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- Trepo, E., et al.
(författare)
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Association Between the PNPLA3 (rs738409 C > G) Variant and Hepatocellular Carcinoma: Evidence From a Meta-Analysis of Individual Participant Data
- 2014
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Ingår i: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 0270-9139. ; 59:6, s. 2170-2177
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Tidskriftsartikel (refereegranskat)abstract
- The incidence of hepatocellular carcinoma (HCC) is increasing in Western countries. Although several clinical factors have been identified, many individuals never develop HCC, suggesting a genetic susceptibility. However, to date, only a few single-nucleotide polymorphisms have been reproducibly shown to be linked to HCC onset. A variant (rs738409 C>G, encoding for p.I148M) in the PNPLA3 gene is associated with liver damage in chronic liver diseases. Interestingly, several studies have reported that the minor rs738409[G] allele is more represented in HCC cases in chronic hepatitis C (CHC) and alcoholic liver disease (ALD). However, a significant association with HCC related to CHC has not been consistently observed, and the strength of the association between rs738409 and HCC remains unclear. We performed a meta-analysis of individual participant data including 2,503 European patients with cirrhosis to assess the association between rs738409 and HCC, particularly in ALD and CHC. We found that rs738409 was strongly associated with overall HCC (odds ratio [OR] per G allele, additive model = 1.77; 95% confidence interval [CI]: 1.42-2.19; P = 2.78 x 10(-7)). This association was more pronounced in ALD (OR = 2.20; 95% CI: 1.80-2.67; P = 4.71 x 10(-15)) than in CHC patients (OR = 1.55; 95% CI: 1.03-2.34; P = 3.52 x 10(-2)). After adjustment for age, sex, and body mass index, the variant remained strongly associated with HCC. Conclusion: Overall, these results suggest that rs738409 exerts a marked influence on hepatocarcinogenesis in patients with cirrhosis of European descent and provide a strong argument for performing further mechanistic studies to better understand the role of PNPLA3 in HCC development.
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| 2. |
- Marchesi, F, et al.
(författare)
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COVID-19 in adult acute myeloid leukemia patients: a long-term follow-up study from the European Hematology Association survey (EPICOVIDEHA)
- 2023
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 108:1, s. 22-33
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Tidskriftsartikel (refereegranskat)abstract
- Patients with acute myeloid leukemia (AML) are at high risk of dying from coronavirus disease 2019 (COVID-19). The optimal management of AML patients with COVID-19 has not been established. Our multicenter study included 388 adult AML patients diagnosed with COVID-19 between February 2020 and October 2021. The vast majority were receiving or had received AML treatment in the preceding 3 months. COVID-19 was severe in 41.2% and critical in 21.1% of cases. The chemotherapeutic schedule was modified in 174 patients (44.8%), delayed in 68 and permanently discontinued in 106. After a median follow-up of 325 days, 180 patients (46.4%) had died; death was attributed to COVID-19 (43.3%), AML (26.1%) or to a combination of both (26.7%), whereas in 3.9% of cases the reason was unknown. Active disease, older age, and treatment discontinuation were associated with death, whereas AML treatment delay was protective. Seventy-nine patients had a simultaneous AML and COVID-19 diagnosis, with better survival when AML treatment could be delayed (80%; P<0.001). Overall survival in patients with a diagnosis of COVID-19 between January 2020 and August 2020 was significantly lower than that in patients diagnosed between September 2020 and February 2021 and between March 2021 and September 2021 (39.8% vs. 60% vs. 61.9%, respectively; P=0.006). COVID-19 in AML patients was associated with a high mortality rate and modifications of therapeutic algorithms. The best approach to improve survival was to delay AML treatment, whenever possible.
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- Peccatori, J, et al.
(författare)
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Prognostic factors for survival in patients with advanced renal cell carcinoma undergoing nonmyeloablative allogeneic stem cell transplantation
- 2005
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Ingår i: Cancer. - : Wiley. - 1097-0142 .- 0008-543X. ; 104:10, s. 2099-2103
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. The objective of this study was to identify prognostic factors for predicting survival in patients with advanced renal cell carcinoma (RCC) who had undergone an allogeneic stem cell transplantation after failure on immunotherapy. METHODS. The authors Studied 70 patients with advanced RCC Who underwent allogeneic transplantation with a fludarabine-based, reduced-intensity regimen. Ten parameters were analyzed at the time of transplantation for their power to predict Survival. Clinical features were examined first univariately; then, variables that were correlated significantly with Survival in the univariate analysis were included in a multivariate Cox regression model. RESULTS. Factors that were found to be associated significantly with limited survival were performance Status, the number of metastatic sites, the presence of mediastinal metastasis, hemoglobin level, C-reactive protein (CRP) level, lactate dehydrogenase (LDH) level, and neutrophil counts. All these variables were included in a multivariate Cox regression model, and three were retained in the final model. Patients were classified according to the score estimated by the final Cox model in two groups (above or below the median Value): The median Survival was 3.5 months for patients who had a poor prognosis patients versus 23 months for patients who had a good prognosis. CONCLUSIONS. The Current findings suggested that three easily available parameters (performance status, CRP level, and LDH level) could be used to stratify patients with advanced RCC who are candidates for allografting and to assist clinicians in decision-making and selection of an appropriate treatment program.
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- Buch, S., et al.
(författare)
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Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study
- 2023
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 72:2, s. 381-391
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Tidskriftsartikel (refereegranskat)abstract
- Objective Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. Design Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case-control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). Results Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41x10(-9), OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94x10(-5), OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12x10(-44)). Conclusion This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.
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- Donati, B., et al.
(författare)
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MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Nonalcoholic fatty liver disease (NAFLD) represents an emerging cause of hepatocellular carcinoma (HCC), especially in non-cirrhotic individuals. The rs641738 C > T MBOAT7/TMC4 variant predisposes to progressive NAFLD, but the impact on hepatic carcinogenesis is unknown. In Italian NAFLD patients, the rs641738 T allele was associated with NAFLD-HCC (OR 1.65, 1.08-2.55; n = 765), particularly in those without advanced fibrosis (p < 0.001). The risk T allele was linked to 3'-UTR variation in MBOAT7 and to reduced MBOAT7 expression in patients without severe fibrosis. The number of PNPLA3, TM6SF2, and MBOAT7 risk variants was associated with NAFLD-HCC independently of clinical factors (p < 0.001), but did not significantly improve their predictive accuracy. When combining data from an independent UK NAFLD cohort, in the overall cohort of non-cirrhotic patients (n = 913, 41 with HCC) the T allele remained associated with HCC (OR 2.10, 1.33-3.31). Finally, in a combined cohort of non-cirrhotic patients with chronic hepatitis C or alcoholic liver disease (n = 1121), the T allele was independently associated with HCC risk (OR 1.93, 1.07-3.58). In conclusion, the MBOAT7 rs641738 T allele is associated with reduced MBOAT7 expression and may predispose to HCC in patients without cirrhosis, suggesting it should be evaluated in future prospective studies aimed at stratifying NAFLD-HCC risk.
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- Salameh, H., et al.
(författare)
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PNPLA3 Gene Polymorphism Is Associated With Predisposition to and Severity of Alcoholic Liver Disease
- 2015
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Ingår i: American Journal of Gastroenterology. - : Ovid Technologies (Wolters Kluwer Health). - 0002-9270. ; 110:6, s. 846-856
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The genetic polymorphism with an isoleucine-to-methionine substitution at position 148 (rs738409 C>G) in the patatin-like phospholipase domain protein 3 (PNPLA3) gene confers risk of steatosis. PNPLA3 polymorphism is shown to be associated with alcoholic liver disease (ALD). We performed a systematic review and meta-analysis to examine association of this genetic polymorphism with ALD spectrum and its severity. METHODS: Medline, Embase, and Cochrane Library were searched for studies on association of PNPLA3 polymorphism and ALD spectrum: alcoholic fatty liver (AFL), alcoholic liver injury (ALI), alcoholic cirrhosis (AC), and hepatocellular carcinoma (HCC). Pooled data are reported as odds ratio (OR) with 95% confidence interval. Heterogeneity was assessed using the I 2 statistics and publication bias using Egger's test and Begg and Mazumdar's test. Individual participant data obtained from five studies were used for subgroup analyses. RESULTS: Among 10 studies included in this pooled analysis, compared with controls, OR for rs738409 CG and GG among ALI patients was 1.45 (1.24-1.69) and 2.22 (1.50-3.28), respectively, compared with CC. Respective OR among AC patients was 2.09 (1.79-2.44) and 3.37 (2.49-4.58) and among AC patients with HCC was 2.87 (1.61-5.10) and 12.41 (6.99-22.03). Data for AFL were inconsistent. Among ALD patients, OR of CG and GG genotypes was 2.62 (1.73-3.97) and 8.45 (2.52-28.37), respectively, for AC compared with fatty liver (FL) patients. Similar OR for AC compared with ALI was 1.98 (1.24-3.17) and 3.86 (1.18-12.60). The OR for CG and GG genotypes among AC patients for HCC occurrence was 1.43 (0.76-2.72) and 2.81 (1.57-5.01), respectively. Individual participant data analysis showed age to predispose to AC among ALI patients. CONCLUSIONS: PNPLA3 genetic polymorphism (rs738409 C>G) is associated with increased risk for the entire spectrum of ALD among drinkers including ALI, AC, and HCC. Studies are needed to clarify association of PNPLA3 polymorphism and steatosis in alcoholics. PNPLA3 gene may potentially be a therapeutic target in ALD.
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| 33. |
- Freislederer, P., et al.
(författare)
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Recent advanced in Surface Guided Radiation Therapy
- 2020
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Ingår i: Radiation oncology (London, England). - : Springer Science and Business Media LLC. - 1748-717X. ; 15:1
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Forskningsöversikt (refereegranskat)abstract
- The growing acceptance and recognition of Surface Guided Radiation Therapy (SGRT) as a promising imaging technique has supported its recent spread in a large number of radiation oncology facilities. Although this technology is not new, many aspects of it have only recently been exploited. This review focuses on the latest SGRT developments, both in the field of general clinical applications and special techniques.SGRT has a wide range of applications, including patient positioning with real-time feedback, patient monitoring throughout the treatment fraction, and motion management (as beam-gating in free-breathing or deep-inspiration breath-hold). Special radiotherapy modalities such as accelerated partial breast irradiation, particle radiotherapy, and pediatrics are the most recent SGRT developments.The fact that SGRT is nowadays used at various body sites has resulted in the need to adapt SGRT workflows to each body site. Current SGRT applications range from traditional breast irradiation, to thoracic, abdominal, or pelvic tumor sites, and include intracranial localizations.Following the latest SGRT applications and their specifications/requirements, a stricter quality assurance program needs to be ensured. Recent publications highlight the need to adapt quality assurance to the radiotherapy equipment type, SGRT technology, anatomic treatment sites, and clinical workflows, which results in a complex and extensive set of tests.Moreover, this review gives an outlook on the leading research trends. In particular, the potential to use deformable surfaces as motion surrogates, to use SGRT to detect anatomical variations along the treatment course, and to help in the establishment of personalized patient treatment (optimized margins and motion management strategies) are increasingly important research topics. SGRT is also emerging in the field of patient safety and integrates measures to reduce common radiotherapeutic risk events (e.g. facial and treatment accessories recognition).This review covers the latest clinical practices of SGRT and provides an outlook on potential applications of this imaging technique. It is intended to provide guidance for new users during the implementation, while triggering experienced users to further explore SGRT applications.
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| 35. |
- Gahrton, G, et al.
(författare)
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Role of stem cell transplantation in myeloma
- 2005
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Ingår i: Hematology (Amsterdam, Netherlands). - : Informa UK Limited. - 1024-5332 .- 1607-8454. ; 1010 Suppl 1, s. 127-128
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| 39. |
- Mauri, Davide, et al.
(författare)
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Next-Generation Sequencing of Circulating Tumor DNA Can Optimize Second-Line Treatment in RAS Wild-Type Metastatic Colorectal Cancer after Progression on anti-EGFR Therapy : Time to Rethink Our Approach
- 2022
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Ingår i: Oncology Research and Treatment. - : S. Karger. - 2296-5270 .- 2296-5262. ; 45:4, s. 216-220
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Tidskriftsartikel (refereegranskat)abstract
- Background: Management of Ras wild-type colorectal cancer (CRC) patients upon disease progression after the successful use of targeted treatment with anti-EGFR monoclonal antibodies and backbone chemotherapy remains a clinical challenge.Summary: Development of treatment resistance with prevalence of preexisting RAS mutated clones, RAS mutation conversion, truncation of extracellular receptor domains as well as HER2 and MET amplification are molecular events that can be difficult to follow without the use of sophisticated laboratory techniques. The clinical hurdle of re-biopsy and tumor heterogeneity can be overcome by the implementation of next-generation sequencing (NGS) to analyze circulating tumor DNA (ctDNA) and identify druggable mutations or recovery of RAS-wildness. In this opinion paper, we summarize with critical thinking the clinical approach to be followed after the failure of first-line treatment in Ras wild-type CRC tumors with the use of NGS. Rechallenge with anti-EGFR inhibitors, in case of persistent or recovery of RAS-wildness, and targeted approach of specific mutations (BRAF inhibitors), amplifications (anti-Her2 treatment), or fusion proteins (NTRK inhibitors) can by guided by the use of NGS. The use of NGS platforms for serial analysis of ctDNA is an important step to better understand the molecular landscape of metastatic CRC and guide clinical decisions.Key Messages: NGS should be considered a mainstay in clinical practice for the management of CRC patients and health authorities should consider reimbursing its use in the appropriate clinical settings.
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| 40. |
- Valenti, L., et al.
(författare)
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PNPLA3 I148M variant and hepatocellular carcinoma: A common genetic variant for a rare disease
- 2013
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Ingår i: Digestive and Liver Disease. - : Elsevier BV. - 1590-8658. ; 45:8, s. 619-624
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Tidskriftsartikel (refereegranskat)abstract
- Hepatocellular carcinoma (HCC) is highly associated with chronic liver disease. The rs738409 genetic variant in the patatin-like phospholipase domain-containing 3 (PNPLA3, adiponutrin) gene has been implicated as a genetic determinant of the entire spectrum of liver diseases, ranging from steatosis, chronic hepatitis, cirrhosis and ultimately to HCC. In this review, first we will examine the current genetic theories of disease susceptibility. Next, we will analyze the evidences for the association between PNPLA3 I148M variant and HCC. Moreover, we will exploit this association to propose a new paradigm in human genetics: a common genetic variant contributing to a rare disease. Finally, we will examine the molecular genetics of PNPLA3 and, specifically, the theories that have been proposed to explain the function of PNPLA3 in health and disease. (C) 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
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