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A history of the treatment of primary liver cancer

2024; Lippincott Williams & Wilkins; Volume: 23; Issue: 1 Linguagem: Inglês

10.1097/cld.0000000000000147

2046-2484

Jordi Bruix,

Hepatitis B Virus Studies

INTRODUCTION It took many centuries, perhaps a dozen or more, for the 3-millenium-old practice of Hepatoscopy [also known as Haruspicy and Hepatomancy], ie, an inspection of the liver for the purpose of divining the intentions of the gods and predicting the future1–3 (Figure 1), to be transformed into Hepatology, namely the study of liver structure, function, and disease. Presumably, the Haruspex—a priest who practiced haruspicy—then retrained as a hepatologist.FIGURE 1: Adjuncts to the practice of hepatoscopy. (A) Clay liver models found in 1935–36 by the French archeologist André Parrot, at Mari, Syria, dated to the 19th and 18th centuries BCE. (B) Inscribed Babylonian clay model of sheep liver ~1600 BCE, showing peg holes for recording the findings seen on inspection of the sacrificed animal's liver. Courtesy—the Trustees of the British Museum, London. (C) Etruscan life-size bronze model of sheep's liver ~100 BCE (left) with explanatory inscriptions (right), found in Piacenza. Courtesy—Musei Civici di Palazzo, Florence.Of course, hepatologists of yore were hampered in their ability to make accurate anatomical and pathological diagnoses, by the limited tools at their disposal, which were initially only visual examination, olfaction, palpation, dissection, and later inspection with a hand lens, and ultimately microscopy enhanced by tissue staining. Little wonder that there was agonizingly slow reliable confirmation of the occurrence of primary cancer of the liver. Along the way, investigators were also stymied by many obstacles to the elucidation of the nature of primary liver malignancies, including the difficult distinction between benign inflammatory nodular entities, like tuberculosis, and all forms of cirrhosis. Indeed, the evocative term tubercle was often applied to any small protuberant rounded lesion distinct from its surroundings. Even when hepatic histopathology was available, there were competing microscopic classifications, and a corresponding lexicon to name them, which was a Tower of Babel of semantic confusion. This perplexity was only made worse when a pathologist as eminent as Rudolf Virchow (Figure 2A) declared confidently that "organs commonly affected by metastases are rarely the site of primary neoplasia."5FIGURE 2: (A) Rudolf Ludwig Karl Virchow by Sir Leslie Ward, chromolithograph, published in Vanity Fair, May 25, 1893, NPG D44648 © National Portrait Gallery, London https://creativecommons.org/licenses/by-nc-nd/3.0/. (B) Aretaeus of Cappadocia. Source: Wikipedia. (C) Friedrich Theodor von Frerichs, Lithography by P. Rohrbach, 1859, from a photograph by G. Schauer. Source: Wikipedia. (D) Galen, Reprinted from Cheselden W: Frontispiece. Osteographia, or the Anatomy of the Bones. London 1733.4 (E) Paulus Aeginata, reprinted from Chriba M, Levell NJ. The bridge from west to east: Paulus Aeginata (625–690 AD).A comprehensive history of the discovery of HCC—the preferred term nowadays for primary liver cancer that also includes cholangiocarcinoma and other less frequent tumors—has recently been consummately reviewed in this series by Yamini Natarajan, MD, and renowned digestive disease epidemiologist Hashem B El-Serag, MD, MPH.6 Other less memorable terms for malignant tumors of hepatocytes included cancer trabeculaire, adenocarcinoma, carcinoma hepatocellulaire, malignant adenoma, and hepatoma that was applied to benign, malignant, and even intermediate lesions. Aside from the challenge of devising therapy for malignancies in general, it is evident that knowledge of the etiology and pathogenesis of HCC, determination of its stage, awareness of demographics, and acknowledgment of both related and independent comorbidities (such as diabetes mellitus, chronic viral hepatitis, and the number and severity of complications of cirrhosis), are adjuvant keys to successful treatment. Many of these variables are used in the various published HCC treatment decision trees, including those generated (Figure 3A)7 and regularly updated (Figure 3B)8,9 by the celebrated Barcelona Clinic Liver Cancer (BCLC) group—discussed further below.FIGURE 3: (A) First BCLC staging classification and treatment schedule. Four stages are considered. Stage A: Patients with early HCC are suitable for radical therapies (resection, liver transplantation, or percutaneous treatments); stage B: patients with intermediate HCC may benefit from chemoembolization; stage C: patients with advanced HCC may receive new agents in the setting of Randomized Controlled Trials; stage D: patients with end-stage disease will receive symptomatic treatment. Reprinted with permission from Llovet et al.7 (B) BCLC staging and treatment strategy in 2022. The prognosis is established in accordance with the 5 stages that are linked to first-line treatment recommendations. No longer divided according to curative or palliative, but stressing that recommended treatments improve survival. The expected outcome is expressed as the median survival of each tumor stage according to the available scientific evidence. Individualized clinical decision-making, according to the data available on November 15, 2021, is defined by teams responsible for integrating all available data with the individual patient's medical profile. Liver function is evaluated beyond the conventional Child-Turcotte-Pugh staging. Reprinted with permission from Reig et al.8 Abbreviations: AFP, alpha-fetoprotein; ALBI, albumin-bilirubin; BSC, best supportive care; CLT, cadaveric liver transplantation; ECOG-PS, Eastern Cooperative Oncology Group-performance status; LDLT, living donor liver transplantation; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; PEI, percutaneous ethanol injection; PS, performance status; PST, performance status test; RF, risk factor; TAE, transarterial embolization; TACE, transarterial chemoembolization.According to Natarajan and El-Serag,6 the Egyptian authors of the Ebers papyrus10 (1500 BCE, Figure 4A), as well as the originators of the equally venerable Edwin Smith surgical papyrus (3000 BCE),13 suspected the existence of liver cancer even though its differentiation from inflammatory swellings and chronic ulcerations was not achievable then. Naturally, it was in the writings (Figure 4B)11 of Hippocrates (460–375 BCE), a contemporary of Socrates (469–399 BCE), and Plato (427–347 BCE) that the term Karkinoma was coined (derived from the Greek word karkinos for crab, καρκίνος)12, which was latinized centuries later by the encyclopedist Galen to carcinoma, representing the malignant form of carcinos, a tumor. Confusingly, in the Hippocratic vernacular carcinoma apertus denoted malignant ulcers, while carcinoma occlusus referred to deep-seated or occult tumors. A less colorful term Phuma, which refers to any concentrated swelling in the body, is sometimes encountered but only rarely. As we have seen, technically Cancer meant a nonhealing malignant ulcer, similar to the 17th-century English words for certain ulcers, like canker and chancre. In contrast, scirrhus, a hard malignant tumor, was different from carcinos and carcinoma,14 in fact, commonly, it would have probably been a carcinoma occlusus.FIGURE 4: (A) The Edwin Smith Papyrus.10 (B) To the writings of Hippocrates, printed in Venice in 1588.11 (C) The frontispiece to the collected writings of Galen, printed in Venice in 1625.12 (D) Title page of Pauli Aeginetae Medici Opera, Apud Gulielmum Rovillium 1589. Source: Wellcome Library, London. (E) The title page from the second volume of Friedrich Theodor von Frerichs's Clinical Treatise on Diseases of the Liver, in an English translation by Charles Murchison, MD, FRCP, published by the New Sydenham Society in 1861.But why a crab? It is said that growing tumors allegedly reminded Hippocrates of a moving crab, resulting as we have seen in carcinos for tumor, and carcinoma for a malignant tumor. It was either Galen (second CE, Figure 2D ) in his writings (Figure 4C) or seventh century Paulus of Ægina (Figure 2E)15 who observed (Figure 4D) "…it appears at length with turgid veins shooting out from it, so as to resemble the figure of a crab; or as others say, because like a crab, where once it has got, it is scarcely possible to drive it away." According to the Theory of Atra Bile favored by Galen and later promoted by Paulus Æginata, an excess of black bile (atra bilis, melancholos, or choler niger), particularly thick black bile, caused severe ulcerated and incurable cancer16,17 unlike thin bile that causes nonulcerated curable cancer. And before Galen's teacher, Aglancon, thought that when the liver was too warm it generated atrabilious blood, ie, blood that was decomposed and not normal, and which overwhelmed the spleen.15 Cancer aside, melancholia, one of the disorders of the humors (ie, dyscrasias, from Ancient Greek dyskrasis "δυσκρασισ," meaning "a bad mixture," is also due to black bile, which comes from the spleen. The popular but erroneous lay notion (as mentioned in the nonspecialist account of cancer "The emperor of all maladies: a biography of cancer" by Siddhartha Mukherjee, published in 2010 by Charles Scribner and Sons, New York) and the professional idea that the Hippocratics thought that black bile causes cancer, may have arisen by innuendo from Paul of Aegina's reading of Galen. Ovid's poetic description,18 quoted by the great English lexicographer Dr. Samuel Johnson, is perhaps the most graphically startling, "As when a cancer on the body feeds, And gradual death from limb to limb proceeds; So does the chillness to each vital part, Spread by degrees, and creeps into the heart" (Figure 5). Incidentally, repeated failure to confirm the existence of black bile once anatomical dissection was permitted during the Renaissance proved fatal to the Atra Bile Theory of cancer pathogenesis.FIGURE 5: (A) Sixty-five-year-old man with otherwise uncomplicated alcohol-associated cirrhosis underwent echocardiography during the investigation of recent onset breathlessness. (A) The transthoracic (left) and transesophageal (right) echocardiograms showed a mass in the right atrium, which seemed to be arising from the inferior vena cava. (B) A combined abdominal and chest CT scan confirmed the presence of an intracardiac mass originating from a HCC in the liver that had invaded the vena cava and, as Ovid observed,18 "creeps into the heart." (C) A biopsy of the cardiac mass confirmed the presence of HCC (inset square) that had developed within the cirrhotic liver. Images courtesy—Adrian Reuben, series editor, from his personal collection.Arguably, the first clinically recognizable description of liver cancer was reported in the second-century CE19 by the Alexandrian physician Aretæus of Cappadocia (Figure 2B) (or Capadocia [Turkish: Kapadokya], the land of fairy chimneys, is a historical region in Central Anatolia, ie, Turkey. It is largely in the provinces of Nevşehir, Kayseri, Aksaray, Kirşehir, Sivas, and Niğde). Aretæus, whose exact dates are unknown even though he was a contemporary of Galen, described patients with livers swollen by inflammation, which transformed to a hardened state, eventually becoming scirrhus, ie, cancerous. This malignant transition then heralded early death because of a deterioration in liver function, which we now appreciate as decompensation of cirrhosis or "acute-on-chronic liver failure" (ACLF).20 This dismal portrait of the disease persisted during the centuries, as related in the 19th-century German Textbook of Liver and Biliary Diseases (Figure 4E) by Friedrich Theodor von Frerichs (Figure 2C). However, von Frerichs did acknowledge that some patients may present with indolent disease that would seem to preclude malignancy, despite vascular invasion and extrahepatic spread at necropsy. Primary liver cancer was considered almost nonexistent in the West so that when Charles Berman, a physician working in South Africa published, over an interval approaching a quarter of a century, a large series of monographs wholly devoted to Primary Carcinoma of the Liver,21–28 principally among the Bantu, these publications were seen as amounting to a unique collection of all the available knowledge. Berman provided information covering the descriptions published by physicians spanning the years from Aretæus to Morgagni, while extensively describing clinical scenarios and showing pathological findings. All the clinical cases were based on his personal experience with Bantu patients who worked in the Witwatersrand gold mines and were seen at the Johannesburg Non-European Hospital. Michael Kew (1939–2021) MB BCh, FCP(SA), MD, PhD, DSc, FRCP, (Figure 6A) single-mindedly pursued the study of all aspects of liver cancer in South Africa. Among the trove of his clinical and translational scientific achievements—upward of 500 publications (https://scholar.google.co.za/citations?user=ONGrV0QAAAAJ&hl=en accessed 2/14/2023)—he is perhaps most noted for his key role in establishing the clinical and molecular association between HBV infection and HCC, in a series of epidemiological, clinical, histological, virological, and molecular studies.29,30 Indeed, he was involved in the seminal description of p53 mutations in HCC,31 thereby pioneering the field of molecular profiling. Later on, this was pursued by Snorri Thorgeirsson, Jessica Zucman Rossi, Josep Llovet, Xin We Wang, and JC Nault among others, but it is still in need of robust validation for use in clinical decision-making. Mike Kew remained throughout a proud citizen of South Africa, which included his appointment as Personal Physician to the President (Figure 6B), but he also exported knowledge in the field through his mentees Morris Sherman (Figure 7A), who migrated to Toronto, Canada, where he developed a career in liver cancer and was a leader of major international clinical practice guidelines for liver cancer; Geoff Dusheiko33 and Adrian Di Bisceglie,32 who relocated to London, UK, and St Louis, MO, respectively (Figure 7B, C).FIGURE 6: Michael Charles Kew (1939–2021). (A) Consummate clinician, hepatologist, and hepatology investigator, reprinted from Thomson et al.29 https://creativecommons.org/licenses/by-nc/4.0/. (B) Personal Physician (1996–2010) to Nelson Mandela, President of South Africa, reprinted with permission from Kassianides et al.30FIGURE 7: (A) Morris Sherman MB BCh, PhD, FRCP(C), reproduced from the inaugural Toronto Liver Cancer Symposium, at which tribute was paid to the "truly phenomenal" career of Dr. Morris Sherman. Credit: UHC News. (B) Geoffrey M. Dusheiko MB BCh, FCP(SA), FRCP, FRCP (Edin), courtesy Geoffrey M. Dusheiko. (C) Adrian Di Bisceglie MB BCh, FAASLD, reprinted with permission from Hoofnagle.32It goes without saying that end-stage clinical status and an absence of effective treatment were common all over the world until it was feasible to diagnose the tumor at a stage before the patient was close to death. Diagnosis by physical examination, sometimes supplemented by obtaining a skinny needle biopsy, was not followed by any effective therapy. Indeed, the biopsy results could be received when the patients had already died, as tissue processing could take its time and, in some instances, may be performed at a distant location. Pathological guidelines for diagnosis and grading were established by Edmonson and Steiner,34 while modern criteria were prepared by a group of international pathologists led by Masamichi Kojiro35 (Figure 8A). Angiography was a conventional diagnostic tool until the development of ultrasonography, CT, and MRI. These latter noninvasive visualization techniques displaced angiography and scintigraphy for diagnosis and staging, and allowed diagnoses to be brought forward to an asymptomatic phase and early stage so that curative treatment resulting in long-term disease-free survival became feasible. The discovery of α-fetoprotein by Gari I Abelev (1928–2013)36,39 in 1963 in Moscow in the former Soviet Union (Figure 8B), provided a serum tumor marker for HCC40 that offered the potential for screening protocols using regular measurements, as was done in China41 and Alaska,42 where the high prevalence of HBV infection in the population was linked to a high liver cancer incidence. Indeed, the high prevalence of liver cancer in Asia and sub-Saharan Africa (Figure 9)43 together with the low prevalence reported in Europe and the Americas (likely due to underdiagnosis) corroborated the erroneous idea that HCC was not a disease that should occasion any attention in the West. Vaccination against HBV translates into a sharp decrease in HCC incidence in children and adults as shown in studies in Taiwan led by Din-Shin Chen44,45 and the same impact is expected by the Gambia project established by Ruggero Montesano.46FIGURE 8: (A) Professor Masamichi Kojiro with the author, from the author's personal collection (Kurume, 2005). Dressed up as required after many years of friendly relationships with Japanese leaders, which started in 1990. (B) Gari Izrailevich Abelev. Reprinted with permission from Engelhardt et al.36 (C and D) Kunio Okuda and his pastimes, reprinted with permission from Reuben et al.37 (E) Claude Couinaud working with his collection of "liver casts" at the school of medicine in Paris 1988. Reprinted with permission from Felekouras et al.38 (F) The somewhat flamboyant gravestone of Claude Couinard's grave, which illustrates his lifelong and seemingly posthumous devotion to the segmental anatomy of the liver. Sad to report that when Claude Couinard died in 2008, he was alone, away from his family. In his honor, anatomists from Tunisia, including Jacques Belghiti, a native of Morocco (who is seen in this photograph) organized the creation and subsequent installation in 2018 of the gravestone that celebrates Couinard's contribution to our knowledge of liver surgical anatomy, and particularly its segmental arrangement. Photograph courtesy of Jacques Belghiti.FIGURE 9: The most prevalent causes of HCC and their percent contributions in causing HCC in different countries in northern Africa and the Middle East. The countries in (1) North Africa were: Egypt, Tunisia, Morocco, Algeria, and Somalia, and in (2) the Middle East were: Iran, Lebanon, Turkey, Yemen, Saudi Arabia, and Pakistan. Reprinted from Alavian, et al.43 https://creativecommons.org/licenses/by-nc/4.0/.Trials in China explored the potential of early detection through ultrasound and α-fetoprotein determination.41 The wide use of ultrasound in Asia, more intensely in Japan47 and Taiwan, allowed HCC detection at an early stage. Such capability was also shown in Europe by studies from Massimo Colombo in Milano48 and Luigi Bolondi in Bologna.49 The ability to diagnose liver cancer at an early stage emphasized the need to stratify the patients according to stage and prognosis, in order to discern if any intervention might be of benefit, compared to the natural history of the disease (ie, no intervention). The 1975 study, by Olweny et al,50 testing the effect of Adriamycin on the survival of patients with advanced disease provided suggestively positive results and thereby gave credence to the Kampala staging system51 (Table 1), based on a cohort with a median survival of less than 2 months. Kampala staging was later replaced by several other schemes with slightly more accurate clinical profiling. Cochrane et al52 developed a western scoring system (Table 2) that included 7 variables aimed at identifying those patients among a cohort of 18 individuals who would survive for more than 14 weeks and thus be considered for systemic treatment. The Okuda staging system53 (Table 3) was proposed later by the Japanese Liver Cancer Study Group and was widely used when the treatment of liver cancer gained more interest. Kunio Okuda (Figure 8C and D) was a worldwide key opinion leader based in Chiba (Japan), whose major research and educational achievements facilitated international progress in the field.37 Some additional scoring or stratifying proposals were put forward but ultimately the emergence of the BCLC model7–9 (Figure 4A) became the backbone of clinical decision-making that was endorsed by several scientific association practice guidelines, research consortia, and reviews. The BCLC model has been regularly updated to include the advances in knowledge with the necessary background evidence; the last update was released in 20228 (Figure 4B). TABLE 1 - Kampala staging classification stratifying patients with liver cancer into 3 categories according to expected survival Stage Ia No ascites, weight loss, or portal hypertension (ie, no abdominal collaterals), bilirubin<2.0 mg/dL Stage IIa Ascites and/or moderate (25%) weight loss, no portal hypertension, bilirubin 2 mg/dL aIA, IIA, and IIIA signify appropriate stages with associated distant metastatic disease.Reprinted with permission from Primack et al.51 TABLE 2 - The Cochrane colleagues scoring system to stratify patients according to prognosis Variable Parameter Score Parameter Score Age (y) 50 2.5 Duration of symptoms (mo) >3 5.8 <3 3.3 Weight loss (%) 15 3.3 Ascites Absent 7.3 Present 1.4 Cirrhosis Absent 10.0 Present 2.5 AST <2x normal 6.3 ≥2x normal 4.0 Bilirubin 35 were classified as Grade A and those with a score ≤35 as Grade B, predicting survivals longer or shorter than 14 weeks, respectively.Abbreviation: AST, aspartate transaminase.Reprinted with permission from Cochrane et al.52 TABLE 3 - The Okuda staging system for HCC Points Variables 0 1 Tumor size 50% of liver volume Ascites Absent Present Albumin (g/dL) >3 <3 Bilirubin (mg/dL) 3 Note: Interpretation: The sum of points according to the profile of four variables is used to stratify patients into 3 stages, namely stage I: 0 points, stage II: 1–2 points, stage III: 3–4 points, which are that would associate with clearly distinct life expectancies.Reprinted with permission from Okuda et al.53 The following sections summarize the development of each of the effective treatment options while highlighting the landmark contributions that paved the way for our current knowledge. Ancient practitioners, especially the Greco-Roman physicians, formulated an imposing spectrum of therapies, which included topical applications—albeit caustic ones, like calcined verdigris (copper sulfate), salts of lead and sulfur, and so-called "Egyptian ointment," ie, arsenic paste, and less noxious concoctions like boiled cabbage and a salted mixture of honey and egg white or fig. Hippocrates wrote that tumors that are not cured by medicine are cured by iron (the knife), those that are not cured by iron are cured by fire (cautery), and those that are not cured by fire are incurable.11 It was even realized that therapy was most likely to be successful at the precursor or first stage of malignancy, known as cacoethes14,15 from the Latin cacoēthes, which was borrowed in turn from the Greek, kakóēthes, ie, κακοήθης—its many meanings include malignant or literally, of "bad character."15 SURGICAL TREATMENT Tumor resection was once the mainstay and the sole available treatment that could offer a long-term cure. However, the desperate situation of patients presenting with advanced disease prompted a less restrictive selection of candidates. This resulted in major morbidity and postoperative mortality due to liver failure. Understaging because of suboptimal accuracy of imaging techniques was common and the presence of advanced liver disease with severe portal hypertension and even clinical decompensation (ascites and overt jaundice) resulted in very poor outcomes, and also in high recurrence rates in those who would survive the early follow-up period. Hippocrates also cautioned against operating on carcinoma occlusus because such surgery was likely to make the patients worse and hasten their demise.15 Although Galen recommended leaving a wide margin of healthy tissue when removing cancer, he believed, notwithstanding, that the best surgeon was the one who only operated as a last resort. Perhaps Galen's affirmation of the Roman prejudice against surgery was underpinned to some extent by his experiences as a surgeon to the gladiators. In the setting of surgery for advanced cancer, Pliny the Elder (23–79 CE), in his Materia Medica (a largely plant-based pharmacopeia), recommended various potions of herbs and other remedies for internal use before and after operations, the most highly praised being a brew of boiled ash of sea crabs, egg white, honey, and powdered feces of falcons.12,16 After the fall of the Western Roman Empire, the baton of medicine passed to physicians of The Islamic Civilization, as deftly related in the forthcoming essay in this series, on the liver in Islam by Rifaat Safadi.54 Arabic and Persian surgeons were similarly wary of operating on cancer, a reluctance that persisted for many centuries.12 Results of several studies clearly established the risk of postoperative morbidity and death related to impaired liver function due to underlying cirrhosis,55 and the prognostic relevance of so-called clinically significant portal hypertension, ie, a portal pressure of >10 mm Hg55 (Figure 10A, B) usually determined by the Hepatic Venous Pressure Gradient method.55–60 At the same time, it was repeatedly shown that resection of multifocal disease or when vascular invasion was already present was associated with a very high risk of recurrence.61 All these observations stimulated the progressive refinement of candidate selection and emphasized the need to avoid major removal of liver tissue in order to spare as much nontumoral liver as possible. Incorporation of the hepatic anatomy according to segments as defined by the Parisian anatomist and surgeon Claude Couinaud (1922–2008),38 from Neuilly-sur-Seine (Figure 8E), gave the rationale for anatomical resection62 (Figure 8F).FIGURE 10: The outcomes of hepatic resection for HCC, in patients with cirrhosis stratified according to portal pressure determined by HVPG measurement. (A) Results in 18 patients who had uneventful perioperative outcomes, including 5 individuals with HVPG ≥10 mm Hg, and in 11 patients who all had HVPG ≥10 mm Hg and all decompensated. There were no deaths in this 29-patient cohort. Reprinted with permission from Bruix et al.56 (B) Long-term postoperative survival (%) in 77 patients, stratified by HVPG and serum bilirubin. Five-year cumulative survivals were (1) 74% in 35 patients with HVPG <10 mm Hg, (2) 50% in 15 patients with HVPG ≥10 mm Hg and normal serum bilirubin, (3) only 25% in 27 patients with HVPG ≥10 mm Hg and bilirubin ≥1 mg/dL. Reprinted with permission from Llovet et al.57Successful surgical achievement was impressive in countries such as China under the leadership of the Shanghai University group led by Zhao-You Tang63 and the Shanghai East Hepatobiliary Surgery Hospital led by Meng-Chao Wu.64 Major contributions such as using intraoperative ultrasonography to guide segmentectomy and a very clinically oriented and still useful decision tree (Figure 11) to decide the magnitude of resection based on liver function65,66 were made by the innovative Masatoshi Makuuchi (Figure 12A) who also developed intraoperative ultrasound to guide resection. Currently, postoperative HCC resection deaths should remain below 1%, the risk of major operative bleeding should be <10%, and 5-year survival rates could be as high as 70%, even though successful tumor resection may still be hampered long-term because of tumor recurrence. No effective intervention existed to reduce this recurrence risk until the positive results achieved by the combination of atezolizumab and bevacizumab.71 So major hope is now invested in further progress with the new immune-oncology agents. Laparoscopic72 and robotic73 resections allow less invasive interventions with less morbidity and shorter hospital stays.FIGURE 11: Flowchart to select patients for surgical resection and extent of liver resection according to the presence of ascites and its response to treatment, serum bilirubin (mg/dL), and ICG retention (%) at 15 minutes as proposed by Professor Masatoshi Makuuchi.65,66 Abbreviation: ICG, indocyanine green.FIGURE 12: (A) Professor Masatoshi Makuuchi, Reprinted from Xu et al.67 https://creativecommons.org/licenses/by-nc-nd/4.0/. (B) Professor Leslie H Blumgart (1931–2022). Reprinted with permission from Bhattacharya et al.68 (C) Professor Henri Bismuth (b 1934). Reprinted with permission from He.69 (D) Professor Jacques Belghiti; recipient of the 2015 International Hepato-Pancreato-Biliary Association Distinguished Service Medal, among a host of other awards. Courtesy—Jacques Belghiti. (E) Professor Thomas E. Starzl (1926–2017). Reprinted with permission from Rakela et al.70 (F) Professor Sir Roy Y. Calne (1930–2024), on the occasion of the naming of the specialist transplant unit at Addenbrooke's Hospital as "The Roy Calne Transplant Unit," in 2021. Picture courtesy of Cambridge University Hospitals NHS Foundation Trust. (G) A somewhat menacing Mafia-style photograph of the author with Professors Michel Beaugrand, Olivier Seror, and Jean-Charles Nault, from the author's personal collection (Saint Victor des Oules, 2019). At a variation of a multispeciality tumor board dinner at Michel Beaugrand's place, there was ample time to debate the past, present, and future of liver cancer research, and offers that could not be refused!!. (H) The author with the members of the Founding Governing Board of the International Liver Cancer Association (ILCA, Milan, 2009), from the author's personal collection. Front row from left to right: Masamichi Kojiro (Japan), Nelson