Valentina Santi

Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival

BACKGROUND & AIMS The current guidelines recommend the surveillance of cirrhotic patients for early diagnosis of hepatocellular carcinoma (HCC), based on liver ultrasonography repetition at either 6 or 12 month intervals, since there is no compelling evidence of superiority of the more stringent program. This study aimed at comparing cancer stage, treatment applicability, and survival between patients on semiannual or annual surveillance. METHODS We analyzed the clinical records of 649 HCC patients in Child-Pugh class A or B, observed in ITA.LI.CA centers. HCC was detected in 510 patients submitted to semiannual surveillance (Group 1) and in 139 submitted to annual surveillance (Group 2). In Group 1 the survival was presented as observed and corrected for the lead time. RESULTS The cancer stage was less severe in Group 1 than in Group 2 (p<0.001), with more single tiny (2 cm) and less advanced tumors. Treatment applicability was improved by the semiannual program (p=0.020). The median observed survival was 45 months (95% CI 40.0-50.0) in Group 1 and 30 months (95% CI 24.0-36.0) in Group 2 (p=0.001). The median corrected survival of Group 1 was 40.3 months (95% CI 34.9-45.7) (p=0.028 with respect to the observed survival of Group 2). Age, platelet count, alpha-fetoprotein, Child-Pugh class, cancer stage, and hepatocellular carcinoma treatment were independent prognostic factors. CONCLUSIONS Semiannual surveillance increases the detection rate of very early hepatocellular carcinomas and reduces the number of advanced tumors as compared to the annual program. This translates into a greater applicability of effective treatments and into a better prognosis.

Hepatocellular Carcinoma: Trends of Incidence and Survival in Europe and the United States at the End of the 20th Century

OBJECTIVES:There is large geographic variation in incidence levels and time trends of hepatocellular carcinoma. We compared population-based liver cancer incidence and survival in European and U.S. populations in order to elucidate geographic differences and time trends for these variables.METHODS:Since comparisons based on cancer registry data are problematic because of variations in liver cancer definition and coding, we considered a subset of cases likely to be mainly hepatocellular carcinoma, suitable for international comparison. Incidence and 5-yr relative survival were calculated from cases diagnosed in five European regions (30,423 cases) and the United States (6,976 cases) in 1982–1994.RESULTS:Age-standardized incidence was highest in southern Europe (12/100,000 in men and 3/100,000 in women in 1992–94) and lowest in northern Europe, where incidence was similar to that of the United States (3/100,000 in men, <1/100,000 in women). Over the study period, incidence remained stable in the United States and most of Europe, except for a notable increase in southern Europe. Five-year relative survival was <10% in Europe, ranging from 8% (southern Europe) to 5% (eastern Europe), and 6% in the United States. Survival increased slightly with time, mainly in southern Europe and was unaffected by sex, but was better in younger patients.CONCLUSIONS:Increasing incidence in southern Europe is probably related to hepatitis B and C infection and increasing alcohol intake, while improving survival may be due to greater surveillance for cirrhosis. The survival gap between clinical and population-based series suggests management is better in centers of excellence.

Treatments for hepatocellular carcinoma in elderly patients are as effective as in younger patients: a 20-year multicentre experience

Objectives The number of elderly patients diagnosed with hepatocellular carcinoma (HCC) is expected to increase. We compared the presenting features and outcome of HCC in elderly (≥70 years) and younger patients (<70 years). Design Multicentre retrospective cohort study and nested case–control study. Patients 614 elderly and 1104 younger patients from the ITA.LI.CA database, including 1834 HCC cases consecutively diagnosed from January 1987 to December 2004. Both groups were stratified according to treatment: hepatic resection, percutaneous procedures, transarterial chemoembolisation (TACE). Survival was assessed in the whole population and in each treatment subgroup. Age, sex, aetiology, cirrhosis, comorbidities and cancer stage (CLIP score) were tested as predictors of survival. In each subgroup, differences in patient survival were also assessed after adjustment and matching by propensity score. Results Ageing was associated with a higher prevalence of comorbidities, better liver function and CLIP score. Regardless of age, two-thirds of patients underwent radical treatments or TACE. Elderly patients underwent more ablative procedures and fewer resections or TACE sessions. The survival of elderly and younger patients was comparable in each treatment subset, and was predicted by CLIP score. This result was confirmed by the propensity analysis. Conclusions The overall applicability of radical or effective HCC treatments was unaffected by old age. However, treatment distribution differed, elderly individuals being more frequently treated with percutaneous procedures and less frequently with resection or TACE. Survival was unaffected by age and primarily predicted by cancer stage, assessed by the CLIP system, both in the overall population and in treatment subgroups.

Hepatocellular carcinoma in non-cirrhotic liver: A reappraisal

Although not frequently, hepatocellular carcinoma (HCC) can ensue in a non-cirrhotic liver. As compared to cirrhotic HCC, this kind of tumour has some peculiarities, such as: (a) a lower male preponderance and a bimodal age distribution; (b) a lower prevalence of the three main risk factors (hepatitis B and C virus infections and alcohol abuse), with an increased prevalence of other etiologic factors, such as exposure to genotoxic substances and sex hormones, inherited diseases, genetic mutations; (c) a more advanced tumour stage at the time of diagnosis, as it is usually detected due to the occurrence of cancer-related symptoms, outside any scheduled surveillance program; (d) a much higher amenability to hepatic resection, due to the low risk of liver failure even after extended parenchymal mutilation; (e) overall and disease-free survivals after resection of non-advanced tumours (meeting the Milano criteria) comparable to that obtained with liver transplantation in cirrhotic patients carrying an early tumour; (f) overall survival strictly dependent on tumour burden (and its recurrence) and barely influenced by liver function.

Surveillance for Early Diagnosis of Hepatocellular Carcinoma: Is It Effective in Intermediate/Advanced Cirrhosis?

OBJECTIVES:Surveillance of cirrhotic patients for early diagnosis of hepatocellular carcinoma (HCC), based on ultrasonography and alpha-fetoprotein (AFP) measurement, is widely used. Its effectiveness depends on liver function, which affects the feasibility of treatments and cirrhosis-related mortality. We assessed whether patients with intermediate/advanced cirrhosis benefit from surveillance.METHODS:We selected 468 Child-Pugh class B and 140 class C patients from the ITA.LI.CA database, including 1,834 HCC patients diagnosed from January 1987 to December 2004. HCC was detected in 252 patients during surveillance (semiannual 172, annual 80 patients; group 1) and in 356 patients outside surveillance (group 2). Survival of surveyed patients was corrected for the estimated lead time.RESULTS:Child-Pugh class B: cancer stage (P < 0.001) and treatment distribution (P < 0.001) were better in group 1 than in group 2. The median (95% CI) survivals were 17.1 (13.5–20.6) versus 12.0 (9.4–14.6) months and the survival rates at 1, 3, and 5 yr were 60.4% versus 49.2%, 26.1% versus 16.1%, and 10.7% versus 4.3%, respectively (P = 0.022). AFP, gross pathology, and treatment of HCC were independent prognostic factors. Child-Pugh class C: cancer stage (P = 0.001) and treatment distribution (P = 0.021) were better in group 1 than in group 2. Nonetheless, median survival did not differ: 7.1 (2.1–12.1) versus 6.0 (4.1–7.9) months (P = 0.740).CONCLUSIONS:These results suggest surveillance be offered to class B patients and maintained for class A patients who migrate to the subsequent class. Surveillance becomes pointless in class C patients probably because the poor liver function adversely affects the overall mortality and HCC treatments.

QT interval prolongation by acute gastrointestinal bleeding in patients with cirrhosis

QT interval prolongation is frequent in cirrhosis, and stressful conditions could further prolong QT. We aimed to test this hypothesis and, if it proved correct, to assess its prognostic meaning.

Terlipressin infusion induces Tako-Tsubo syndrome in a cirrhotic man with hepato-renal syndrome

Dr. Di Micoli, Dr. Buccione, Prof. Trevisani: TakoTsubo cardiomyopathy (TTC), also known as transient left ventricular apical ballooning syndrome, is a clinical entity characterized by (1) reversible left ventricular apical wall motion abnormalities, (2) typical electrocardiographic changes and (3) relatively minor elevation of troponine, creatinine-kinase (CK) and CK-MB that mimics an acute myocardial infarction (AMI) without any acute obstructive coronary disease [1]. Typically, the left ventricular imbalance almost always recovers in a period of days to weeks, so that the management and prognosis of this condition are clearly different from those of AMI [2]. TTC is generally observed in post-menopausal women without prior history of heart disease or clear risk factors for coronary artery disease, who have often experienced recent emotional or physical stress, non-cardiac surgery or extracardiac diseases [1]. Recently, TTC has also been described in critically ill patients without prior heart disease admitted to a medical intensive care unit for severe non-cardiac diseases, such as sepsis, acute respiratory failure, systemic inflammatory response syndrome, anaphylaxis and trauma injuries [3, 4]. Herein, we report a case of TTC occurring in a cirrhotic man, waiting for liver transplantation (LT), probably favored by the intravenous infusion of terlipressin, a synthetic analog of vasopressin (AVP), for the treatment of hepato-renal syndrome (HRS). A 67-year-old Caucasian man with hepatitis B virusrelated cirrhosis and ascites, waiting for LT, was admitted to our unit because of the onset of hepatic encephalopathy, and the worsening of renal sodium retention. As a candidate for LT, he had undergone clinical, laboratory and instrumental tests aimed at excluding extrahepatic diseases precluding surgery. Myocardial single photon emission computed tomography had excluded ischemic damage, and trans-thoracic echocardiography had ruled out dyskinesia of ventricular segments and documented a normal (65%) left ventricular ejection fraction (LVEF). On admission, the patient presented with peripheral edema, ascites and grade III hepatic encephalopathy. Daily diuresis was around 200 mL. The ongoing therapy included oral diuretics (furosemide 25 mg b.i.d. and spironolactone 100 mg b.i.d.), lamivudine and tenofovir for HBV infection control, norfloxacine (400 mg/day) for secondary prophylaxis of the spontaneous peritoneal peritonitis, lactulose, and periodic albumin infusion. The serum creatinine was 2.2 mg/dL and blood urea nitrogen 0.9 g/dL, while serum electrolyte concentrations were normal (sodium 138 mEq/L, potassium 3.5 mEq/L, calcium 8.9 mg/dL and magnesium 2.6 mEq/L). The hemoglobin level was 10.4 g/dL, platelet count 134.000/lL, leukocytes 8.0 9 10/mmc, serum bilirubin 18.8 mg/dL, albumin 3.4 g/dL, INR 2.11. A. Di Micoli D. Buccione V. Santi L. Bastagli M. Bernardi F. Trevisani Dipartimento di Medicina Clinica, Alma Mater Studiorum-Universita degli Studi di Bologna, Bologna, Italy

Prognostication of the outcome of hepatocellular carcinoma: How to rely on science instead of on the art of Nostradamus

A suitable prognostic assessment is of paramount imporance for the correct management of any progressive and ventually lethal disease. In fact, an outcome prediction, ased on the presenting features of the disease, allows physiians: (1) to assess, in phase I and phase II studies, if a reatment can improve the expected natural course of the illess (when no established treatment is currently available) or f the tested intervention promises to be better than the usual reatment (when the prognostication also takes into account he effect of established treatments); (2) to allocate patients ith an equivalent baseline prognosis to each group of phase II clinical trials; (3) last but not least, to provide correct nformation to patients and relatives at the time of diagnosis nd treatment selection, helping the doctor to properly mange the delicate relationship with both the patient and their amily. Prognostic systems rely on a combination of survivalssociated variables emerging from the analysis of the natural” history of the disease (when no effective treatment s available or using data from placebo groups of randomzed trials) or the “treatment-modified” outcome, which are he integrated result of both the natural course as well as he treatment of the disease (Fig. 1). To generate these sysems, patients are usually graded according to a “scoring” ethod, summing the different weight given to each variable ccording to a clinical judgment or mathematical models. The validity of a staging system depends on the degree ith which it accomplishes the following performance charcteristics:

Telangiectasia as a Presenting Sign of Graves’ Disease

Acquired nevoid telangiectasia (ANT) is observed in several conditions including primary cutaneous disorders, systemic autoimmune disease and hyperestrogenism occurring in puberty, pregnancy and chronic liver disease. We describe a patient in whom ANT was a presenting sign of autoimmune hyperthyroidism, which improved after thyroidectomy. A 43-year-old Caucasian woman experienced an asymptomatic development of multiple widespread red skin lesions, diagnosed to be ANT. Blood tests revealed increased serum levels of free tri-iodothyronine and thyroxine and suppressed thyroid-stimulating hormone. Other causes of ANT were excluded. ANT improved but did not disappear after thyroidectomy. The possible pathogenetic factors linking ANT and Graves’ disease, such as an immune-mediated process, altered estrogen metabolism or vasodilatation associated with hyperdynamic circulation, are discussed.