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Paziente maschio di 74 anni Storia di ipertensione arteriosa. Giunge alla nostra osservazione nel giugno 2002 per ictus ischemico. In tale occasione viene.

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Presentazione sul tema: "Paziente maschio di 74 anni Storia di ipertensione arteriosa. Giunge alla nostra osservazione nel giugno 2002 per ictus ischemico. In tale occasione viene."— Transcript della presentazione:

1 Paziente maschio di 74 anni Storia di ipertensione arteriosa. Giunge alla nostra osservazione nel giugno 2002 per ictus ischemico. In tale occasione viene diagnostica epatopatia cronica HCV-relata in fase cirrotica ben compensata (Child- Pugh A5). Inizia follow up ecografico e clinico semestrale. Ottobre 2002, sfumata area iperecogena di 10 mm nel VI segmento sottocapsulare. Lieve splenomegalia (area 54 cmq) Vene epatiche con flusso appiattito. Vena porta con velocità di 19 cm/sec, RI splenico 0.70) Storia clinica

2 1. 1.Viene rivisto a 4 mesi circa (febbraio 2003). Si conferma il piccolo nodulo di 11 mm. Si consiglia TC. Viene eseguita e risulta negativa. Si programma uno stretto follow up Maggio 2003 Permane immodificata la lesione debolmente iperecogena di 11 mm nel VI segmento. Non ulteriori lesioni focali Ottobre 2003 In sede centroepatica, strettamente adiacente al ramo portale posteriore destro, è presente un'area ipoecogena di 17 mm con scarsi segnali vascolari al suo interno.Permane invariata la lesione focale debolmente iperecogena di 11 mm al 6° segmento. Si procede ad angioecografia perfusionale.

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5 Fase arteriosaFase portale TC spirale trifasica ( )

6 Fase portale TC spirale trifasica ( ) ?

7 CLINICA, DIAGNOSTICA E TERAPIA DELLEPATOCARCINOMA Luigi Bolondi Cattedra di Clinica Medica Dipartimento di Medicina Interna e Gastroenterologia Università di Bologna - Policlinico S. Orsola Malpighi

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9 INCIDENCE OF HCC IN LIVER CIRRHOSIS annual incidence Oka et al, % Colombo et al, % Pateron et al, % Benvegnu et al, % Cottone et al, % Solmi et al, % Bolondi et al, %

10 CIRROSI VIRUS HCC Flogosi cronica Necrosi Rigenerazione epatocitaria Diminuita capacità riparatrice dei danni al DNA Aumento errori di replicazione e trascrizione del DNA Eterogeneità geografica Diversi fattori di rischio Diversi bersagli a livello molecolare

11 Acute hepatitis Chronic hepatitis Cirrhosis DecompensationHCC Death 85% 20% 6%4% 3,6% Di Bisceglie, Hepatology, 2000 Factors affecting natural history HLA type Male gender Age on onset Alcohol Interferon Hepatitis B Alcohol Interferon Transplantation

12 INCIDENCE OF HCC DURING THE SURVEILLANCE PROGRAMME OF LIVER CIRRHOSIS ( ) 313 patients with a follow-up of months 74 nodules (23,6 %) 13 cases non HCC61 HCC (19,5 %) Bolondi et al. Gut 2001

13 SCREENING FOR HCC IN CIRRHOSIS ANALYSIS OF SURVIVAL BENEFIT Significant longer survivals for screened vs non screened p = 0.009(Wong, Liver Transpl 2000) p < (Yuen, Hepatology 2000) p < 0.02(Bolondi, Gut 2001) p < 0.001(Trevisani, Am J Gastro 2002) No Significant difference * (Sarasin, Am J Med 1996) * transplantation not included in the model

14 Tailoring screening on RISK FACTORS FOR HCC IN CIRRHOSIS Age ( Aizawa, Cancer 2000) Male gender ( Zoli, Cancer 1996 Bolondi, Gut 2001 El Serag, J Clin Gastro 2002) Child-Pugh score (Bolondi, GUT 2001) HBsAg + (Solmi, Am J Gastro 1996) Tsukuma, N Engl J Med 1993) HCV+ (Velazquez, Hepatology 2003) HBV + HCV (Parkin, IARC 1992) HCV + alcol (Benvegnù, Gut 2001) AFP (Bolondi, Gut 2001)

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17 DEVELOPEMENT OF NEOPLASTIC GROWTH IN MACROREGENERATIVE NODULES ARAKAWA 1986RECOGNITION OF EARLY MALIGNANT FOCI IN 5 ADENOMATOUS HYPERPLASTIC NODULES N°nodulesmean follow-up 9 neoplastic growth TAKAYAMA yrs 9 benign behaviour 10 neoplastic growth RAPACCINI mos 2 benign behaviour 0 neoplastic growth KONDO > 1 yr 17 benign behaviour 7 neoplastic growth BOLONDI mos 5 benign behaviour

18 PREDICTION OF MALIGNANT EVOLUTION IN SMALL NODULES (< 1.5 cm) DETECTED AT IMAGING TECHNIQUES IMAGINGNEW TISSUE MARKERSMOLECULAR ANALYSIS Assessment of vascularity Markers of proliferation (AgNORs, PCNA, Ki67...) Enzymatic cytochemistry DNA ploidy Assessment of monoclonality Genomic instability and LOH CLINICAL CRITERIA Volume increase at 4 month Probably no consequence on outcome

19 Largeregenerativenodule DysplasticnoduleBorderlinelesion HCC Portal flow Arterial flow Blood supply of liver nodules in cirrhosis

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22 CHARACTERIZATION OF LIVER MASSES: ASSESSMENT OF VASCULARITY BY IMAGING TECHNIQUES DOPPLER QUANTITATIVEQUALITATIVE SPECTRAL ANALYSIS COLOR and POWER mapping + mdc SPIRAL CT Contrast-enhanced NMR CONTRAST-ENHANCED US Stimulated Acoustic EmissionHarmonic Imaging Pulse InversionC 3 -mode CnTi

23 ARTERIAL HYPERVASCULARITY IN SMALL HEPATOCELLULAR CARCINOMA Perfusional Angiosonography with Sonovue Spiral CT enhanced artherial phase

24 HCC - Hyperintensity in the arterial phase - Iso or Hypointensity in the portal and late phases

25 DIAGNOSIS OF HCC Cirrhotic patients(US + AFP/6m) Liver noduleNo nodule Normal AFP Increased AFP* Spiral CT Surveillance US + AFP/6m 1-2 cm> 2 cm< 1 cm US /3m No HCC AFP > 400 ng/ml Doppler/CT/MRI/An HCC FNAB * AFP level >200ng/dl Bruix, J Hepatol,2001

26 STAGING: OPEN PROBLEMS AND AREAS FOR FUTURE RESEARCHES Multinodularity Vascular invasion Selection between radical treatment or palliation Imaging techniques insufficient Selection between OLT and ablation/destruction therapies Need for adjuvant therapy Recurrence potential Tissue and molecular markers (Currently not done)

27 Local therapy Surgical resection Transplant Percutaneous echo-guided Intra-arterial Systemic chemotherapy or hormonal therapy THERAPEUTIC OPTIONS FOR HCC

28 EFFECT OF TREATMENT ON SURVIVAL OF 1108 PTS WITH HCC Multicentric Italian Study Group on HCC SURVIVAL OF SINGLE HCC <5 cm Child A J Hepatol, 1995

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30 SCREENING FOR HCC IN CIRRHOSIS ELIGIBILITY FOR CURATIVE TREATMENTS HCC detected within surveillance programme HCC detected outside surveillance programme 47.5 % 31.7 % p < 0.01 (Bolondi, Gut 2001)

31 High rate of exclusion criteria from surgical resection (5-9% of pts arising from screening are candidate to surgery) High recurrence rate after surgical resection 3 year recurrence 72% Ikeda et al, year recurrence 83% Ng et al, % Belghiti et al, % Gouillat et al, 1999 Rationale for the use of local treatments

32 HEAT laser, radiofrequency, highly focused ultrasound FROST cryosurgery DRUGS alcohol injection RADIOACTIVITY implantation of radioactive seeds INTERSTITIAL TUMOR ABLATION

33 Survival Outcomes in PEI-Treated Pts (Retrospective Studies) Author and year Shiina S et al, AJR 1993 Livraghi T et al, Radiology 1995 Child A, single < 5 cm Child B, single < 5 cm Lencioni R et al, Cancer 1995 Child A, single / multiple < 3 cm Child B, single / multiple < 3 cm No. of Pts Survival (%) 3-yr5-yr1-yr

34 SURVIVAL AFTER SURGICAL AND NONSURGICAL TREATMENT FOR HCC HCC < 2 cm clinical stage I 5 cm > HCC > 2 cm all clinical stages Surgery > PEI (n=8.010) (n=4.037) (retrospective study) (Arii et al, Hepatology 2000 Liver Cancer Study Group of Japan)

35 Castells et al, Hepatology 1993 p = N.S. Yamamoto et al, Hepatology 2001 p = N.S. - Same tumor stage - Poorer liver function in PEI groups PEI versus Surgical Resection (Non-Randomized Studies)

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37 os s Quae maedicamenta non sanant, ferrum sanat,quae ferrum non sanat, ignis sanat,quae vero ignis non sanat, insanabilia reputari oportet Ippocrate, Aforisma 7, 87

38 RF THERMAL ABLATION EXPANDABLE NEEDLE (1.9 mm) 4 to 10 nickel-titanium hooks with tip thermistors °C90-115°C

39 RF THERMAL ABLATION COOLED-TIP NEEDLE ( mm) 20-25°C20-25°C Peristaltic pump with 0°C saline solution

40 RF Ablation of HCC: Local Effect (histologic assessment after OLT) 24 pts, 47 HCC lesions (0.4 – 5.5 cm; mean, 2.3 cm) - Complete necrosis on histology: 35 / 47 (74%) Lu DSK et al, Radiology 2005

41 PEI series (n = 184) - Lencioni R et al, Eur Radiol 1997 Overall Survival 67 %

42 Lin SM et al Gastroenterology % 74 %

43 RANDOMIZED COMPARISON OF RF THERMAL ABLATION vs PEI 232 patients with up to 3 HCC < 3 cm each RF PEI Treatment sessions p< yr survival74%57% p=0.01 4yr Overall recurrence 70% 85%p= yr Local progression 1.7% 11%p=0.003 Shiina, Gastroenterology 2005

44 COMPARING THE OUTCOMES OF RF ABLATION AND SURGERY IN PTS WITH SINGLE SMALL HCC AND WELL-PRESERVED HEPATIC FUNCTION Hong SN et al, J Clin Gastroenterol 2005

45 Barcelona PERCUTANEOUS ABLATION Summary and conclusions RF thermal ablation has emerged as the most valid alternative to PEI. According to various studies, its failure in achieving local control is lower than PEI. Data on survival are still preliminary and are influenced by different patient selection The complication rate of RF was initially considered higher but recent reports do not confirm this finding In HCCs of 3 to 5 cm the efficacy of a percutaneous treatment in achieving local control is questionable Individual factors play an important role in treatment selection Other techniques such as microwave or Laser have a minor impact PEI can probably maintain a place in the treatment of very small nodules (<2 cm) or in difficult locations (perivascular)

46 multifocal HCC

47 PROBLEMS IN EVALUATION RCTs ON TRANSARTERIAL CHEMOEMBOLIZATION Small sample size Differences in treatment procedures (chemoterapeutic agent - Cysplatin, Mytomicin, Doxorubicin -, embolization, number and interval of procedures) Patients selection and stratification

48 TERAPIA DELL HCC UNIFOCALE IN FEGATO CIRROTICO CONCETTI CHIAVE Pz con nodulo singolo < 5 cm (e buon compenso epatico) ottimi candidati alle terapie locoregionali percutanee: lalcolizzazione è la tecnica di scelta Pz in classe Child-Pugh A a basso rischio operatorio e nodulo unico candidati a resezione anatomica Noduli >3 cm: Se non resecabili, si può associare PEI + TACE Noduli < 3 cm: Risultati migliori

49 TERAPIA DELLHCC UNIFOCALE IN FEGATO CIRROTICO CONCETTI CHIAVE Pz < 65 aa con nodulo singolo in classe Child-Pugh B e C Considerare indicazione a trapianto di fegato La TACE può essere utile nei pz in lista dattesa per contrastare la crescita e la diffusione della neoplasia (?)

50 BARCELONA RECOMMENDATIONS CURATIVE TREATMENTS PEI vs SURGICAL RESECTION Recurrence rate after percutaneous treatments is as frequent as after surgical resection (>50% at 3 years and > 70% at 5 years) The are no RCTs comparing surgical resection and PEI. While some series report that survival after PEI is lower than after surgical resection, some cohort studies have failed to detect significant differences PEI can be recommended for well compensated patients when surgery is precluded J Hepatol 2001 CURATIVE TREATMENTS PEI vs SURGICAL RESECTION Recurrence rate after percutaneous treatments is as frequent as after surgical resection (>50% at 3 years and > 70% at 5 years) The are no RCTs comparing surgical resection and PEI. While some series report that survival after PEI is lower than after surgical resection, some cohort studies have failed to detect significant differences PEI can be recommended for well compensated patients when surgery is precluded J Hepatol 2001

51 TERAPIA DELLHCC MULTIFOCALE IN FEGATO CIRROTICO CONCETTI CHIAVE Pz con HCC bifocale nello stesso segmento Candidabili a resezione epatica con gli stessi criteri dellHCC singolo Pz fino a 3 noduli <3 cm, età <65 aa Candidabili a trapianto di fegato CHEMIOEMBOLIZZAZIONE TRANSARTERIOSA: è stato il trattamento più impiegato nel trattamento dei pz con HCC multifocale mancano chiare dimostrazioni di efficacia sulla sopravvivenza TERAPIE INTERSTIZIALI: l efficacia in pz con HCC multifocale non è sufficientemente nota

52 BARCELONA RECOMMENDATIONS TREATMENT OF INTERMEDIATE – ADVANCED HCC Six RCTs, comparing arterial embolisation alone or associated with chemotherapy have failed to identify a survival benefit, even in those patients with local response to treatment Additional large RCTs are needed to clarify wheter differences in the selection of patients or in treatment schedules may result in a therapeutic benefit at least in a subgroup of HCC (Recent demonstration of advantages of TACE emerging from a metanalysis of puvblished RCTs and 2 new RCTs) None of the available options including tamoxifen, antiandrogens, Interferon and chemotherapeutic agents, offers an unequivocal survival benefit J Hepatol 2001 TREATMENT OF INTERMEDIATE – ADVANCED HCC Six RCTs, comparing arterial embolisation alone or associated with chemotherapy have failed to identify a survival benefit, even in those patients with local response to treatment Additional large RCTs are needed to clarify wheter differences in the selection of patients or in treatment schedules may result in a therapeutic benefit at least in a subgroup of HCC (Recent demonstration of advantages of TACE emerging from a metanalysis of puvblished RCTs and 2 new RCTs) None of the available options including tamoxifen, antiandrogens, Interferon and chemotherapeutic agents, offers an unequivocal survival benefit J Hepatol 2001

53 DIVISIONE DI MEDICINA INTERNA Centro per lo studio dei tumori del fegato UNIVERSITA DI BOLOGNA POLICLINICO S.ORSOLA MALPIGHI Luigi Bolondi Gianni Zironi Laura Gramantieri Patrizia Pini Fabio Piscaglia Valeria Camaggi Elena Silvagni Natascia Celli Simona Leoni

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55 NON-SURGICAL ABLATION OF SMALL HCC PEIRF Efficacy Complications Pts compliance + ++ Physician involvement Cost ++++

56 SURGICAL RESECTION LIVER TRANSPLANTATION PERCUTANEOUS TECHNIQUES SURGICAL RESECTION LIVER TRANSPLANTATION PERCUTANEOUS TECHNIQUES CURATIVE/EFFECTIVE TREATMENTS High rate of complete response in selected candidates Assumed to improve the natural history, prolonging the survival of patients with single < 5 cm HCC or 3 nodules < 3 cm EASL Conference J Hepatol 2001

57 5 years survival in unifocal (<5 cm) HCC Median: Child A 23 months Child B 19 months % Multicentric Italian Study on PEI in HCC (746 cases) (Bologna, Brescia, Clusone, Napoli Cotugno, Napoli Policlinico, Padova, Roma, Torino, Vimercate) Radiology 1996


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