Metastatic disease to the liver in colorectal cancer is a common entity that may present synchronously or metachronously. Suitability for resection

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3 Metastatic disease to the liver in colorectal cancer is a common entity that may present synchronously or metachronously. Suitability for resection depends on patient age and constitution, primary tumour characteristics, size and the number of liver metastases, and the extent of liver involvement. 3

4 Surgery remains the only treatment option that offers a chance of long-term survival for patients amenable to curative resection. Synchronicity suggests more aggressive disease although a unifying theory for biological differences explaining the disparity in tumour behaviour has not been found. Anyway long term-survival is still rather low. 4

5 Liver autotransplantation for resection of liver metastases is a viable option pending careful patient selection and institutional experience. Given the current evidence, surgical management of colorectal liver metastases needs to be individualised to the needs of each patient. 5

6 The ability to selectively hit the tumour cells is an essential characteristic of an anti-tumour therapy. In boron neutron capture therapy (BNCT) this characteristic is based on the selective uptake of (10)B in the tumour cells with respect to normal tissues. An important step in the BNCT planning is the measurement of the boron concentration in the tissue samples, both tumour and healthy. When the tumour is spread through the healthy tissue, as in the case of metastases, the knowledge of the different kinds of tissues in the sample being analysed is crucial. 6

7 The technique of livr autotransplantation can be employed also for the extracorporeal BNCT in the case of diffused (unresectable) liver metastases. 7

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9 Suitability for BNCT must be carefully assessed. 9

10 Almost nine years ago, in December 2001, we performed for the first time in the world thermal neutron irradiation on an isolated liver of a patient. The organ was affected by diffuse metastases of a colon carcinoma and had been previously loaded with a (10)B compound. 10

11 The patient underwent an accurate pre-operative surgical work-up. 11

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15 Finally the patient underwent surgical operation. The purpose of the first phase was to evaluate boron distribution for a safe and effective BNCT (Boron Neutron Capture Therapy) of liver metastases. Samples both from healthy and tumour liver parenchyma were analysed, after i.v. boron administration, by: alpha particles counting under neutron irradiation; morphological analysis by standard haematoxylin-eosin staining; neutron autoradiography. Our method was unaffected by the cytological heterogeneity inside tumour nodules; it demonstrated selective boron distribution in tumour tissue and predicted estimated mean therapeutic doses in tumour and safety doses in healthy tissue. The time interval for efficient BNCT was 2 to 4 hours after i.v. boron administration. 15

16 The classical orthotopic liver autotransplantation is a very challenging and time wasting technique; it includes the division of major hepatic vessels and choledocus, and subsequent reconnection by end to end anastomoses. 16

17 The procedure required very long operating times and the extracorporeal circulation (ECC) set up. 17

18 The liver was irradiated inside the thermal column of the TRIGA reactor of the University of Pavia. 18

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20 Finally the irradiated liver returned to the surgical theatre for reimplant. 20

21 We adopted the classical orthotopic liver autotransplantation technique: the caval end to end anastomoses are the most difficult to be performed and the interposition of a prosthesis was required. 21

22 We obtained favourable Boron concentrations in blood, tumour and healthy tissues. 22

23 Nevertheless we observed in our patient the symptoms and biochemical derangements of the "post-irradiation syndrome, with a dramatic--even though totally reversible--clinical condition. 23

24 The tumor masses resulted completely necrotic and unknown metastases too appeared radically treated. 24

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27 Healthy hepatic tissue was preserved from both morphological and functional impairments. 27

28 No symptoms of cirrhosis appeared even four years after treatment. 28

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37 The procedure is feasible; the original concept of complete immersion of the liver in a homogeneous neutron field seems to be effective and winning. The quality of life after the treatment was excellent. 37

38 Other findings require to be tackled in depth. For our patient, cancer recurrence was a late yet fatal complication, for which even a further surgical revision was ineffective. We think that cancer stem cells may be involved in the mechanism of resistance to the treatment and we offer some hypotheses about possible prevention. 38

39 Furthetmore we propose a "modified orthotopic piggy-back technique" to simplify liver reconnection and shorten the operating time. The technique was developed in the swine (25 kg body weight), under general anaesthesia. We performed the resection of the retro-hepatic vena cava with preservation of the caval flow during the anhepatic phase, by interposing a goretex-prosthesis. The reconstruction of the vena cava was then performed by a side-to-side cava-prosthesis anastomosis with lateral clamping of the prosthesis. The procedure was then completed according to the classical technique of liver transplantation Also the time of total extracorporeal circulation was reduced, as during the anhepatic phase and during the side-toside cava-prosthesis anastomosis the flow in the inferior vena cava was uninterrupted. 39

40 To test the possibility to apply boron neutron capture therapy (BNCT) to lung tumors, some rats are planned to be irradiated in the thermal column of the TRIGA reactor of the University of Pavia. Finally the possibility to realize a thermal or epithermal neutron source is under evaluation. 40