H. Richard Alexander, Jr., M.D. Department of Surgery and The Greenebaum Cancer Center University of Maryland School of Medicine Baltimore, Md

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1 Major Advances in Cancer Prevention, Diagnosis and Treatment~ Why Mesothelioma Leads the Way H. Richard Alexander, Jr., M.D. Department of Surgery and The Greenebaum Cancer Center University of Maryland School of Medicine Baltimore, Md

2 University of Maryland-Baltimore

3 Features of Carcinomatosis Peritoneal carcinomatosis is commonly a surface condition, multiple tumors small in size Disease frequently remains confined to the peritoneal cavity as the principal mode of progressive disease

4 CT Scan Appearance in a Patient with Symptomatic Ascites from Peritoneal Mesothelioma

5 CT Scan Demonstrating Diffuse Mesenteric Nodularity and Thickening in a Patient with Peritoneal Mesothelioma

6 Peritoneal Carcinomatosis from Peritoneal Mesothelioma

7 Tubulo-Papillary Pattern of Malignant Peritoneal Mesothelioma

8 Epithelioid Histological Type of Malignant Peritoneal Mesothelioma

9 Sarcomatoid Histological Type of Malignant Peritoneal Mesothelioma

10 HIPEC Schematic

11 Rationale for Using HIPEC Combines operative resection/cytoreduction and intensive regional treatment for diseases with known propensity to progress in the peritoneum (ovarian, GI cancers, mesothelioma) Delivers chemotherapy and hyperthermia to all serosal surfaces Applies IP Hyperthermia Has direct lethal effects on tumor Potentiates the cytotoxicity of chemotherapy

12 Pharmacokinetic Profile of Cisplatin Administered via HIPEC

13 Historical Perspective on Treatment of Peritoneal Dissemination from GI Cancers: First reports of HIPEC First report of hyperthermia and chemotherapy administered via a recirculating system in the peritoneum was published in 1980 by Spratt from Louisville. Pt was a 35 year old male with PMP who traveled to Louisville and insisted on treatment at his own expense! Throughout the 1980s there were numerous reports from Japan on the use of cytoreduction and HIPEC for prophylaxis or treatment of PD from gastric carcinoma. Poorly controlled Outcome data inconsistent Technical aspects of the procedure variable From these studies other centers developed programs using this approach for CRC, Appendiceal, MPM, and other cancers

14 Actuarial Overall Survival in 93 Patients with MPM Undergoing Cytoreduction and HIPEC CHPP: Primary Peritoneal Mesothelioma Patients Overall Survival 1.0 Proportion Surviving Median: 60 months (1-141) (41 Failed/ 93 Total) Months

15 Adverse Prognostic Factors Based on Cox Proportional Hazards Model Analysis

16 Molecular Characterization of MPM Tumor or NormalReference RNA RNA Reverse Transcription Hybridization 22K H.Array RNAi (in vivo, in vitro) Q-RT-PCR Gene specific inhibitors (in vivo, in vitro) Protein

17 Distinct Gene Expression Profiles Are Associated with Survival of Patients with MPM Group A Group B Group B 6/20 failed Group A 15/21 failed p=0.035

18 Gene Expression Profiling of MPM Identifies Upregulation of IL-1 Responsive Genes

19 Does IL-1 in the Tumor Microenvironment Promote Tumor Growth and Metastasis? IL-1 has been shown to mediate a number of acute and chronic inflammatory conditions An increase in metastases is observed in experimental animals pre-treated with IL-1 IL-1 is associated with virulent tumor biology in some human cancers Gastric and breast

20 IL-1 Receptors Type I receptor (IL-1RI) - involved in signal transduction once complexed to IL-1RAcP Type II receptor (IL-1RII) - a decoy receptor which can bind IL-1 but does not cause signal transduction Acta Physiol Scand 2001;173:5-9

21 a A IL-1RAcP Knockdown in MPM Cells Results in Decreased Gene Expression of IL-8 and VEGF sirna clones for IL-1RAcP

22 IL-1Ra Tet off/on Expression Plasmid: Effects of Inducible IL-1Ra on MPM Xenograft Growth

23 Summary Surgical resection with regional chemotherapy for selected patients with MM is associated with durable PFS,OS, and improved QOL Factors associated with favorable outcome are: age <60 yrs, favorable tumor biology, and completeness of tumor resection Molecular profiles of MPM are associated with distinct biological behaviors The molecular characteristics of peritoneal mesothelioma have identified potential new targets for therapy

24 Progress Made Possible Thanks to the Hamilton Jordan Family and MARF

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