who received curative hepatectomy in the Sun Yat-Sen University Cancer Center from 2013 to 2014 were enrolled in this study. Vessels that encapsulate tumor cluster pattern was confirmed by immunochemistry staining. 243 were randomly assigned to the training cohort while the rest was assigned to the validation cohort. Independent predictive factors for VETC estimation were determined by univariate and multivariate logistic analysis. We further constructed a predictive nomogram for VETC in HCC. The performance of the nomogram was evaluated by C-index, receiver operating characteristic (ROC) curve, and calibration curve. Besides, the decision curve was plotted to evaluate the clinical usefulness. Ultimately, Kaplan–Meier survival curves were utilized to confirm the association between the nomogram and survival.
Results
Immunochemistry staining revealed VETC in 87 patients (23.8%). lymphocyte to monocyte ratio (>7.75, OR = 4.06), neutrophil (>7, OR = 4.48), AST to ALT ratio (AAR > .86, OR = 2.16), ALT to lymphocyte ratio index (BLRI > 21.73, OR = 2.57), alpha-fetoprotein (OR = 1.1), and tumor diameter (OR = 2.65) were independent predictive factors. The nomogram incorporating these predictive factors performed well with an area under the curve (AUC) of .746 and .707 in training and validation cohorts, respectively. Calibration curves indicated the predicted probabilities closely corresponded with the actual VETC status. Moreover, the decision curve proved our nomogram could provide clinical benefits with patients. Finally, low probability of VETC group had significantly longer recurrence free survival (RFS) and overall survival (OS) than the high probability of the VETC group (all P < .001).
Conclusion
A novel predictive nomogram integrating clinical indicators and image characteristics shows strong predictive VETC performance and might provide standardized net clinical benefits.
In recent years, metabolic reprogramming has been identified as a hallmark of cancer. Accumulating evidence suggests that glutamine metabolism plays a crucial role in oncogenesis and the tumor ...microenvironment. In this study, we aimed to perform a systematic and comprehensive analysis of six key metabolic node genes involved in the dynamic regulation of glutamine metabolism (referred to as GLNM regulators) across 33 types of cancer.
We analyzed the gene expression, epigenetic regulation, and genomic alterations of six key GLNM regulators, including
,
,
,
,
, and
, in pan-cancer using several open-source platforms and databases. Additionally, we investigated the impacts of these gene expression changes on clinical outcomes, drug sensitivity, and the tumor microenvironment. We also attempted to investigate the upstream microRNA-mRNA molecular networks and the downstream signaling pathways involved in order to uncover the potential molecular mechanisms behind metabolic reprogramming.
We found that the expression levels of GLNM regulators varied across cancer types and were related to several genomic and immunological characteristics. While the immune scores were generally lower in the tumors with higher gene expression, the types of immune cell infiltration showed significantly different correlations among cancer types, dividing them into two clusters. Furthermore, we showed that elevated GLNM regulators expression was associated with poor overall survival in the majority of cancer types. Lastly, the expression of GLNM regulators was significantly associated with PD-L1 expression and drug sensitivity.
The elevated expression of GLNM regulators was associated with poorer cancer prognoses and a cold tumor microenvironment, providing novel insights into cancer treatment and possibly offering alternative options for the treatment of clinically refractory cancers.
Immunocheckpoint inhibitors have shown significant efficacy in the treatment of hepatocellular carcinoma (HCC), but there are individual differences. The aim of this study was to explore body mass ...index (BMI) as a predictor of anti-PD-1 efficacy in patients with HCC. We retrospectively analyzed 101 HCC patients who treated with anti-PD-1 at Sun Yat-sen University Cancer Center from July 2018 to November 2019 and divided them into overweight (BMI > 24.9) and non-overweight (BMI ≤ 24.9) groups based on baseline BMI levels. BMI > 24.9 accounted for 22 cases (21.8%) and BMI ≤ 24.9 accounted for 79 cases (78.2%) in the study cohort. Overweight patients had higher disease control rates than non-overweight patients (
P
= 0.019, respectively). The mean progression-free survival (PFS) in overweight patients (10.23 months) was significantly longer than that of non-overweight patients (6.85 months;
P
= 0.027). Among patients with immune-related adverse events (irAEs), the mean PFS was also significantly longer in overweight patients (7.72 months) than in non-overweight patients (5.31 months,
P
= 0.034). Multivariate analysis showed that BMI was an independent prognostic factor for PFS in HCC patients treated with anti-PD-1 (hazard ratio: 0.47,
P
= 0.044). Thus, higher BMI predicts a better prognosis among HCC patients treated with anti-PD-1. In clinical practice, patients' BMI can provide a useful tool for predicting the efficacy of anti-PD-1 therapy.
Purpose
For hepatocellular carcinoma (HCC) located in the left lateral lobe, the optimal surgical procedure is still controversial. This study aimed to optimize surgical strategies and to construct a ...nomogram to predict the postoperative survival of patients with HCC.
Methods
Between 1 January 2005 and 30 September 2018, a total of 493 patients were enrolled. Propensity score matching (PSM) was performed between the left lateral lobectomy (LLL) and left hepatectomy (LH) groups (1:1). The study endpoints were overall survival (OS), recurrence‐free survival (RFS), and safety. A nomogram was generated using a multivariate Cox proportional hazards model. The discriminative ability and calibration of the nomogram were evaluated using C‐statistics and calibration plots.
Results
After matching, 87 pairs were included. The LH group had better 1‐, 3‐, and 5‐year OS rates than the LLL group (88%, 73%, and 69% vs. 73%, 57%, and 49%, respectively; p = 0.017). The 1‐, 3‐, and 5‐year RFS rates of the LH group were similar to those of the LLL group (64%, 49%, and 46% vs. 63%, 51%, and 42%, respectively; p = 0.652). There were no significant differences in postoperative complications. Eight factors were integrated into the nomogram and it had good discriminative ability and calibration.
Conclusion
Our data revealed that compared to LLL, LH may result in better OS and have similar postoperative complications for HCC. The nomogram may serve as a practical tool for the individual prognostic evaluation of patients with HCC.
Left hepatectomy is a more feasible and safer surgical approach for the treatment of HCC in the left lateral lobe. The proposed nomograms can provide patient‐specific survival information for patients with HCC in the left lateral lobe after surgery.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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