1. HEPATOCELLULAR CARCINOMA Heba Mohamed Fahmy

2. إخلاص  النية 1- التخفيف من الام و اوجاع مرضي السرطان و محاولة إيجاد علاجات تفتح باب الأمل و تكون بأقل أعراض جانبية 2- هذا التعاون من باب تعاونوا علي البر و التقوي.... 3- تنمية روح الفريق الواحد فيد الله مع الجماعة... 4- نبذ الخلافات و المشاكل بيننا و ليكن هدفنا الاسمي أن نقوي بعضنا البعض 5- مساعدة صغار الباحثين و ضمهم إلينا بقدر المستطاع 6- لن يكون هناك كراهية و لا حقد بيننا.. لأننا ببساطة سننجح معا أو نفشل معا أن نسلك طريقا نلتمس فيه علما فيسهل الله لنا طريقا إلي الجنة 7-

3. General info. Hepatocellular carcinoma is the 5th most common malignancy worldwide & the 3rd cause of cancer related death Most common in males Incidence depends on geographic distribution HCC increases with age HCC increases during last years

4. Causes Hepatitis B (increases risk 100-200 fold) Cirrhosis Toxins (Alcohol, tobacco & alfactoxins) Hepatitis CDiabetes mellitusOverweight in males Autoimmune hepatitis

5. Signs & symptoms Nonspecific symptoms abdominal pain Fever, chills anorexia, weight loss jaundice Physical findings abdominal mass in one third splenomegaly ascites abdominal tenderness

6. Diagnosis AFP produced by 70% of HCC > 400ng/ml AFP increases over time Imaging - focal lesion in the liver of a patient with cirrhosis is highly likely to be HCC - Spiral CT of the liver - MRI with contrast enhancement Biopsy is rarely required for diagnosis Biopsy of potentially operable lesions should be avoided where possible

7. Treatment (Surgery) The only proven potentially curative therapy for HCCHepatic resection or liver transplantationPatients with single small HCC (≤5 cm) or up to three lesions ≤3 cm Recurrence rates of 50–60% after 5 years after resection are usual (intrahepatic) Patients with replicating HBV/ HCV had a worse outlook due to recurrence and were previously not considered candidates for transplantation.

8. Treatment (non-Surgical) should only be used where surgical therapy is not possible. 1)Percutaneous ethanol injection (PEI) has been shown to produce necrosis of small HCC. It is best suited to peripheral lesions, less than 3 cm in diameter 2)Radiofrequency ablation (RFA) High frequency ultrasound to generate heat good alternative ablative therapy Useful for tumor control in patients awaiting liver transplant

9. Treatment (non-Surgical) 3) Cryotherapy intraoperatively to ablate small solitary tumors outside a planned resection in patients with bilobar disease 4) Chemoembolisation Concurrent administration of hepatic arterial chemotherapy (doxirubicin) with embolization of hepatic artery Produce tumour necrosis in 50% of patients Effective therapy for pain or bleeding from HCC Affect survival in highly selected patients with good liver reserve Complications: (pain, fever and hepatic decompensation)

10. Treatment (non-Surgical) 5) Systemic chemotherapy very limited role in the treatment of HCC with poor response rate Best single agent is doxorubicin Combination chemotherapy didn’t response but survival should only be offered in the context of clinical trials 6) Hormonal therapy - Nolvadex, stilbestrol and flutamide 7) Interferon-alfa 8) retinoids and adoptive immunotherapy (adjuvant)

11. Investigational combination therapies in HCC Combinations under investigations Bevacizumzb + erlotinib Sorafenib +erlotinib Combination therapy will likely be used to treat HCC in the future

12. HCC (What’s ahead?) Combinations therapy Bevacizumzb or Sorafenib + Erlotinib Sorafenib + mTOR inhibitor Early sequential therapies

13. De Minicis, S., Kisseleva, T., Francis, H., Baroni, G. S., Benedetti, A., Brenner, D., Alvaro, D., et al. (2012). Liver carcinogenesis: Rodent models of hepatocarcinoma and cholangiocarcinoma. Digestive and liver disease: official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. doi:10.1016/j.dld.2012.10.008 The paper

14. Genotoxic Promoting agents Carcinogenic agents

15. The “N-nitrosodiethylamine” model DEN acts in 2 different ways By alkylating DNA structures, so leas to DNA damage and cell degeneration Inducing ROS through activation of cytochrome P450 in hepatocytes

16. DEN model depends on : 1- Dose 2- Timing of administration 3-Sex, age, mice strains. 4- Association with promoting agents

17. DEN + Phenobarbital (PB) - Adult male B6C3F1 mice initiated with DEN (6- 10 weeks age) Then PB is added to drink water for 36 weeks (promoting agent)

18. The peroxisome poliferators model - The preroxisome poliferator-activated receptors (PPARs) are nuclear receptors that bind to fatty acid-derived ligands and activate the transcription of genes that regulated lipid metabolism The formed PPARs ligand activated peroxisomal oxidase and induced ROS thus promoting HCC development.