Management of the Hepatic Lymph Nodes during Resection of Liver Metastases from Colorectal Cancer: A Systematic Review

Background. Hepatic lymph node involvement is generally considered a contraindication for liver resection performed for colorectal liver metastases. However, some advocate hepatic lymphadenectomy in the presence of macroscopic involvement and others routine lymphadenectomy. The aim of this review is to assess the role of lymphadenectomy in resection of liver metastases from colorectal cancer. Methods. Medline, Embase and Central databases were searched using a formal search strategy. Trials with survival data with a minimum follow-up of 1 year were considered for inclusion. Meta-analysis was performed using Revman. Results. A total of 4230 references were identified. Ten reports of nine studies including 926 patients qualified for the review. The prevalence of nodal metastases after routine lymphadenectomy was 16.3%. The overall 3-year and 5-year survival rates in node-positive patients were 9/151 (11.3%) and 2/137 (1.5%), respectively, compared to 3-year and 5-year survival rates of 424/787 (53.9%) and 246/767 (32.1%) in node-negative patients. The odds ratios for 3-year and 5-year survivals in node positive disease compared to node-negative disease were 0.12 (95% CI 0.06 to 0.24) and 0.08 (95% CI 0.03 to 0.22). There was no randomized controlled trial which assessed the survival benefit of routine or “selective” lymphadenectomy. Conclusion. Currently, there is no evidence of survival benefit for routine or selective lymphadenectomy. Survival rates are low in patients with positive lymph nodes draining the liver irrespective of whether they are detected by routine lymphadenectomy or by macroscopic involvement. Further trials in this patient group are required

Treatment options for resectable hypopharyngeal squamous cell carcinoma: A systematic review and meta-analysis of randomized controlled trials

BACKGROUND: There is uncertainty in the treatment options for resectable hypopharyngeal squamous cell carcinoma. METHODS: A systematic review of randomised controlled trials (RCTs) was performed. Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, Science Citation Index, and Conference Proceedings databases and trial registries were searched until November 2020 for randomized controlled trials performed on resectable hypopharyngeal squamous cell carcinoma. Two systematic review authors independently identified studies and extracted data. The primary outcomes evaluated were overall survival, disease-free survival, any recurrence, local recurrence, loco-regional recurrence, distal recurrence and laryngectomy-free survival. The secondary outcomes were response rates following neoadjuvant treatment and comparison of treatment-related toxicity. Assessment of risk of bias was performed for the selected studies using Cochrane's tool for assessing risk of bias. The studies were evaluated for the quality of evidence using GRADE (Grading of Recommendations, Assessment, Development and Evaluations). Risk ratios (RR), rate ratios, and hazard ratios (HR) were calculated along with 95% confidence intervals (95% CI). The Meta-analysis was performed using a random-effects model. RESULTS: Five RCTs met the inclusion criteria for this review. The risk of bias was unclear or high for the trials. Non-organ preservation(n = 140) versus organ preservation (n = 144) (two trials): no statistically significant difference could be identified for any of the primary outcomes. Concurrent chemoradiotherapy (n = 37) versus sequential chemotherapy followed by radiotherapy (n = 34) (one trial): no statistically significant difference was noted between the two treatment arms for overall survival, disease-free survival and loco-regional recurrence. Laryngectomy-free survival was found to be superior in concurrent chemoradiotherapy arm (HR:0.28, 95% CI 0.13, 0.57). Induction chemotherapy followed by concurrent chemoradiotherapy (n = 53) versus induction chemotherapy followed by radiotherapy (n = 60) (one trial): no statistically significant difference was noted between the treatment arms for overall survival, disease-free survival and laryngectomy-free survival. Preoperative radiotherapy (n = 24) versus postoperative radiotherapy (n = 23) (one trial): overall survival was found to be better in the postoperative radiotherapy arm (HR:2.44, 95% CI1.18, 5.03). No statistically significant difference was noted in terms of treatment-related toxicity. CONCLUSIONS: There are considerable uncertainties in the management of resectable hypopharyngeal cancer. TRAIL REGISTRATION: PROSPERO registration: CRD42019155613

Treatment for hepatorenal syndrome in people with decompensated liver cirrhosis: a network meta‐analysis

Background: Hepatorenal syndrome is defined as renal failure in people with cirrhosis in the absence of other causes. In addition to supportive treatment such as albumin to restore fluid balance, the other potential treatments include systemic vasoconstrictor drugs (such as vasopressin analogues or noradrenaline), renal vasodilator drugs (such as dopamine), transjugular intrahepatic portosystemic shunt (TIPS), and liver support with molecular adsorbent recirculating system (MARS). There is uncertainty over the best treatment regimen for hepatorenal syndrome. Objectives: To compare the benefits and harms of different treatments for hepatorenal syndrome in people with decompensated liver cirrhosis. Search methods: We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trial registers until December 2018 to identify randomised clinical trials on hepatorenal syndrome in people with cirrhosis. Selection criteria: We included only randomised clinical trials (irrespective of language, blinding, or publication status) in adults with cirrhosis and hepatorenal syndrome. We excluded randomised clinical trials in which participants had previously undergone liver transplantation. Data collection and analysis: Two authors independently identified eligible trials and collected data. The outcomes for this review included mortality, serious adverse events, any adverse events, resolution of hepatorenal syndrome, liver transplantation, and other decompensation events. We performed a network meta‐analysis with OpenBUGS using Bayesian methods and calculated the odds ratio (OR), rate ratio, hazard ratio (HR), and mean difference (MD) with 95% credible intervals (CrI) based on an available‐case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. Main results: We included a total of 25 trials (1263 participants; 12 interventions) in the review. Twenty‐three trials (1185 participants) were included in one or more outcomes. All the trials were at high risk of bias, and all the evidence was of low or very low certainty. The trials included participants with liver cirrhosis of varied aetiologies as well as a mixture of type I hepatorenal syndrome only, type II hepatorenal syndrome only, or people with both type I and type II hepatorenal syndrome. Participant age ranged from 42 to 60 years, and the proportion of females ranged from 5.8% to 61.5% in the trials that reported this information. The follow‐up in the trials ranged from one week to six months. Overall, 59% of participants died during this period and about 35% of participants recovered from hepatorenal syndrome. The most common interventions compared were albumin plus terlipressin, albumin plus noradrenaline, and albumin alone. There was no evidence of a difference in mortality (22 trials; 1153 participants) at maximal follow‐up between the different interventions. None of the trials reported health‐related quality of life. There was no evidence of differences in the proportion of people with serious adverse events (three trials; 428 participants), number of participants with serious adverse events per participant (two trials; 166 participants), proportion of participants with any adverse events (four trials; 402 participants), the proportion of people who underwent liver transplantation at maximal follow‐up (four trials; 342 participants), or other features of decompensation at maximal follow‐up (one trial; 466 participants). Five trials (293 participants) reported number of any adverse events, and five trials (219 participants) reported treatment costs. Albumin plus noradrenaline had fewer numbers of adverse events per participant (rate ratio 0.51, 95% CrI 0.28 to 0.87). Eighteen trials (1047 participants) reported recovery from hepatorenal syndrome (as per definition of hepatorenal syndrome). In terms of recovery from hepatorenal syndrome, in the direct comparisons, albumin plus midodrine plus octreotide and albumin plus octreotide had lower recovery from hepatorenal syndrome than albumin plus terlipressin (HR 0.04; 95% CrI 0.00 to 0.25 and HR 0.26, 95% CrI 0.07 to 0.80 respectively). There was no evidence of differences between the groups in any of the other direct comparisons. In the network meta‐analysis, albumin and albumin plus midodrine plus octreotide had lower recovery from hepatorenal syndrome compared with albumin plus terlipressin. Funding: two trials were funded by pharmaceutical companies; five trials were funded by parties who had no vested interest in the results of the trial; and 18 trials did not report the source of funding. Authors' conclusions: Based on very low‐certainty evidence, there is no evidence of benefit or harm of any of the interventions for hepatorenal syndrome with regards to the following outcomes: all‐cause mortality, serious adverse events (proportion), number of serious adverse events per participant, any adverse events (proportion), liver transplantation, or other decompensation events. Low‐certainty evidence suggests that albumin plus noradrenaline had fewer 'any adverse events per participant' than albumin plus terlipressin. Low‐ or very low‐certainty evidence also found that albumin plus midodrine plus octreotide and albumin alone had lower recovery from hepatorenal syndrome compared with albumin plus terlipressin. Future randomised clinical trials should be adequately powered; employ blinding, avoid post‐randomisation dropouts or planned cross‐overs (or perform an intention‐to‐treat analysis); and report clinically important outcomes such as mortality, health‐related quality of life, adverse events, and recovery from hepatorenal syndrome. Albumin plus noradrenaline and albumin plus terlipressin appear to be the interventions that should be compared in future trials

Antibiotic prophylaxis to prevent spontaneous bacterial peritonitis in people with liver cirrhosis:a network meta-analysis

BACKGROUND:Approximately 2.5% of all hospitalisations in people with liver cirrhosis are for spontaneous bacterial peritonitis. Spontaneous bacterial peritonitis is associated with significant short-term mortality; therefore, it is important to prevent spontaneous bacterial peritonitis in people at high risk of developing it. Antibiotic prophylaxis forms the mainstay preventive method, but this has to be balanced against the development of drug-resistant spontaneous bacterial peritonitis, which is difficult to treat, and other adverse events. Several different prophylactic antibiotic treatments are available; however, there is uncertainty surrounding their relative efficacy and optimal combination. OBJECTIVES:To compare the benefits and harms of different prophylactic antibiotic treatments for prevention of spontaneous bacterial peritonitis in people with liver cirrhosis using a network meta-analysis and to generate rankings of the different prophylactic antibiotic treatments according to their safety and efficacy. SEARCH METHODS:We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers to November 2018 to identify randomised clinical trials in people with cirrhosis at risk of developing spontaneous bacterial peritonitis. SELECTION CRITERIA:We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis undergoing prophylactic treatment to prevent spontaneous bacterial peritonitis. We excluded randomised clinical trials in which participants had previously undergone liver transplantation, or were receiving antibiotics for treatment of spontaneous bacterial peritonitis or other purposes. DATA COLLECTION AND ANALYSIS:We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio (HR) with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS:We included 29 randomised clinical trials (3896 participants; nine antibiotic regimens (ciprofloxacin, neomycin, norfloxacin, norfloxacin plus neomycin, norfloxacin plus rifaximin, rifaximin, rufloxacin, sparfloxacin, sulfamethoxazole plus trimethoprim), and 'no active intervention' in the review. Twenty-three trials (2587 participants) were included in one or more outcomes in the review. The trials that provided the information included people with cirrhosis due to varied aetiologies, with or without other features of decompensation, having ascites with low protein or previous history of spontaneous bacterial peritonitis. The follow-up in the trials ranged from 1 to 12 months. Many of the trials were at high risk of bias, and the overall certainty of evidence was low or very low. Overall, approximately 10% of trial participants developed spontaneous bacterial peritonitis and 15% of trial participants died. There was no evidence of differences between any of the antibiotics and no intervention in terms of mortality (very low certainty) or number of serious adverse events (very low certainty). However, because of the wide CrIs, clinically important differences in these outcomes cannot be ruled out. None of the trials reported health-related quality of life or the proportion of people with serious adverse events. There was no evidence of differences between any of the antibiotics and no intervention in terms of proportion of people with 'any adverse events' (very low certainty), liver transplantation (very low certainty), or the proportion of people who developed spontaneous bacterial peritonitis (very low certainty). The number of 'any' adverse events per participant was fewer with norfloxacin (rate ratio 0.74, 95% CrI 0.59 to 0.94; 4 trials, 546 participants; low certainty) and sulfamethoxazole plus trimethoprim (rate ratio 0.19, 95% CrI 0.02 to 0.81; 1 trial, 60 participants; low certainty) versus no active intervention. There was no evidence of differences between the other antibiotics and no intervention in the number of 'any' adverse events per participant (very low certainty). There were fewer other decompensation events with rifaximin versus no active intervention (rate ratio 0.61, 65% CrI 0.46 to 0.80; 3 trials, 575 participants; low certainty) and norfloxacin plus neomycin (rate ratio 0.06, 95% CrI 0.00 to 0.33; 1 trial, 22 participants; low certainty). There was no evidence of differences between the other antibiotics and no intervention in the number of decompensations events per participant (very low certainty). None of the trials reported health-related quality of life or development of symptomatic spontaneous bacterial peritonitis. One would expect some correlation between the above outcomes, with interventions demonstrating effectiveness across several outcomes. This was not the case. The possible reasons for this include sparse data and selective reporting bias, which makes the results unreliable. Therefore, one cannot draw any conclusions from these inconsistent differences based on sparse data. There was no evidence of any differences in the subgroup analyses (performed when possible) based on whether the prophylaxis was primary or secondary. FUNDING:the source of funding for five trials were organisations who would benefit from the results of the study; six trials received no additional funding or were funded by neutral organisations; and the source of funding for the remaining 18 trials was unclear. AUTHORS' CONCLUSIONS:Based on very low-certainty evidence, there is considerable uncertainty about whether antibiotic prophylaxis is beneficial, and if beneficial, which antibiotic prophylaxis is most beneficial in people with cirrhosis and ascites with low protein or history of spontaneous bacterial peritonitis. Future randomised clinical trials should be adequately powered, employ blinding, avoid postrandomisation dropouts (or perform intention-to-treat analysis), and use clinically important outcomes such as mortality, health-related quality of life, and decompensation events

Treatment for ascites in adults with decompensated liver cirrhosis:a network meta-analysis

BACKGROUND:Approximately 20% of people with cirrhosis develop ascites. Several different treatments are available; including, among others, paracentesis plus fluid replacement, transjugular intrahepatic portosystemic shunts, aldosterone antagonists, and loop diuretics. However, there is uncertainty surrounding their relative efficacy. OBJECTIVES:To compare the benefits and harms of different treatments for ascites in people with decompensated liver cirrhosis through a network meta-analysis and to generate rankings of the different treatments for ascites according to their safety and efficacy. SEARCH METHODS:We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until May 2019 to identify randomised clinical trials in people with cirrhosis and ascites. SELECTION CRITERIA:We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis and ascites. We excluded randomised clinical trials in which participants had previously undergone liver transplantation. DATA COLLECTION AND ANALYSIS:We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio (HR) with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS:We included a total of 49 randomised clinical trials (3521 participants) in the review. Forty-two trials (2870 participants) were included in one or more outcomes in the review. The trials that provided the information included people with cirrhosis due to varied aetiologies, without other features of decompensation, having mainly grade 3 (severe), recurrent, or refractory ascites. The follow-up in the trials ranged from 0.1 to 84 months. All the trials were at high risk of bias, and the overall certainty of evidence was low or very low. Approximately 36.8% of participants who received paracentesis plus fluid replacement (reference group, the current standard treatment) died within 11 months. There was no evidence of differences in mortality, adverse events, or liver transplantation in people receiving different interventions compared to paracentesis plus fluid replacement (very low-certainty evidence). Resolution of ascites at maximal follow-up was higher with transjugular intrahepatic portosystemic shunt (HR 9.44; 95% CrI 1.93 to 62.68) and adding aldosterone antagonists to paracentesis plus fluid replacement (HR 30.63; 95% CrI 5.06 to 692.98) compared to paracentesis plus fluid replacement (very low-certainty evidence). Aldosterone antagonists plus loop diuretics had a higher rate of other decompensation events such as hepatic encephalopathy, hepatorenal syndrome, and variceal bleeding compared to paracentesis plus fluid replacement (rate ratio 2.04; 95% CrI 1.37 to 3.10) (very low-certainty evidence). None of the trials using paracentesis plus fluid replacement reported health-related quality of life or symptomatic recovery from ascites. FUNDING:the source of funding for four trials were industries which would benefit from the results of the study; 24 trials received no additional funding or were funded by neutral organisations; and the source of funding for the remaining 21 trials was unclear. AUTHORS' CONCLUSIONS:Based on very low-certainty evidence, there is considerable uncertainty about whether interventions for ascites in people with decompensated liver cirrhosis decrease mortality, adverse events, or liver transplantation compared to paracentesis plus fluid replacement in people with decompensated liver cirrhosis and ascites. Based on very low-certainty evidence, transjugular intrahepatic portosystemic shunt and adding aldosterone antagonists to paracentesis plus fluid replacement may increase the resolution of ascites compared to paracentesis plus fluid replacement. Based on very low-certainty evidence, aldosterone antagonists plus loop diuretics may increase the decompensation rate compared to paracentesis plus fluid replacement

Top research priorities in liver and gallbladder disorders in the UK

OBJECTIVES: There is a mismatch between research questions considered important by patients, carers and healthcare professionals and the research performed in many fields of medicine. The non-alcohol-related liver and gallbladder disorders priority setting partnership was established to identify the top research priorities in the prevention, diagnostic and treatment of gallbladder disorders and liver disorders not covered by the James-Lind Alliance (JLA) alcohol-related liver disease priority setting partnership. DESIGN: The methods broadly followed the principles of the JLA guidebook. The one major deviation from the JLA methodology was the final step of identifying priorities: instead of prioritisation by group discussions at a consensus workshop involving stakeholders, the prioritisation was achieved by a modified Delphi consensus process. RESULTS: A total of 428 unique valid diagnostic or treatment research questions were identified. A literature review established that none of these questions were considered 'answered' that is, high-quality systematic reviews suggest that further research is not required on the topic. The Delphi panel achieved consensus (at least 80% Delphi panel members agreed) that a research question was a top research priority for six questions. Four additional research questions with highest proportion of Delphi panel members ranking the question as highly important were added to constitute the top 10 research priorities. CONCLUSIONS: A priority setting process involving patients, carers and healthcare professionals has been used to identify the top 10priority areas for research related to liver and gallbladder disorders. Basic, translational, clinical and public health research are required to address these uncertainties

Is Sustained Virological Response a Marker of Treatment Efficacy in Patients with Chronic Hepatitis C Viral Infection with No Response or Relapse to Previous Antiviral Intervention?

Background: Randomised clinical trials (RCTs) of antiviral interventions in patients with chronic hepatitis C virus (HCV) infection use sustained virological response (SVR) as the main outcome. There is sparse information on long-term mortality from RCTs.  Methods: We created a decision tree model based on a Cochrane systematic review on interferon retreatment for patients who did not respond to initial therapy or who relapsed following SVR. Extrapolating data to 20 years, we modelled the outcome from three scenarios: (1) observed medium-term (5 year) annual mortality rates continue to the long term (20 years); (2) long-term annual mortality in retreatment responders falls to that of the general population while retreatment non-responders continue at the medium-term mortality; (3) long-term annual mortality in retreatment non-responders is the same as control group non-responders (i.e., the increased treatment-related medium mortality “wears off”).  Results: The mean differences in life expectancy over 20 years with interferon versus control in the first, second, and third scenarios were -0.34 years (95% confidence interval (CI) -0.71 to 0.03), -0.23 years (95% CI -0.69 to 0.24), and -0.01 (95% CI -0.3 to 0.27), respectively. The life expectancy was always lower in the interferon group than in the control group in scenario 1. In scenario 3, the interferon group had a longer life expectancy than the control group only when more than 7% in the interferon group achieved SVR.  Conclusions: SVR may be a good prognostic marker but does not seem to be a valid surrogate marker for assessing HCV treatment efficacy of interferon retreatment. The SVR threshold at which retreatment increases life expectancy may be different for different drugs depending upon the adverse event profile and treatment efficacy. This has to be determined for each drug by RCTs and appropriate modelling before SVR can be accepted as a surrogate marker

Medical Therapies for Uterine Fibroids - A Systematic Review and Network Meta-Analysis of Randomised Controlled Trials

BACKGROUND: Uterine fibroids are common, often symptomatic and a third of women need repeated time off work. Consequently 25% to 50% of women with fibroids receive surgical treatment, namely myomectomy or hysterectomy. Hysterectomy is the definitive treatment as fibroids are hormone dependent and frequently recurrent. Medical treatment aims to control symptoms in order to replace or delay surgery. This may improve the outcome of surgery and prevent recurrence. PURPOSE: To determine whether any medical treatment can be recommended in the treatment of women with fibroids about to undergo surgery and in those for whom surgery is not planned based on currently available evidence. STUDY SELECTION: Two authors independently identified randomised controlled trials (RCT) of all pharmacological treatments aimed at the treatment of fibroids from a list of references obtained by formal search of MEDLINE, EMBASE, Cochrane library, Science Citation Index, and ClinicalTrials.gov until December 2013. DATA EXTRACTION: Two authors independently extracted data from identified studies. DATA SYNTHESIS: A Bayesian network meta-analysis was performed following the National Institute for Health and Care Excellence-Decision Support Unit guidelines. Odds ratios, rate ratios, or mean differences with 95% credible intervals (CrI) were calculated. RESULTS AND LIMITATIONS: A total of 75 RCT met the inclusion criteria, 47 of which were included in the network meta-analysis. The overall quality of evidence was very low. The network meta-analysis showed differing results for different outcomes. CONCLUSIONS: There is currently insufficient evidence to recommend any medical treatment in the management of fibroids. Certain treatments have future promise however further, well designed RCTs are needed

WSES Jerusalem guidelines for diagnosis and treatment of acute appendicitis

Acute appendicitis (AA) is among the most common cause of acute abdominal pain. Diagnosis of AA is challenging; a variable combination of clinical signs and symptoms has been used together with laboratory findings in several scoring systems proposed for suggesting the probability of AA and the possible subsequent management pathway. The role of imaging in the diagnosis of AA is still debated, with variable use of US, CT and MRI in different settings worldwide. Up to date, comprehensive clinical guidelines for diagnosis and management of AA have never been issued. In July 2015, during the 3rd World Congress of the WSES, held in Jerusalem (Israel), a panel of experts including an Organizational Committee and Scientific Committee and Scientific Secretariat, participated to a Consensus Conference where eight panelists presented a number of statements developed for each of the eight main questions about diagnosis and management of AA. The statements were then voted, eventually modified and finally approved by the participants to The Consensus Conference and lately by the board of co-authors. The current paper is reporting the definitive Guidelines Statements on each of the following topics: 1) Diagnostic efficiency of clinical scoring systems, 2) Role of Imaging, 3) Non-operative treatment for uncomplicated appendicitis, 4) Timing of appendectomy and in-hospital delay, 5) Surgical treatment 6) Scoring systems for intra-operative grading of appendicitis and their clinical usefulness 7) Non-surgical treatment for complicated appendicitis: abscess or phlegmon 8) Pre-operative and post-operative antibiotics.Peer reviewe