Southwestern Medical Center

BACKGROUND: Establishing cardiovascular safety of new therapies for type 2 diabetes is important. Safety data are available for the subcutaneous form of the glucagon-like peptide-1 receptor agonist semaglutide but are needed for oral semaglutide. METHODS: We assessed cardiovascular outcomes of once-daily oral semaglutide in an event-driven, randomized, double-blind, placebo-controlled trial involving patients at high cardiovascular risk (age of ≥50 years with established cardiovascular or chronic kidney disease, or age of ≥60 years with cardiovascular risk factors only). The primary outcome in a time-to-event analysis was the first occurrence of a major adverse cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The trial was designed to rule out 80% excess cardiovascular risk as compared with placebo (noninferiority margin of 1.8 for the upper boundary of the 95% confidence interval for the hazard ratio for the primary outcome). RESULTS: A total of 3183 patients were randomly assigned to receive oral semaglutide or placebo. The mean age of the patients was 66 years; 2695 patients (84.7%) were 50 years of age or older and had cardiovascular or chronic kidney disease. The median time in the trial was 15.9 months. Major adverse cardiovascular events occurred in 61 of 1591 patients (3.8%) in the oral semaglutide group and 76 of 1592 (4.8%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.57 to 1.11; P<0.001 for noninferiority). Results for components of the primary outcome were as follows: death from cardiovascular causes, 15 of 1591 patients (0.9%) in the oral semaglutide group and 30 of 1592 (1.9%) in the placebo group (hazard ratio, 0.49; 95% CI, 0.27 to 0.92); nonfatal myocardial infarction, 37 of 1591 patients (2.3%) and 31 of 1592 (1.9%), respectively (hazard ratio, 1.18; 95% CI, 0.73 to 1.90); and nonfatal stroke, 12 of 1591 patients (0.8%) and 16 of 1592 (1.0%), respectively (hazard ratio, 0.74; 95% CI, 0.35 to 1.57). Death from any cause occurred in 23 of 1591 patients (1.4%) in the oral semaglutide group and 45 of 1592 (2.8%) in the placebo group (hazard ratio, 0.51; 95% CI, 0.31 to 0.84). Gastrointestinal adverse events leading to discontinuation of oral semaglutide or placebo were more common with oral semaglutide. CONCLUSIONS: In this trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo. (Funded by Novo Nordisk; PIONEER 6 ClinicalTrials.gov number, NCT02692716.).

BACKGROUND: Patients with chronic kidney disease have a high risk of adverse kidney and cardiovascular outcomes. The effect of dapagliflozin in patients with chronic kidney disease, with or without type 2 diabetes, is not known. METHODS: of body-surface area and a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 200 to 5000 to receive dapagliflozin (10 mg once daily) or placebo. The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. RESULTS: The independent data monitoring committee recommended stopping the trial because of efficacy. Over a median of 2.4 years, a primary outcome event occurred in 197 of 2152 participants (9.2%) in the dapagliflozin group and 312 of 2152 participants (14.5%) in the placebo group (hazard ratio, 0.61; 95% confidence interval [CI], 0.51 to 0.72; P<0.001; number needed to treat to prevent one primary outcome event, 19 [95% CI, 15 to 27]). The hazard ratio for the composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45 to 0.68; P<0.001), and the hazard ratio for the composite of death from cardiovascular causes or hospitalization for heart failure was 0.71 (95% CI, 0.55 to 0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (hazard ratio, 0.69; 95% CI, 0.53 to 0.88; P = 0.004). The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes. The known safety profile of dapagliflozin was confirmed. CONCLUSIONS: Among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo. (Funded by AstraZeneca; DAPA-CKD ClinicalTrials.gov number, NCT03036150.).

Bcl-2 is an integral membrane protein located mainly on the outer membrane of mitochondria. Overexpression of Bcl-2 prevents cells from undergoing apoptosis in response to a variety of stimuli. Cytosolic cytochrome c is necessary for the initiation of the apoptotic program, suggesting a possible connection between Bcl-2 and cytochrome c, which is normally located in the mitochondrial intermembrane space. Cells undergoing apoptosis were found to have an elevation of cytochrome c in the cytosol and a corresponding decrease in the mitochondria. Overexpression of Bcl-2 prevented the efflux of cytochrome c from the mitochondria and the initiation of apoptosis. Thus, one possible role of Bcl-2 in prevention of apoptosis is to block cytochrome c release from mitochondria.

Marrero, Jorge A.; Kulik, Laura M.; Sirlin, Claude B.; Zhu, Andrew X.; Finn, Richard S.; Abecassis, Michael M.; Roberts, Lewis R.; Heimbach, Julie K. Author Information

Cell death can be executed through different subroutines. Since the description of ferroptosis as an iron-dependent form of non-apoptotic cell death in 2012, there has been mounting interest in the process and function of ferroptosis. Ferroptosis can occur through two major pathways, the extrinsic or transporter-dependent pathway and the intrinsic or enzyme-regulated pathway. Ferroptosis is caused by a redox imbalance between the production of oxidants and antioxidants, which is driven by the abnormal expression and activity of multiple redox-active enzymes that produce or detoxify free radicals and lipid oxidation products. Accordingly, ferroptosis is precisely regulated at multiple levels, including epigenetic, transcriptional, posttranscriptional and posttranslational layers. The transcription factor NFE2L2 plays a central role in upregulating anti-ferroptotic defense, whereas selective autophagy may promote ferroptotic death. Here, we review current knowledge on the integrated molecular machinery of ferroptosis and describe how dysregulated ferroptosis is involved in cancer, neurodegeneration, tissue injury, inflammation, and infection.

Potential conflict of interest: Laura M. Kulik is on the advisory board for Gilead, Bayer, Eisai, Salix, and Bristol‐Myers Squibb. Richard Finn consults for Pfizer, Bayer, Novartis, Merck, and Bristol‐Myers Squibb. Claude B. Sirlin consults for and has received grants from Virtualscopics. Lewis R. Roberts consults for Wako, Medscape, and Axis; advises Tavec and Bayer; is on the speakers' bureau for Onlive; and has received grants from Ariad, BTG, and Gilead. Andrew Zhu consults for Bristol‐Myers Squibb, Eisai, Merck, Novartis, Sanofi, and Bayer. The funding for the development of this Practice Guideline was provided by the American Association for the Study of Liver Diseases. Guiding Principles and Objectives GUIDING PRINCIPLES This document presents official recommendations of the American Association for the Study of Liver Diseases (AASLD) on the surveillance, diagnosis, and treatment of hepatocellular carcinoma (HCC) occurring in the setting of adults with cirrhosis. Unlike previous AASLD practice guidelines, the current guideline was developed in compliance with the Institute of Medicine standards for trustworthy practice guidelines and uses the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach.1 Multiple systematic reviews of the literature were conducted to support the recommendations in this practice guideline. An enhanced understanding of the guideline can be obtained by reading the applicable portions of the systematic reviews. In addition, more detailed information may be found in the associated guidance document related to clinically important aspects of HCC that lacked sufficient evidence to warrant a systematic review. The guideline focuses on a broad spectrum of clinical practice, including surveillance of patients with cirrhosis for HCC, establishing the diagnosis of HCC, and various therapeutic options for the treatment of HCC. To address other issues on HCC such as epidemiology, staging, and additional aspects of diagnosis and treatment, the authors have created a new guidance document that will be published soon and is based upon the previous HCC AASLD guidelines by Bruix and Sherman.2 KEY QUESTIONS The guideline developers from the AASLD identified key questions that health care providers are faced with frequently in the evaluation and management of patients with HCC. These questions were: Should adults with cirrhosis undergo surveillance for HCC? If so, which surveillance test is best? Should adults with cirrhosis and suspected HCC undergo diagnostic evaluation with multiphasic computed tomography (CT) or multiphasic magnetic resonance imaging (MRI)? Should adults with cirrhosis and an indeterminate hepatic nodule undergo a biopsy, repeated imaging, or alternative imaging for the diagnostic evaluation? Should adults with Child‐Pugh class A cirrhosis and early‐stage HCC (T1 or T2) be treated with resection or local‐regional (LRT) therapy? Should adults with cirrhosis and HCC that has been resected or ablated successfully undergo adjuvant therapy? Should adults with cirrhosis awaiting liver transplantation and HCC (T1) be treated or undergo observation? Should adults with cirrhosis and HCC (Organ Procurement and Transplantation Network [OPTN] T2) awaiting liver transplantation undergo transplantation alone or transplantation with bridging therapy while waiting? Should adults with cirrhosis awaiting liver transplantation and HCC beyond Milan criteria (T3) undergo transplantation after being down‐staged to within Milan criteria? Should adults with cirrhosis and HCC (T2 or T3, no vascular involvement) who are not candidates for resection or transplantation be treated with transarterial chemoembolization, transarterial radioembolization, or external radiation? Should adults with Child‐Pugh class A/B cirrhosis and advanced HCC with macrovascular invasion and/or metastatic disease be treated with systemic or locoregional therapies or no therapy? TARGET AUDIENCE This guideline is intended primarily for health care providers who care for patients with cirrhosis. Additionally, the guideline may inform policy decisions regarding patients with HCC. Background BURDEN OF DISEASE According to the World Health Organization, HCC is the fifth most common tumor worldwide and the second most common cause of cancer‐related death (http://globocan.iarc.fr/old/FactSheets/cancers/liver-new.asp). Male‐to‐female predominance is greater than 2:1 with liver cancer, and approximately 83% of the estimated 782,000 new HCC cases in 2012 occurred in less developed regions of the world, with East and South Asia plus sub‐Saharan Africa being the regions of highest incidence, Southern Europe and North America being the regions of intermediate incidence, and Northern Europe and South Central Asia being the regions of lowest incidence.3 The incidence of HCC has been rising rapidly in the United States over the last 20 years.4 According to estimates from the Surveillance Epidemiology End Results (SEER) program of the National Cancer Institute, the United States will have an estimated cases of HCC and HCC in In addition, a the that the incidence of HCC will to with the highest in by and with a The in incidence of HCC in the United States is primarily to the to that the with the highest of have that as liver disease and the more to the of HCC than other including which is primarily to the of in the The of cirrhosis a key for the development of HCC. The of cirrhosis patients with HCC has been estimated to be and the HCC incidence patients with cirrhosis has been to be patients with cirrhosis a for and The that patients with HCC have liver disease the management and therapeutic options The key questions common in this and the for this practice guideline. the Child‐Pugh to the of liver of the for Liver is more in this of Guideline Development An and the of the key A of AASLD with an in systematic reviews to the The provided evidence the In this the of evidence in systematic is as or based on the of and of a of systematic the guideline based recommendations on the of the of and and and other clinical on this the guideline AASLD recommendations that are as to most patients with or to a of The of is not by the of the of and and and of the a in the of are to recommendations to the of the with the of the evidence and to for the systematic for of the key questions are in the the key questions with are after The the of evidence Study of of evidence of the of the of a of evidence of and and and of the of a in this the of and a Health care the of The can be as policy in most The of in this the of Health care to patients a that is with and is a for and of a that most patients in this the of and a this that patients the of with and policy the be as a policy in most and be as a the is by AASLD a a for patients that the of patients in this the of a the of and is and be to patients a that is with a policy this a for and of and is to be as a the is by AASLD with cirrhosis Surveillance for HCC surveillance with cirrhosis and suspected HCC evaluation with multiphasic evaluation with multiphasic and with cirrhosis and an indeterminate hepatic nodule or alternative imaging and with Child‐Pugh class A cirrhosis and or HCC therapy with cirrhosis and HCC successfully resected or ablated therapy adjuvant therapy with cirrhosis awaiting liver transplantation and HCC therapy to with cirrhosis awaiting liver transplantation and HCC therapy to with cirrhosis awaiting liver transplantation and HCC and with cirrhosis and HCC (T2 or T3, no vascular involvement) who are not candidates for resection or transplantation or external with Child‐Pugh class A/B cirrhosis and advanced HCC with macrovascular invasion and/or metastatic disease therapy therapy or no therapy Should Surveillance for HCC, and If Surveillance The AASLD surveillance of adults with cirrhosis of of The AASLD surveillance with or of of The AASLD not surveillance of patients with Child‐Pugh class cirrhosis are on the the for of the of is not to which of surveillance alone or the of plus to a greater in The of surveillance from to in surveillance based on of liver or be this The of surveillance and is to HCC the criteria for the development of a surveillance that patients with cirrhosis are a and can be The previous AASLD guidelines on the the highest to have and cirrhosis to A surveillance in a in for who are no in with cirrhosis to or liver and is surveillance to a in in this of patients with cirrhosis. of is which surveillance be is that be of surveillance, is the of such as for The previous AASLD guidelines as the of the of this was to current are in support of HCC surveillance in adults with and so, of surveillance is and The evidence of surveillance for HCC is in which uses the from a systematic on were no of surveillance in patients with cirrhosis. were that surveillance in patients with the of the evidence The of the was with The was the patients who HCC surveillance, with the patients previous surveillance, with an of were that for and the in of for surveillance the were in which the with surveillance was greater than no surveillance In to surveillance to an in the of early‐stage HCC, with an of with no In of surveillance to more patients with no In addition, surveillance to more with no surveillance in with surveillance to be to early‐stage and treatment The surveillance most were and the the on and The of plus of early‐stage HCC with no surveillance, with an of alone an of alone and plus to of treatment for and for plus were no that alone plus to which was in of early‐stage or The were to alone or plus plus a of for alone a of for was no the are issues surveillance for on which no of the to a diagnostic to or than the no of the of and most the were not to an in the current of HCC and the in incidence of this including with plus as surveillance are the of including and as a surveillance test in In addition, be important to other in to such as and other Should and HCC Evaluation or Recommendation The AASLD diagnostic evaluation for HCC with multiphasic or multiphasic of diagnostic of for of The of the and for a on beyond diagnostic These and and were of the greater of multiphasic with multiphasic to liver is not In patients with cirrhosis and suspected HCC, diagnostic imaging is to the of HCC and The are to tumor and patients for liver Unlike most other the diagnosis of HCC can be and treatment may be based on imaging The is that in patients with the of HCC is and the of that may HCC imaging is such that a HCC imaging criteria can be and to be HCC. is that the imaging diagnosis of HCC multiphasic imaging, is not which diagnostic imaging test to in clinical practice multiphasic with multiphasic with that in the and of and multiphasic with that in and of hepatocellular in to The evidence of diagnostic for HCC is in which uses the from a systematic on imaging in HCC to address this were no of no identified that multiphasic with an multiphasic with and no on were in patients with cirrhosis and suspected HCC that the diagnostic of and and An additional are not as be in the of on and/or of evidence was and was of the of the and The of imaging and for of are to multiphasic an multiphasic with an provided than with multiphasic with multiphasic with provided than with than multiphasic with an multiphasic and a with a of in HCC and were that multiphasic and this and HCC multiphasic multiphasic with an The of for was with the a multiphasic may be more than in a of the in diagnostic are to over the of the to and that beyond diagnostic inform the of imaging in with multiphasic multiphasic has important and greater more of nodule and liver and of greater to less of such as or of the United and a is more and less patients to and the of which may be in patients with or not in North multiphasic can be to HCC and are multiphasic multiphasic with an and multiphasic with and on and be a of transplantation patients with HCC and while awaiting transplantation has and may which is in this Should and an a or for the The AASLD options in patients with cirrhosis and an indeterminate including imaging, imaging with an alternative or alternative or biopsy, over the of of The AASLD of indeterminate of of may be in is not has the to a diagnosis in cases in which a diagnosis is to therapeutic has a of tumor and the that a is to the to of the nodule than a imaging criteria with for HCC have been developed by the American of Liver and the and previous AASLD and in with and/or that not guidelines or are than are In previous HCC clinical practice the AASLD for indeterminate by surveillance with the being that can a diagnosis, of may not be an in is may cause or and has a of including tumor and for is an additional A may not and repeated may be to a imaging may be in patients awaiting liver transplantation with a indeterminate that of HCC not management or to liver transplantation is regarding for an indeterminate the of this was to current are to an The evidence is in which uses the from a systematic on imaging in HCC to address this on an detailed in the systematic were no identified that address this were identified that the of in for hepatic surveillance in patients with cirrhosis. The authors of in to and found a and of to be and was and with the which was were in the was with a of as patients with imaging or were to In that in patients with of to indeterminate surveillance are the of that for indeterminate hepatic may be and an alternative of imaging with imaging an for most indeterminate with for with or in the of a HCC. other of indeterminate as by or not most indeterminate hepatic are for are the of indeterminate or The indeterminate were as intermediate of HCC, and HCC based on imaging as to HCC of as intermediate to HCC, and of as HCC to HCC. in that the various are associated with of HCC in patients with as the that a of to indeterminate are and to to HCC imaging a of a of indeterminate in a of indeterminate diagnostic options imaging, imaging with an alternative or and to a A by and for a of patients with identified by surveillance The authors that and of the of the diagnostic was and and that be for on or An diagnostic based on clinical and imaging such as nodule of biopsy, and may be the In a may to a HCC and patients to be that such treatment may is to the of and the of nodule and to additional to more including other than such as or from the Should Child‐Pugh A and HCC (T1 T2) or Recommendation The AASLD that adults with Child‐Pugh class A cirrhosis and or HCC undergo resection over of of of resection other of as transarterial and transarterial or other of such as and not evidence The of is not or in clinical practice, and is not in is as from a in such as of and This to in and HCC a of tumor from to and the of therapies in on the and of the that are may be treated by resection or than or vascular or may have Multiple that are or may not be to to resection have been primarily in East in is a of and a of other liver such as or with The of on of therapies is cirrhosis is of the for HCC, the of treatment as on the liver and the of as on the of the therapeutic options are for patients who with advanced liver disease and/or advanced tumor options for with cirrhosis and These such as and as as patients with HCC as with to with an of for and for more than to evidence of disease or macrovascular and occurring in the setting of or no and in the of Liver Cancer or a of clinical and and including the of alternative can the to with The of a of a of the of from of resection to of and may to and In this be that the evidence was to resection with therapy to the therapeutic for patients with early‐stage HCC occurring in the setting of cirrhosis or no and that liver transplantation is for patients with HCC, not a of transplantation to resection or The evidence is in which the from a systematic by on treatment for early‐stage HCC in patients with Child‐Pugh class A or cirrhosis. This systematic not the of or other with or found evidence that In the resection and the other the authors of the systematic that the of patients was to a were that with including a of of a of and evidence and a of The of the that hepatic resection is more than regarding as as a with a of is to the the in resection and The for an of in the is related to an of patients who from the to the resection were within the of to the of The additional of and resection of of the the was for resection with In to the in the systematic by resection with published the of for patients after resection with with was by within and and for the resection resection with alone for to and Milan criteria to with the being and found resection to be in and of was a for in of the systematic review. This is not that is that is more in the of for patients with HCC treated with resection has not been in an A from this This Child‐Pugh class A patients from and the authors for for for for and for for A for of was not by the in the systematic that resection with in patients with This was not in the other The of other than such as and In addition, the of such as transarterial and have not been with resection or in Child‐Pugh class A patients with or HCC. Should and HCC or Recommendation The AASLD the of adjuvant therapy for patients with HCC resection or of of The Evaluation in may be the most common criteria to in patients by HCC and treated with other are The of after resection or is related to of the tumor the of such as of and the or of the of HCC in which of the tumor and the development of the adjuvant therapy have an the tumor and a the development of a The of is and based on the of the with the to be related to the development of a with the adjuvant of were with a in the development of not a The of in advanced disease has the development of early‐stage To most of the adjuvant not have clinical evidence that in of HCC. the in the adjuvant has been to in advanced not in for the adjuvant treatment of HCC in of HCC with or is associated with of as as is a for adjuvant systemic The evidence is in which uses the from a systematic by on adjuvant treatment for HCC after The systematic by identified that adjuvant therapy can and in patients with liver the of are in clinical of adjuvant and therapy were in the systematic and to or The of has been in and has been to in advanced which in the adjuvant is a for the development of for treatment of HCC in the advanced setting and in the adjuvant In addition, the of by therapies on the of HCC is and the of therapy in the adjuvant setting is may warrant the of an associated in HCC for patients with who are on HCC Recommendation The AASLD with imaging over treatment for patients with cirrhosis awaiting liver transplantation who HCC. of of This is intended for patients who are on the liver transplantation with an for transplantation in to is based on current in the United policy may this The of with imaging treatment on including of of the of liver and The to of or transarterial treatment to patients with cirrhosis who have a HCC nodule and (T1) and are for liver transplantation is in on an of the liver and to undergo the and In the United current liver policy patients with HCC a or or not for with a is treated with may not the for of a HCC may be of to patients who are and have no other for as may be to the will for HCC and will This is the by the by which is If the has other for other than the of HCC, are not by the current such as or the to with If is a key is the that the may to beyond criteria and/or the This is the in the by which is The are in including the of a systematic of that adults with cirrhosis awaiting liver transplantation and treated with bridging or therapies were no were and of address the of for patients with HCC who were or were not treated with The by is a of patients with HCC for liver transplantation a United States who were not treated with The was with in Child‐Pugh class A and Child‐Pugh class The was and the patients from to a of patients within other patients from to beyond a of from and additional patients of The of was within within and within and the of tumor was estimated to be for and The authors that for patients with HCC for liver transplantation is an based on of the patients who than for patients with HCC with or with is important to that this was in an with and the may not be to with The by on for patients in with and HCC who were for transplantation who were treated with were treated with a of including or and treated with the lowest of patients with HCC a of for tumor beyond this of patients treated with a of patients in the and were of than the transplantation which may the of the In addition, the of the by was to a the than to the of on patients with or HCC. from of patients with HCC be to a understanding of In addition, of such as inform decisions of HCC with to a Should HCC Liver Transplantation or The AASLD bridging to in patients for liver transplantation within criteria to of disease and from the of of The AASLD not of therapy over for the of bridging to liver transplantation for patients within of of is as the of as or a of of such as and tumor death and tumor beyond the Milan The of hepatic to be patients for bridging in the United States with HCC within Milan criteria have been to liver transplantation by of patients with HCC have to have to liver to the policy to with have the of and in the of with current that is the for liver transplantation for HCC may based on and to and The with additional for HCC is not The of bridging therapy is to the of HCC while awaiting liver with with the Milan have been additional HCC of an with a for HCC beyond the Milan criteria while awaiting transplantation to and tumor within or while for transplantation is the to have that the is as as and and This the of the of bridging therapy for patients with HCC awaiting The are in including the of a systematic of that adults with cirrhosis awaiting liver transplantation and treated with bridging or therapies were that the of were no The of HCC and of and after liver the patients Milan patients within and the Milan and not The of the evidence was of with of and The were and the of in the United States to for the This not the various was a of and from in patients who received bridging and the not and were not the the of and for regarding which patients were to were to be by transarterial or The of was in patients treated with and alone with a and was to with in this bridging therapy is of for the patients to as as the with the and the of for the with the of have been associated with of of and and after liver transplantation has been to be in patients with HCC who received with who not the The to patients with HCC to transplantation is upon with being for based on the of hepatic An bridging not bridging for patients with HCC is to be primarily to including within the United States for in patients with HCC. to based on may to the from The of may HCC with to and to Should and HCC Milan (T3) to Milan Recommendation The AASLD that patients beyond the Milan criteria (T3) be for liver transplantation after the Milan of of The of therapy for the of be based on the in the United may be by to the board for patients with HCC after to within or may with a this is not a practice that is HCC policy may be in the to to for down‐staged patients than is no to of and for liver as a in tumor to within Milan criteria based on as a of tumor by to which is not in and of is as a in tumor to most the Milan the of may the Milan criteria to be the and support to to patients within the United patients who criteria who can be successfully down‐staged to within the Milan criteria may for HCC after by with is This is of in tumor of of as as to and of a which to therapy is have the of tumor in to tumor and to criteria for This key to patients with HCC beyond Milan criteria undergo liver transplantation after to within Milan The are in including the of a systematic of that adults with cirrhosis awaiting liver transplantation and treated with bridging or therapies were a of for associated with and were no of of with no liver the were as in were no for transplantation of with and The in the were to transplantation and and and of patients with no therapy liver transplantation was associated with and The with an of to no provided the United States which patients transplantation and and In this patients a in the patients or transplantation and in were of patients who were successfully down‐staged from to within the of in was the that were down‐staged with the patients in the most of were the of for patients to be beyond treated with with within who were not treated with no in The was from Asia and of liver with of A of patients were successfully down‐staged to the Milan criteria and were with patients who within Milan criteria and A of patients resection for was a for and the down‐staged patients being a more advanced not The of the that were the that with the lowest to be in that the was These are to has been patients with HCC within Milan The of that various transarterial and were with a of for The highest was in treated with and the lowest was in that were treated with A of a beyond the of may patients who are not liver candidates for other advanced or and the of may be by the of candidates in is in the which after as as the and transplantation are key for of transplantation can be the that can are and have criteria that be in including such as and tumor such as Liver Cancer treatment and such as and Should and HCC (T2 or T3, not for or Transplantation or The AASLD over no treatment in adults with cirrhosis and HCC (T2 or T3, no vascular involvement) who are not candidates for resection or of of The AASLD not of over of of The evidence is for Child‐Pugh class A and Child‐Pugh class B. are no to support the of for

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

The SOC-8 guidelines are intended to be flexible to meet the diverse health care needs of TGD people globally. While adaptable, they offer standards for promoting optimal health care and guidance for the treatment of people experiencing gender incongruence. As in all previous versions of the SOC, the criteria set forth in this document for gender-affirming medical interventions are clinical guidelines; individual health care professionals and programs may modify these in consultation with the TGD person.

Cells may die from accidental cell death (ACD) or regulated cell death (RCD). ACD is a biologically uncontrolled process, whereas RCD involves tightly structured signaling cascades and molecularly defined effector mechanisms. A growing number of novel non-apoptotic forms of RCD have been identified and are increasingly being implicated in various human pathologies. Here, we critically review the current state of the art regarding non-apoptotic types of RCD, including necroptosis, pyroptosis, ferroptosis, entotic cell death, netotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis and oxeiptosis. The in-depth comprehension of each of these lethal subroutines and their intercellular consequences may uncover novel therapeutic targets for the avoidance of pathogenic cell loss.

This document is the report of a task group of the AAPM and has been prepared primarily to advise medical physicists involved in the external-beam radiation therapy of patients with thoracic, abdominal, and pelvic tumors affected by respiratory motion. This report describes the magnitude of respiratory motion, discusses radiotherapy specific problems caused by respiratory motion, explains techniques that explicitly manage respiratory motion during radiotherapy and gives recommendations in the application of these techniques for patient care, including quality assurance (QA) guidelines for these devices and their use with conformal and intensity modulated radiotherapy. The technologies covered by this report are motion-encompassing methods, respiratory gated techniques, breath-hold techniques, forced shallow-breathing methods, and respiration-synchronized techniques. The main outcome of this report is a clinical process guide for managing respiratory motion. Included in this guide is the recommendation that tumor motion should be measured (when possible) for each patient for whom respiratory motion is a concern. If target motion is greater than 5 mm, a method of respiratory motion management is available, and if the patient can tolerate the procedure, respiratory motion management technology is appropriate. Respiratory motion management is also appropriate when the procedure will increase normal tissue sparing. Respiratory motion management involves further resources, education and the development of and adherence to QA procedures.

Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death caused by lipid peroxidation, which is controlled by integrated oxidation and antioxidant systems. The iron-containing enzyme lipoxygenase is the main promoter of ferroptosis by producing lipid hydroperoxides, and its function relies on the activation of ACSL4-dependent lipid biosynthesis. In contrast, the selenium-containing enzyme GPX4 is currently recognized as a central repressor of ferroptosis, and its activity depends on glutathione produced from the activation of the cystine-glutamate antiporter SLC7A11. Many metabolic (especially involving iron, lipids, and amino acids) and degradation pathways (macroautophagy/autophagy and the ubiquitin-proteasome system) orchestrate the complex ferroptotic response through direct or indirect regulation of iron accumulation or lipid peroxidation. Although the detailed mechanism of membrane injury during ferroptosis remains a mystery, ESCRT III-mediated plasma membrane repair can make cells resistant to ferroptosis. Here, we review the recent rapid progress in understanding the molecular mechanisms of ferroptosis and focus on the epigenetic, transcriptional, and posttranslational regulation of this process.Abbreviations: 2ME: beta-mercaptoethanol; α-KG: α-ketoglutarate; ccRCC: clear cell renal cell carcinoma; EMT: epithelial-mesenchymal transition; FAO: fatty acid beta-oxidation; GSH: glutathione; MEFs: mouse embryonic fibroblasts; MUFAs: monounsaturated fatty acids; NO: nitric oxide; NOX: NADPH oxidase; PPP: pentose phosphate pathway; PUFA: polyunsaturated fatty acid; RCD: regulated cell death; RNS: reactive nitrogen species; ROS: reactive oxygen species; RTAs: radical-trapping antioxidants; UPS: ubiquitin-proteasome system; UTR: untranslated region.

CONTEXT: Patients with serum thyroid-stimulating hormone (TSH) levels outside the reference range and levels of free thyroxine (FT4) and triiodothyronine (T3) within the reference range are common in clinical practice. The necessity for further evaluation, possible treatment, and the urgency of treatment have not been clearly established. OBJECTIVES: To define subclinical thyroid disease, review its epidemiology, recommend an appropriate evaluation, explore the risks and benefits of treatment and consequences of nontreatment, and determine whether population-based screening is warranted. DATA SOURCES: MEDLINE, EMBASE, Biosis, the Agency for Healthcare Research and Quality, National Guideline Clearing House, the Cochrane Database of Systematic Reviews and Controlled Trials Register, and several National Health Services (UK) databases were searched for articles on subclinical thyroid disease published between 1995 and 2002. Articles published before 1995 were recommended by expert consultants. STUDY SELECTION AND DATA EXTRACTION: A total of 195 English-language or translated papers were reviewed. Editorials, individual case studies, studies enrolling fewer than 10 patients, and nonsystematic reviews were excluded. Information related to authorship, year of publication, number of subjects, study design, and results were extracted and formed the basis for an evidence report, consisting of tables and summaries of each subject area. DATA SYNTHESIS: The strength of the evidence that untreated subclinical thyroid disease is associated with clinical symptoms and adverse clinical outcomes was assessed and recommendations for clinical practice developed. Data relating the progression of subclinical to overt hypothyroidism were rated as good, but data relating treatment to prevention of progression were inadequate to determine a treatment benefit. Data relating a serum TSH level higher than 10 mIU/L to elevations in serum cholesterol were rated as fair but data relating to benefits of treatment were rated as insufficient. All other associations of symptoms and benefit of treatment were rated as insufficient or absent. Data relating a serum TSH concentration lower than 0.1 mIU/L to the presence of atrial fibrillation and progression to overt hyperthyroidism were rated as good, but no data supported treatment to prevent these outcomes. Data relating restoration of the TSH level to within the reference range with improvements in bone mineral density were rated as fair. Data addressing all other associations of subclinical hyperthyroid disease and adverse clinical outcomes or treatment benefits were rated as insufficient or absent. Subclinical hypothyroid disease in pregnancy is a special case and aggressive case finding and treatment in pregnant women can be justified. CONCLUSIONS: Data supporting associations of subclinical thyroid disease with symptoms or adverse clinical outcomes or benefits of treatment are few. The consequences of subclinical thyroid disease (serum TSH 0.1-0.45 mIU/L or 4.5-10.0 mIU/L) are minimal and we recommend against routine treatment of patients with TSH levels in these ranges. There is insufficient evidence to support population-based screening. Aggressive case finding is appropriate in pregnant women, women older than 60 years, and others at high risk for thyroid dysfunction.

OBJECTIVE: To compare the efficacy and safety of adalimumab plus methotrexate (MTX) versus MTX monotherapy or adalimumab monotherapy in patients with early, aggressive rheumatoid arthritis (RA) who had not previously received MTX treatment. METHODS: This was a 2-year, multicenter, double-blind, active comparator-controlled study of 799 RA patients with active disease of < 3 years' duration who had never been treated with MTX. Treatments included adalimumab 40 mg subcutaneously every other week plus oral MTX, adalimumab 40 mg subcutaneously every other week, or weekly oral MTX. Co-primary end points at year 1 were American College of Rheumatology 50% improvement (ACR50) and mean change from baseline in the modified total Sharp score. RESULTS: Combination therapy was superior to both MTX and adalimumab monotherapy in all outcomes measured. At year 1, more patients receiving combination therapy exhibited an ACR50 response (62%) than did patients who received MTX or adalimumab monotherapy (46% and 41%, respectively; both P < 0.001). Similar superiority of combination therapy was seen in ACR20, ACR70, and ACR90 response rates at 1 and 2 years. There was significantly less radiographic progression (P < or = 0.002) among patients in the combination treatment arm at both year 1 and year 2 (1.3 and 1.9 Sharp units, respectively) than in patients in the MTX arm (5.7 and 10.4 Sharp units) or the adalimumab arm (3.0 and 5.5 Sharp units). After 2 years of treatment, 49% of patients receiving combination therapy exhibited disease remission (28-joint Disease Activity Score <2.6), and 49% exhibited a major clinical response (ACR70 response for at least 6 continuous months), rates approximately twice those found among patients receiving either monotherapy. The adverse event profiles were comparable in all 3 groups. CONCLUSION: In this population of patients with early, aggressive RA, combination therapy with adalimumab plus MTX was significantly superior to either MTX alone or adalimumab alone in improving signs and symptoms of disease, inhibiting radiographic progression, and effecting clinical remission.

BACKGROUND: The effectiveness of surgery versus observation for men with localized prostate cancer detected by means of prostate-specific antigen (PSA) testing is not known. METHODS: From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatectomy or observation and followed them through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostate-cancer mortality. RESULTS: During the median follow-up of 10.0 years, 171 of 364 men (47.0%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio, 0.88; 95% confidence interval [CI], 0.71 to 1.08; P=0.22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (hazard ratio, 0.63; 95% CI, 0.36 to 1.09; P=0.09; absolute risk reduction, 2.6 percentage points). The effect of treatment on all-cause and prostate-cancer mortality did not differ according to age, race, coexisting conditions, self-reported performance status, or histologic features of the tumor. Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng per milliliter (P=0.04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P=0.07 for interaction). Adverse events within 30 days after surgery occurred in 21.4% of men, including one death. CONCLUSIONS: Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostate-cancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points. (Funded by the Department of Veterans Affairs Cooperative Studies Program and others; PIVOT ClinicalTrials.gov number, NCT00007644.).

Although amyloid imaging with PiB-PET ([C-11]Pittsburgh Compound-B positron emission tomography), and now with F-18-labeled tracers, has produced remarkably consistent qualitative findings across a large number of centers, there has been considerable variability in the exact numbers reported as quantitative outcome measures of tracer retention. In some cases this is as trivial as the choice of units, in some cases it is scanner dependent, and of course, different tracers yield different numbers. Our working group was formed to standardize quantitative amyloid imaging measures by scaling the outcome of each particular analysis method or tracer to a 0 to 100 scale, anchored by young controls (≤ 45 years) and typical Alzheimer's disease patients. The units of this scale have been named "Centiloids." Basically, we describe a "standard" method of analyzing PiB PET data and then a method for scaling any "nonstandard" method of PiB PET analysis (or any other tracer) to the Centiloid scale.

Fragile X syndrome, the most common inherited form of human mental retardation, is caused by mutations of the Fmr1 gene that encodes the fragile X mental retardation protein (FMRP). Biochemical evidence indicates that FMRP binds a subset of mRNAs and acts as a regulator of translation. However, the consequences of FMRP loss on neuronal function in mammals remain unknown. Here we show that a form of protein synthesis-dependent synaptic plasticity, long-term depression triggered by activation of metabotropic glutamate receptors, is selectively enhanced in the hippocampus of mutant mice lacking FMRP. This finding indicates that FMRP plays an important functional role in regulating activity-dependent synaptic plasticity in the brain and suggests new therapeutic approaches for fragile X syndrome.

BACKGROUND & AIMS: Society guidelines differ in their recommendations for surveillance to detect early-stage hepatocellular carcinoma (HCC) in patients with cirrhosis. We compared the performance of surveillance imaging, with or without alpha fetoprotein (AFP), for early detection of HCC in patients with cirrhosis. METHODS: Two reviewers searched MEDLINE and SCOPUS from January 1990 through August 2016 to identify published sensitivity and specificity of surveillance strategies for overall and early detection of HCC. Pooled estimates were calculated and compared using the DerSimonian and Laird method for a random effects model. The study was conducted in accordance with Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. RESULTS: Thirty-two studies (comprising 13,367 patients) characterized sensitivity of imaging with or without AFP measurement for detection of HCC in patients with cirrhosis. Ultrasound detected any stage HCC with 84% sensitivity (95% confidence interval [CI] 76%-92%), but early-stage HCC with only 47% sensitivity (95% CI 33%-61%). In studies comparing ultrasound with vs without AFP measurement, ultrasound detected any stage HCC with a lower level of sensitivity than ultrasound plus AFP measurement (relative risk [RR] 0.88; 95% CI 0.83-0.93) and early-stage HCC with a lower level of sensitivity than ultrasound plus AFP measurement (RR 0.81; 95% CI 0.71-0.93). However, ultrasound alone detected HCC with a higher level of specificity than ultrasound plus AFP measurement (RR 1.08; 95% CI 1.05-1.09). Ultrasound with vs without AFP detected early-stage HCC with 63% sensitivity (95% CI 48%-75%) and 45% sensitivity (95% CI 30%-62%), respectively (P = .002). Only 4 studies evaluated computed tomography or magnetic resonance image-based surveillance, which detected HCC with 84% sensitivity (95% CI 70%-92%). CONCLUSIONS: We found ultrasound alone has a low sensitivity to detect early stage HCC in patients with cirrhosis. Addition of AFP to ultrasound significantly increases sensitivity of early HCC detection in clinical practice.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors reduce blood pressure and urine protein excretion and slow the progression of chronic kidney disease. PURPOSE: To determine the levels of blood pressure and urine protein excretion associated with the lowest risk for progression of chronic kidney disease during antihypertensive therapy with and without ACE inhibitors. DATA SOURCES: 11 randomized, controlled trials comparing the efficacy of antihypertensive regimens with or without ACE inhibitors for patients with predominantly nondiabetic kidney disease. STUDY SELECTION: MEDLINE database search for English-language studies published between 1977 and 1999. DATA EXTRACTION: Data on 1860 nondiabetic patients were pooled in a patient-level meta-analysis. Progression of kidney disease was defined as a doubling of baseline serum creatinine level or onset of kidney failure. Multivariable regression analysis was performed to assess the association of systolic and diastolic blood pressure and urine protein excretion with kidney disease progression at 22 610 patient visits. DATA SYNTHESIS: Mean duration of follow-up was 2.2 years. Kidney disease progression was documented in 311 patients. Systolic blood pressure of 110 to 129 mm Hg and urine protein excretion less than 2.0 g/d were associated with the lowest risk for kidney disease progression. Angiotensin-converting enzyme inhibitors remained beneficial after adjustment for blood pressure and urine protein excretion (relative risk, 0.67 [95% CI, 0.53 to 0.84]). The increased risk for kidney progression at higher systolic blood pressure levels was greater in patients with urine protein excretion greater than 1.0 g/d (P < 0.006). CONCLUSION: Although reverse causation cannot be excluded with certainty, a systolic blood pressure goal between 110 and 129 mm Hg may be beneficial in patients with urine protein excretion greater than 1.0 g/d. Systolic blood pressure less than 110 mm Hg may be associated with a higher risk for kidney disease progression.

Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and insights into both disease etiology and targeted intervention are needed. A total of 109 micro-dissected PDA cases were subjected to whole-exome sequencing. Microdissection enriches tumour cellularity and enhances mutation calling. Here we show that environmental stress and alterations in DNA repair genes associate with distinct mutation spectra. Copy number alterations target multiple tumour suppressive/oncogenic loci; however, amplification of MYC is uniquely associated with poor outcome and adenosquamous subtype. We identify multiple novel mutated genes in PDA, with select genes harbouring prognostic significance. RBM10 mutations associate with longer survival in spite of histological features of aggressive disease. KRAS mutations are observed in >90% of cases, but codon Q61 alleles are selectively associated with improved survival. Oncogenic BRAF mutations are mutually exclusive with KRAS and define sensitivity to vemurafenib in PDA models. High-frequency alterations in Wnt signalling, chromatin remodelling, Hedgehog signalling, DNA repair and cell cycle processes are observed. Together, these data delineate new genetic diversity of PDA and provide insights into prognostic determinants and therapeutic targets.

Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.