Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality, and healthcare expenditure in patients with chronic liver disease in India. The Indian National Association for Study of the Liver (INASL) had published its first guidelines on diagnosis and management of HCC (The Puri Recommendations) in 2014, and these guidelines were very well received by the healthcare community involved in diagnosis and management of HCC in India and neighboring countries. However, since 2014, many new developments have taken place in the field of HCC diagnosis and management, hence INASL endeavored to update its 2014 consensus guidelines. A new Task Force on HCC was constituted that reviewed the previous guidelines as well as the recent developments in various aspects of HCC that needed to be incorporated in the new guidelines. A 2-day round table discussion was held on 5th and 6th May 2018 at Puri, Odisha, to discuss, debate, and finalize the revised consensus statements. Each statement of the guideline was graded according to the Grading of Recommendations Assessment Development and Evaluation system with minor modifications. We present here the 2019 Update of INASL Consensus on Prevention, Diagnosis, and Management of Hepatocellular Carcinoma in India: The Puri-2 Recommendations. Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality, and healthcare expenditure in patients with chronic liver disease in India. The Indian National Association for Study of the Liver (INASL) had published its first guidelines on diagnosis and management of HCC (The Puri Recommendations) in 2014, and these guidelines were very well received by the healthcare community involved in diagnosis and management of HCC in India and neighboring countries. However, since 2014, many new developments have taken place in the field of HCC diagnosis and management, hence INASL endeavored to update its 2014 consensus guidelines. A new Task Force on HCC was constituted that reviewed the previous guidelines as well as the recent developments in various aspects of HCC that needed to be incorporated in the new guidelines. A 2-day round table discussion was held on 5th and 6th May 2018 at Puri, Odisha, to discuss, debate, and finalize the revised consensus statements. Each statement of the guideline was graded according to the Grading of Recommendations Assessment Development and Evaluation system with minor modifications. We present here the 2019 Update of INASL Consensus on Prevention, Diagnosis, and Management of Hepatocellular Carcinoma in India: The Puri-2 Recommendations. Primary liver cancer or hepatocellular carcinoma (HCC) is one of the major causes of mortality among patients with chronic liver disease.1Kumar A. Acharya S.K. Singh S.P. et al.The Indian national association for study of the liver (INASL) consensus on prevention, diagnosis and management of hepatocellular carcinoma in India: the Puri recommendations.J Clin Exp Hepatol. 2014; 4: S3-S26https://doi.org/10.1016/j.jceh.2014.04.003Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar The incidence and prevalence of HCC is rising in India, mainly because of the epidemic of non-alcoholic fatty liver disease and is poised to become the leading cause of cancer in India.2Three year report of PBCR 2012-2014. http://ncdirindia.org/NCRP/ALL_NCRP_REPORTS/PBCR_REPORT_2012_2014/ALL_CONTENT/Printed_Version.htm. Accessed August 12, 2018.Google Scholar,3Younossi Z. Stepanova M. 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Singh S.P. et al.The Indian national association for study of the liver (INASL) consensus on prevention, diagnosis and management of hepatocellular carcinoma in India: the Puri recommendations.J Clin Exp Hepatol. 2014; 4: S3-S26https://doi.org/10.1016/j.jceh.2014.04.003Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar) in 2014, and these guidelines were very well received by the healthcare community involved in diagnosis and management of HCC in India and neighboring countries. However, since 2014 many new developments have taken place in the field of HCC diagnosis and management, hence INASL endeavored to update its 2014 consensus guidelines. A new Task Force on HCC. For the development of these revised guidelines, the task force reviewed the previous guidelines as well as the recent developments that have happened in various aspects of HCC that needed to be incorporated in the new guidelines. A 2-day round table discussion was held on 5th and 6th May 2018 at Puri, Odisha, to discuss, debate, and finalize the revised consensus statements. Each topic was discussed considering the most relevant data available in literature and the final consensus statements were formulated according to both scientific evidence and clinical expertise of the involved physicians. Only those statements were accepted which were unanimously approved by the majority of the members of the taskforce. Each statement of the guideline was graded according to the Grading of Recommendations Assessment Development and Evaluation (GRADE) system with minor modifications.12Atkins D. Best D. Briss P.A. et al.Grading quality of evidence and strength of recommendations.BMJ. 2004; 328: 1490https://doi.org/10.1136/bmj.328.7454.1490Crossref PubMed Google Scholar The strength of recommendations (strong or weak) thus reflects the quality (grade) of underlying evidence (I, II-1, II-2, II-3, and III) (Table 1).Table 1Modified Grading of Recommendations, Assessment, Development and Evaluation (GRADE).Quality of evidenceCriteriaIRandomized controlled trialsII-1Controlled trials without randomizationII-2Cohort or case-control analytical studiesII-3Multiple time series, dramatic uncontrolled experimentsIIIOpinions of respected authorities, descriptive epidemiologyStrength of recommendationsCriteriaStrongFactors influencing the strength of the recommendation included the quality of the evidence, presumed patient-important outcomes, and costWeakVariability in preferences and values, or more uncertainty. Recommendation is made with less certainty, higher cost, or resource consumption Open table in a new tab HCC is among the leading causes of cancer death globally.11European Association for the Study of the LiverElectronic address: [email protected], European association for the study of the liver. EASL clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol. 2018; 69: 182-236https://doi.org/10.1016/j.jhep.2018.03.019Abstract Full Text Full Text PDF PubMed Scopus (741) Google Scholar According to the Global Burden of Disease Study 2015, there were 854,000 incident cases of and 810,000 deaths due to liver cancer globally in 2015, contributing to 20,578,000 disability-adjusted life-years. Number of cases with incident liver cancer increased by 75% between 1990 and 2015; of this, 47% can be explained by changing population age structures, 35% by population growth, and −8% to changing age-specific incidence rates. The male-to-female ratio for age-standardized liver cancer mortality was 2.8. Globally, hepatitis B virus (HBV) is estimated to account for 33% of liver cancer deaths, alcohol for 30%, hepatitis C virus (HCV) for 21%, and other causes for 16%; these relative figures show substantial variation between countries.13Akinyemiju T. Abera S. et al.Global Burden of Disease Liver Cancer CollaborationThe burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015.JAMA Oncol. 2017; 3: 1683-1691https://doi.org/10.1001/jamaoncol.2017.3055Crossref PubMed Scopus (241) Google Scholar Data on the epidemiology of HCC from India are sparse and of variable and uncertain quality. Data on incidence of HCC as reported by various population-based registries across the country show a marked (>30-fold) variation in crude and age-adjusted incidence rates of HCC. However, it is uncertain whether the data from these different registries can be directly compared. Estimates based on these data suggest that crude incidence rate of HCC in India in the year 2015 was 2.8 cases per 100,000 population per year (males: 3.9, females: 1.6), and the crude mortality rate was 2.7 per 100,000 population per year.2Three year report of PBCR 2012-2014. http://ncdirindia.org/NCRP/ALL_NCRP_REPORTS/PBCR_REPORT_2012_2014/ALL_CONTENT/Printed_Version.htm. Accessed August 12, 2018.Google Scholar The registry data also suggest a slight increase in the incidence of HCC over time, but whether this reflects a true increase remains uncertain. In the only observational study, incidence of HCC in patients with cirrhosis was 1.6 per 100 person-years of follow-up, with fairly wide confidence intervals (CIs) (0.55–2.64).14Paul S.B. Sreenivas V. Gulati M.S. et al.Incidence of hepatocellular carcinoma among Indian patients with cirrhosis of liver: an experience from a tertiary care center in northern India.Indian J Gastroenterol Off J Indian Soc Gastroenterol. 2007; 26: 274-278PubMed Google ScholarTabled 1Consensus statementsLevelGrade•Data on epidemiology of HCC from India are sparse and of variable and uncertain quality.•The available data suggest that crude incidence rate of HCC in India is 2.8 cases per 100,000 population per year (males: 3.9, females: 1.6), and crude mortality rate is around 2.7 per 100,000 population per year.II-2•One study reported the incidence of HCC in patients with cirrhosis is 1.6 per 100 person-years, with wide uncertainty bounds (95% CI: 0.55–2.64).II-2 Open table in a new tab Cirrhosis due to any cause may be complicated by development of HCC. The risk is higher in persons with cirrhosis due to chronic viral hepatitis than that due to other causes. 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Barbàra M. et al.A meta-analysis of single HCV-untreated arm of studies evaluating outcomes after curative treatments of HCV-related hepatocellular carcinoma.Liver Int Off J Int Assoc Study Liver. 2017; 37: 1157-1166https://doi.org/10.1111/liv.13357Crossref PubMed Scopus (33) Google Scholar A subsequent meta-analysis showed that there is no evidence that HCC occurrence or recurrence is different between patients receiving DAA or interferon (IFN) therapy.37Waziry R. Hajarizadeh B. Grebely J. et al.Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression.J Hepatol. 2017; 67: 1204-1212https://doi.org/10.1016/j.jhep.2017.07.025Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar In fact, sustained virological response (SVR) post DAA reduces the incidence of HCC. Cirrhosis, low albumin, low platelet, and alpha-fetoprotein (AFP) level posttreatment are indicators of high HCC occurrence even after SVR.38Guarino M. Sessa A. Cossiga V. et al.Direct-acting antivirals and hepatocellular carcinoma in chronic hepatitis C: a few lights and many shadows.World J Gastroenterol. 2018; 24: 2582-2595https://doi.org/10.3748/wjg.v24.i24.2582Crossref PubMed Scopus (16) Google Scholar Long-term follow-up studies are required to assess surveillance strategy in patients treated with DAA. Chronic alcohol consumption is an important risk factor for HCC development. However, the incidence of HCC associated with alcoholic cirrhosis is lower than the incidence associated with cirrhosis of other etiologies, including chronic HCV, chronic HBV, and hereditary hemochromatosis. It appears that the linkage between compensated alcoholic liver disease-associated cirrhosis and HCC is medium to high risk, with the risk increasing with age and with quantity and duration of alcohol consumption and is more pronounced in females. Studies evaluating HCC risk in patients with cirrhosis associated exclusively with alcohol consumption (with no evidence of ongoing viral hepatitis infection) have suggested that the 10-year cumulative incidence may range from 6.8 to 28.7%.39Joshi K. Kohli A. Manch R. Gish R. Alcoholic liver disease: high risk or low risk for developing hepatocellular carcinoma?.Clin Liver Dis. 2016; 20: 563-580https://doi.org/10.1016/j.cld.2016.02.012Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar There is increasing evidence from observational studies suggests that DM is an important risk factor for HCC. In a systematic review of 26 case–control and cohort studies, diabetes was associated significantly with HCC in 16 studies with a pooled odds ratio of 2.5. The significant association between HCC and diabetes was independent of alcohol use or viral hepatitis.40El-Serag H.B. Hampel H. Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence.Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2006; 4: 369-380https://doi.org/10.1016/j.cgh.2005.12.007Abstract Full Text Full Text PDF PubMed Scopus (558) Google Scholar Presence of diabetes mellitus has also been shown to increase the risk of HCC in patients with chronic HCV and HBV infection.19Dyal H.K. Aguilar M. 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Study Design: A perspective case control study. Introduction and background data:The degenerative spine disease is a very common but complicated to treat and is prevalent in regions of Russia.The past decade has been witnessed with an increasing interest in evaluating the outcomes of medical care.Outcome research focuses on the meticulous measurement of symptoms, functional status, patient satisfaction with treatment, and health care costs associated with spinal treatment options.Whatsoever, no specific method exists that analyzes the effectiveness of the surgical procedures employed. Purpose of study:To find out the early outcomes after lumber discectomy for lumbar degenerative spine disease in the patients at 6 months post-operative period. Methods:The study was performed on 75 patients (mean age of 43.8±9.2years) who had undergone lumber discectomy for lumbar degenerative spine disease in their pre and six months post-operative stages of treatment.The outcomes were measured using modified ODI, VAS ( for both leg pain and back pain). Results:The questionnaire pertaining to severity of pain (VAS) and ODI was compared in the pre-operative and postoperative stages and was evaluated using paired 't test'.It was also noted that there was a significant change with reference to variables like pain severity in VAS and general well-being in ODI.It was also noted that 75% of the study population indicated that their pain was rapidly getting better in the post-operative stages; whereas only 2% of them indicated that their pain got worst even after the treatment. Conclusion:From the findings it was evident that most of the patients indicated that they benefitted with the surgery for the spine disorders.The results will be useful and more accurate information could be provided to the patients.It also facilitates in the development of changes in the clinical practice of spine disorders.
Abstract Background and Aim Plasma‐exchange (PE) has improved survival in acute liver failure by ameliorating systemic inflammatory response syndrome (SIRS). We evaluated PE and compared it to Fractional Plasma Separation and Adsorption (FPSA) and standard medical treatment (SMT) in a large multinational cohort of ACLF patients. Methods Data were prospectively collected from the AARC database and analysed. Matching by propensity risk score (PRS) was performed. Competing risk survival analysis was done to identify deaths because of multiorgan failure (MOF). In a subset of 10 patients, we also evaluated the mechanistic basis of response to PE. Results ACLF patients (n = 1866, mean age 44.3 ± 12.3 yrs, 93% males, 65% alcoholics) received either artificial liver support (ALS) (n = 162); [PE (n = 131), FPSA (n = 31)] or were continued on standard medical therapy (SMT) (n = 1704). In the PRS‐matched cohort (n = 208, [ALS‐119; PE‐94, FPSA‐25)], SMT‐89). ALS therapies were associated with a significantly higher resolution of SIRS (Odd's ratio 9.23,3.42‐24.8), lower and delayed development of MOF (Hazard ratio 7.1, 4.5‐11.1), and lower liver‐failure‐related deaths as compared to FPSA and SMT ( P < .05). PE cleared inflammatory cytokines, damage‐associated molecular patterns, and endotoxin in all patients. Responders improved monocyte phagocytic function and mitochondrial respiration and increased the anti‐inflammatory cytokine interleukin‐1 receptor antagonist (IL‐1RA) compared to non‐responders. PE was associated with lesser adverse effects as compared to FPSA. Conclusions PE improves systemic inflammation and lowers the development of MOF in patients with ACLF. Plasma‐exchange provides significant survival benefit over FPSA and could be a preferred modality of liver support for ACLF patients.
Abstract Objective Activation of NF-κB alongside STAT3 by IL-6 plays major role in inflammation-induced disease pathophysiology. Here, we report the mechanism of downregulation of NF-κB and JAK-STAT pathways by pinoresinol in IL6-induced macrophages. Methods Bioinformatic analysis screened Pinoresinol, among 100 dietary polyphenols, as the most potent to interact with the proteins in NF-κB and JAK-STAT cascades. The effect of pinoresinol on IL-6-activated p65 NF-κB and STAT3 and their regulators was studied by immunoblotting. Localization of the transcription factors were investigated by immunofluorescence and fractionation studies. Effect of pinoresinol on the downstream genes of the NF-κB and JAK-STAT pathways was studied by RT-PCR or immunoblotting. Biological implication this inhibition was shown by attenuation of cellular adhesion and migration. Results Pinoresinol repressed IL-6-mediated activation and nuclear translocation of both p65 NF-κB and STAT3. It reduced the phosphorylation of IKK and IκB-α, and degradation of the latter. The expressions of downstream genes e.g. IL-1β, TNF-α, and COX-2 were also attenuated following pinoresinol treatment. The polyphenol reduced the IL-6-mediated macrophage adhesion and migration, which was supported by downregulation of VCAM-1, ICAM-1, MCP-1, MMP-9 and MMP-2 in pinoresinol-treated cells. Conclusion Pinoresinol targets NF-κB and JAK-STAT pathways to attenuate IL-6-induced inflammatory condition which highlights its potential as a candidate for anti-inflammatory therapy.
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