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Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study.
Trépo, E, Caruso, S, Yang, J, Imbeaud, S, Couchy, G, Bayard, Q, Letouzé, E, Ganne-Carrié, N, Moreno, C, Oussalah, A, et al
The Lancet. Oncology. 2022;(1):161-171
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Abstract
BACKGROUND Hepatocellular carcinoma is a frequent consequence of alcohol-related liver disease, with variable incidence among heavy drinkers. We did a genome-wide association study (GWAS) to identify common genetic variants for alcohol-related hepatocellular carcinoma. METHODS We conducted a two-stage case-control GWAS in a discovery cohort of 2107 unrelated European patients with alcohol-related liver disease aged 20-92 years recruited between Oct 22, 1993, and March 12, 2017. Cases were patients with alcohol-related hepatocellular carcinoma diagnosed by imaging or histology. Controls were patients with alcohol-related liver disease without hepatocellular carcinoma. We used an additive logistic regression model adjusted for the first ten principal components to assess genetic variants associated with alcohol-related hepatocellular carcinoma. We did another analysis with adjustment for age, sex, and liver fibrosis. New candidate associations (p<1 × 10-6) and variants previously associated with alcohol-related hepatocellular carcinoma were evaluated in a validation cohort of 1933 patients with alcohol-related liver disease aged 29-92 years recruited between July 21, 1995, and May 2, 2019. We did a meta-analysis of the two case-control cohorts. FINDINGS The discovery cohort included 775 cases and 1332 controls. Of 7 962 325 variants assessed, we identified WNT3A-WNT9A (rs708113; p=1·11 × 10-8) and found support for previously reported regions associated with alcohol-related hepatocellular carcinoma risk at TM6SF2 (rs58542926; p=6·02 × 10-10), PNPLA3 (rs738409; p=9·29 × 10-7), and HSD17B13 (rs72613567; p=2·49 × 10-4). The validation cohort included 874 cases and 1059 controls and three variants were replicated: WNT3A-WNT9A (rs708113; p=1·17 × 10-3), TM6SF2 (rs58542926; p=4·06 × 10-5), and PNPLA3 (rs738409; p=1·17 × 10-4). All three variants reached GWAS significance in the meta-analysis: WNT3A-WNT9A (odds ratio 0·73, 95% CI 0·66-0·81; p=3·93 × 10-10), TM6SF2 (1·77, 1·52-2·07; p=3·84×10-13), PNPLA3 (1·34, 1·22-1·47; p=7·30 × 10-10). Adjustment for clinical covariates yielded similar results. We observed an additive effect of at-risk alleles on alcohol-related hepatocellular carcinoma. WNT3A-WNT9A rs708113 was not associated with liver fibrosis. INTERPRETATION WNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt-β-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis. FUNDING Ligue Nationale contre le Cancer, Bpifrance, INSERM, AFEF, CARPEM, Labex OncoImmunology, and Agence Nationale de la Recherche.
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Prediagnostic alterations in circulating bile acid profiles in the development of hepatocellular carcinoma.
Stepien, M, Lopez-Nogueroles, M, Lahoz, A, Kühn, T, Perlemuter, G, Voican, C, Ciocan, D, Boutron-Ruault, MC, Jansen, E, Viallon, V, et al
International journal of cancer. 2022;(8):1255-1268
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Abstract
Bile acids (BAs) play different roles in cancer development. Some are carcinogenic and BA signaling is also involved in various metabolic, inflammatory and immune-related processes. The liver is the primary site of BA synthesis. Liver dysfunction and microbiome compositional changes, such as during hepatocellular carcinoma (HCC) development, may modulate BA metabolism increasing concentration of carcinogenic BAs. Observations from prospective cohorts are sparse. We conducted a study (233 HCC case-control pairs) nested within a large observational prospective cohort with blood samples taken at recruitment when healthy with follow-up over time for later cancer development. A targeted metabolomics method was used to quantify 17 BAs (primary/secondary/tertiary; conjugated/unconjugated) in prediagnostic plasma. Odd ratios (OR) for HCC risk associations were calculated by multivariable conditional logistic regression models. Positive HCC risk associations were observed for the molar sum of all BAs (ORdoubling = 2.30, 95% confidence intervals [CI]: 1.76-3.00), and choline- and taurine-conjugated BAs. Relative concentrations of BAs showed positive HCC risk associations for glycoholic acid and most taurine-conjugated BAs. We observe an association between increased HCC risk and higher levels of major circulating BAs, from several years prior to tumor diagnosis and after multivariable adjustment for confounders and liver functionality. Increase in BA concentration is accompanied by a shift in BA profile toward higher proportions of taurine-conjugated BAs, indicating early alterations of BA metabolism with HCC development. Future studies are needed to assess BA profiles for improved stratification of patients at high HCC risk and to determine whether supplementation with certain BAs may ameliorate liver dysfunction.
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Camrelizumab Combined with FOLFOX4 Regimen as First-Line Therapy for Advanced Hepatocellular Carcinomas: A Sub-Cohort of a Multicenter Phase Ib/II Study.
Li, H, Qin, S, Liu, Y, Chen, Z, Ren, Z, Xiong, J, Meng, Z, Zhang, X, Wang, L, Zhang, X, et al
Drug design, development and therapy. 2021;:1873-1882
Abstract
BACKGROUND Immune checkpoint inhibitors and chemotherapy can synergistically increase efficacy in a variety of malignancies. We conducted this phase Ib/II study to assess the safety and efficacy of anti-PD-1 antibody camrelizumab in combination with FOLFOX4 for treatment-naive advanced hepatocellular carcinoma (aHCC). METHODS This open-label, multicenter phase Ib/II study (NCT03092895) enrolled patients with aHCC and without prior systemic treatment for treatment with camrelizumab (3 mg/kg) and FOLFOX4 every two weeks. First, six patients were enrolled, followed by an additional 28 patients after dose-limiting toxicity cases were determined to be <33% of patients. The primary endpoint was tolerability and safety of treatment. RESULTS A total of 34 aHCC patients were enrolled and received study treatment. No dose-limiting toxicity were observed in the first six patients enrolled. Twenty-nine (85.3%) of the total 34 patients had grade ≥3 treatment-related adverse events (TRAEs), with the most common ones being decreased neutrophil count (55.9%) and decreased white blood cell count (38.2%). No TRAEs-related deaths occurred. The objective response and disease control rate were 29.4% (95% CI, 15.1-47.5) and 79.4% (95% CI, 62.1-91.3), respectively. The median duration of response, progression-free survival, and overall survival was 6.9 months (range, 3.3-11.5), 7.4 months (95% CI, 3.9-9.2), and 11.7 months (95% CI, 8.2-22.0), respectively. CONCLUSION Camrelizumab combined with FOLFOX4 for first-line treatment of patients with aHCC showed good safety and tolerability, with promising preliminary antitumor activity.
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Pediatric Oncology Patients With Vincristine-Induced Recurrent Laryngeal Nerve Palsy: Two Case Reports and a Brief Review of Literature.
Tay, SY, Foster, J, Heczey, A, Sitton, M
Ear, nose, & throat journal. 2021;(10):NP459-NP463
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INTRODUCTION Vincristine (VCR) is a chemotherapeutic agent used widely in the treatment of hematologic and solid tumors, known to result in neurotoxicity, especially with cumulative administrations. Bilateral vocal fold palsy (VFP) is a rare but life-threatening complication of VCR. We report 2 patients with hepatoblastoma presenting with stridor following VCR treatment and propose a management plan. METHODS Electronic medical records of oncology patients treated at a tertiary hospital with VCR-induced VFP were reviewed. Literature review was performed in PubMed using the terms: hoarseness, VFP, stridor, vincristine. RESULTS A total of 23 children with VCR-induced VFP were identified from the literature review and adding on our 2 cases. Seventeen (77.3%) were male and 5 (22.7%) were female. The median presenting age was 36.0 months (5-204 months). Acute lymphoblastic leukemia, 15 of 23 (65.2%), was the most common malignancy. Eighteen patients (78.3%) had bilateral VFP and 5 (21.7%) had unilateral VFP. The mean time to VF function recovery was 167.3 days (median: 200.5 days, range: 7-270 days) in the intervention group versus 72.1 days (median: 31.5 days, range: 3-240 days) in the conservative group. One patient in the intervention group had persistent VFP. Sixteen patients (69.6%) were observed, 4 (17.4%) underwent tracheostomy, 1 (4.35%) was intubated, 1 (4.35%) underwent cordectomy, and 1 (4.35%) required positive pressure support. Vincristine was restarted in 12 patients (54.5%), of which 4 developed recurrence of airway symptoms and had to stop VCR. CONCLUSION A new-onset hoarseness or stridor in a child on VCR should raise the suspicions of VFP. The assumption of an upper respiratory-induced hoarseness or stridor should be avoided. Decisions regarding readministration of VCR and possible airway interventions should be made via a multidisciplinary team approach.
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Magnesium intake is associated with a reduced risk of incident liver cancer, based on an analysis of the NIH-American Association of Retired Persons (NIH-AARP) Diet and Health Study prospective cohort.
Shah, SC, Zhu, X, Dai, Q, Peek, RM, Shrubsole, MJ
The American journal of clinical nutrition. 2021;(3):630-638
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BACKGROUND Liver cancer incidence and mortality are escalating globally. Magnesium intake has been studied extensively in nonmalignant liver pathology, but the association between dietary intake of magnesium and primary liver malignancy has not been previously evaluated. OBJECTIVES We aimed to determine the association between total magnesium intake and primary liver cancer risk. METHODS Using the NIH-American Association of Retired Persons (NIH-AARP) Diet and Health Study prospective cohort, we estimated the association between magnesium intake and the risk of incident primary liver cancer using Cox proportional hazard modeling adjusted for relevant confounders. Comprehensive stratified and sensitivity analyses were performed. RESULTS During 6.4 million person-years of follow-up time, 1067 primary liver cancers occurred in 536,359 participants. Higher magnesium intake was independently associated with a lower risk of liver cancer (P-trend = 0.005), with intakes in the highest compared with lowest quartile associated with 35% lower risk (HR: 0.65; 95% CI: 0.48, 0.87). The dose-related inverse association was more pronounced in moderate and heavy alcohol users (HR: 0.54; 95% CI: 0.35, 0.82; P-trend = 0.006), and this interaction was statistically significant (P-interaction = 0.04). CONCLUSIONS Based on a prospective cohort analysis, we demonstrated that magnesium intake is associated with a lower risk of primary liver cancer, which was more pronounced among moderate and heavy alcohol users. Robust experimental and mechanistic data provide a biological basis to support these findings.
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Targeting CALM2 Inhibits Hepatocellular Carcinoma Growth and Metastasis by Suppressing E2F5-mediated Cell Cycle Progression.
Park, SY, Seo, YR, Ko, MJ, Lee, JH, Chun, KS, Kim, MJ, Choo, YK, Lee, TJ, Lee, YH
Anticancer research. 2021;(3):1315-1325
Abstract
BACKGROUND/AIM: The aim of this study was to reveal the novel roles of calmodulin 2 (CALM2) in hepatocellular carcinoma (HCC) progression. MATERIALS AND METHODS The effects of knockdown of CALM2 expression by siRNA were investigated using various experimental approaches in both cellular and molecular levels. RESULTS Silencing of CALM2 inhibited HCC cell proliferation and colony formation through induction of apoptosis. At the molecular level, CALM2-specific knockdown led to the common dysregulation of 154 genes in HCC cells. Notably, E2F transcription factor 5 (E2F5), which is functionally associated with migration, invasion and proliferation, was generally down-regulated. These functional associations were confirmed in HCC clinical samples. Reflecting the molecular changes, CALM2 knockdown reduced the migration and invasion abilities of HCC cells and abrogated the potency of tumor formation in vivo. CONCLUSION Targeting CALM2 may be a molecular strategy for both primary HCC treatment and prevention of metastasis or recurrence.
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Nutritional considerations for the management of the older person with hepato-pancreatico-biliary malignancy.
Bibby, N, Griffin, O
European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2021;(3 Pt A):533-538
Abstract
Malnutrition and cancer cachexia are prevalent in older people with hepato-pancreatico-biliary (HPB) malignancy, with the resultant loss of muscle mass and function accelerating normal age-associated losses. Unintentional weight loss may be missed in patients with pre-illness obesity, delaying diagnosis and limiting treatment potential and access. Sarcopenia and/or sarcopenic obesity increase the risk of dose-limiting chemotherapy toxicity, post-operative mortality and overall survival. The aetiology of malnutrition and weight loss is multi-factorial in patients with HPB malignancy, necessitating systematic evaluation of endocrine and exocrine function, and multi-modal therapeutic strategies. Prehabilitation aims to reduce the complications and side effects associated with treatment, aid recovery and improve quality of life, with the greatest benefits potentially being seen in high risk groups, such as people who are older and frail. Post-operatively, individualised nutritional support therapies targeting the preservation of weight and muscle indices are required to improve post-operative morbidity, and avoid delay or early cessation of any necessary adjuvant therapy.
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The use of nanotechnology to combat liver cancer: Progress and perspectives.
Mintz, KJ, Leblanc, RM
Biochimica et biophysica acta. Reviews on cancer. 2021;(2):188621
Abstract
Liver cancer is one of the most common cancers worldwide and is also one of the most difficult cancers to treat, resulting in almost one million deaths per year, and the danger of this cancer is compounded when the tumor is nonresectable. Hepatocellular carcinoma (HCC) is the most common type of liver cancer and has the third highest mortality rate worldwide. Considering the morbid statistics surrounding this cancer it is a popular research topic to target for better therapy practices. This review summarizes the role of nanotechnology in these endeavors. Nanoparticles (NPs) are a very broad class of material and many different kinds have been used to potentially combat liver cancer. Gold, silver, platinum, metal oxide, calcium, and selenium NPs as well as less common materials are all inorganic NPs that have been used as a therapeutic, carrier, or imaging agent in drug delivery systems (DDS) and these efforts are described. Carbon-based NPs, including polymeric, polysaccharide, and lipid NPs as well as carbon dots, have also been widely studied for this purpose and the role they play in DDS for the treatment of liver cancer is illustrated in this review. The multifunctional nature of many NPs described herein, allows these systems to display high anticancer activity in vitro and in vivo and highlights the advantage of and need for combinatorial therapy in treating this difficult cancer. These works are summarized, and future directions are presented for this promising field.
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A Phase 1 dose-escalation study of disulfiram and copper gluconate in patients with advanced solid tumors involving the liver using S-glutathionylation as a biomarker.
Kelley, KC, Grossman, KF, Brittain-Blankenship, M, Thorne, KM, Akerley, WL, Terrazas, MC, Kosak, KM, Boucher, KM, Buys, SS, McGregor, KA, et al
BMC cancer. 2021;(1):510
Abstract
BACKGROUND Disulfiram and metals inactivate key oncoproteins resulting in anti-neoplastic activity. The goal of this study was to determine the maximum tolerated dose of copper when administered with disulfiram in patients with advanced solid tumors and liver involvement. METHODS Disulfiram 250 mg was administered daily in 28-day cycles. Four doses of copper gluconate were tested (2, 4, 6, and 8 mg of elemental copper) in a standard 3 + 3 dose escalation design. Patients were evaluated for dose limiting toxicities and response. Protein S-glutathionylation was evaluated as a pharmacodynamic marker. RESULTS Twenty-one patients were enrolled and 16 patients were evaluable for dose limiting toxicities. Among the 21 patients, there was a median of 4 lines of prior chemotherapy. Five Grade 3 toxicities were observed (anorexia, elevated aspartate aminotransferase or AST, elevated alkaline phosphatase, fever, and fatigue). Response data was available for 15 patients. Four patients had stable disease with the longest duration of disease control being 116 days. The median duration of treatment for evaluable patients was 55 days (range 28-124). Reasons for discontinuation included functional decline, disease progression, and disease-associated death. Increased S-glutathionylation of serum proteins was observed with treatment. CONCLUSION Disulfiram 250 mg daily with copper gluconate (8 mg of elemental copper) was well-tolerated in patients with solid tumors involving the liver and was not associated with dose limiting toxicities. While temporary disease stabilization was noted in some patients, no objective responses were observed. Treatment was associated with an increase in S-glutathionylation suggesting that this combination could exert a suppressive effect on cellular growth and protein function. TRIAL REGISTRATION NCT00742911 , first posted 28/08/2008.
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The effectiveness of enteral nutrition for patients with primary liver cancer: A randomized controlled study protocol.
Wang, L, Wang, X, Wang, X
Medicine. 2021;(3):e23973
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OBJECTIVE The objective of this study is to explore the influence of the enteral nutrition on primary liver cancer patients after receiving hepatectomy. METHOD This is a prospective randomized controlled research, which will be conducted between April 2021 and April 2022. Approval is obtained from the Research Ethics Committee of Chun’ an County First People's Hospital (A20201108). Patients who meet the following conditions will be included in this experiment: (1).. the patients aged 18 to 70 years; (2).. in line with clinical diagnostic criteria for primary liver cancer; (3).. planned liver resection for primary liver cancer; (4).. liver function status of Child-Pugh A. Patients with the following characteristics are excluded: (1).. a history of other malignancy; (2).. mental disorder; (3).. severe diabetes or poor glycemic control; (4).. serious complications: bleeding and bile leakage; (5).. poor medical condition: renal failure, respiratory or heart failure. Our investigation includes sixty patients who meet our inclusion criteria. The primary endpoints are length of postoperative hospital stay and liver function index. The secondary results involve the first flatus time and the first defecation time. RESULTS Table 1 indicates the postoperative outcomes between treatment group and control group. CONCLUSION Enteral nutrition can improve recovery in the primary liver cancer patients after receiving hepatectomy. TRIAL REGISTRATION The protocol has been registered in Research Registry (researchregistry6275)