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From: Sultan Bin Sulayem To: Jeffrey Epstein leevacation@gmail.com> Subject: Date: The, 08 Nov 2011 06:32:20 *0000 put In the keywords for search search Hone About FUDA News mesa Tawas* Treatirred Suedes Canted Us FAO Admission Procedures Therapies P r riPt Cancer lacrovessn Intervention. CAB Cryosurgery knenunotherapy Brachytherapy Phondynamic Therapy Trartilional Chiles* meson Vandal Intervention READ MORE sit Awards • Forum Kanker Patu•Paru Chins Ulara-Selatan ke N 2008 • Medal Emas: Perlimpunan Pengobatan Suhu Rendah Jepang 2008 • Yayasan Inslitut Stud Lanjut Kedokteran Philippine • 2007 • Gals Kola Chins Malaysia 2008 READ MORE so Stades • A postcard from a US patient • The Symphony destiny or Brian ran • A letter from Malaysian Chinese manufacturers • Mr Holing Yuzhang Story —1-fis Days At Fuda Hospital • MR. LU OINGZHI STORY AT FUDA HOSPITAL • The Story of Vide Guervero-Fitart READ MORE » 1.8.2 Effectiveness of Cryosurgery Itiocheng Ku zeithaw cycles There is some evidence that a double freeze-01n cycle induces a higher percentage of tissue destruction within a given lesion. thus impedes uniformity of cell death. Kollman(20j using a patine model. studied 7intrahepalic cryolesions induced by freezing the hepatic tissue for a total of 15 mks. Additional animas underwent a double freeze-thaw cycled 7.5 mhs each RIF). Seven days after freezing. DF did not change the volume of the coolest:on compared to SF. howreet resorted in enhanced destruction of htioatocyte nuclear morphology. He showed nal double !radii° may improve uniformity of hepatocyse nuclear destruction within the margin of the lesion due to a more pronounced showdown of microrascutar perfusion. resulting in irreversble ischemia 121 .221. In adcition. as it is well known that thawing is a more inhaled rr.echanism of cell death than cooling i23). the application of a double thaw cycle in double freezing may account for the more compete marginal hepadcyle nuclear destruction. Robinson(2w) showed that for bone cryohisgery. the difference of the nanny of targeted cells between we freezing cycle and two freezing cycles was highly significant But the Satiny following three freezing cycles was similar to that after two freezing cycles (Figure 1-8-10). Also. after a single cycle of feeding. most specimens were necrotic. some were still viable. In contrast. there were no specimens tut had viable eels folowing two freezing cycles (Figure 1.8.11). cti rigor° 15.10. Average Wedgy° standard deviation of tumor morsels (expressed as optical density per 100 mg wet weight) From Robinson? D. et at Cryobiology 2001;43:440 c! ‘.. A Figure 1-8.11.7 A. Cell necrosis following a single freezing cycle is not tniform (Aldan blue stain, anginal metrification 3200). B. Cell necrosis folhowing two freezing cycles appears unform (Alcian blue 'balm crigka magrificabon 3200). From Robinson? O. of at Cryobiology 200f:43:410 Interestingly. Kollmaris study indicates a marked reduction of leukocylic infilbation alter double freezing compared to single freezing(20]. This may be due to the fact that the double freeze procedure picmdet a more distinct microvascular shutdown at the margn of the cryoleson COTIVared to the single freeze procedure/21.25k which can prevent rapid marginal tissue infiltration by lekftogles derived from the blood stream. The distinct eosinophilic ingestion it marginal zone of cryolesion was more pronounced after double fretting compared with single freezing. and thus hverse to leukocyte (mainly neutrophil) infiltration. This may indicate a specific immune response after double freezing. which rernans to be elucidated in further nudes. A doodole freeze thaw cycle was shown to produce agnicant increases in cell destruction for every set of thermal parameters irreestigaled. This finding is also in agreement with the two factor theory. At high cooing rates a double freeze thaw cycle should increase the statistical probaLdity of intracel ular ice formation and cell damage. At lower cooing rates the effect of a double freeze thaw cycle is to increase the amount of time cells exposed to the hyperemic conditions. and thus increase the degree of osmotic injuryg3). Selective vascular inflow occlusion Selective vascular inflow occlusion claim the application of a lunge freeze-thaw cycle eflectieely enhances marprod cell destruction. additionally. significantly increases the overall Lawns of the lesion. In diliCal practice. additional Pringle maneuver (vascular occlusion) was introduced with the idea to increase the EFTA00661250 volume and effectiveness of the cryosurgical penoedure(28.27). In a sheep model of ayosurgery. OiIley(27) reported that the rale of increase of iceball diameter is significantly greater after vascular inflow occlusion, and Mat the necrosis as a mean percentage of initial iceball diameter after 1 month is more pronounced after double versus single freezing. KollmanI20j used a porcine model to study whether selective vascular inflow occlusion can achieve complete hepatic tissue destruction. Results showed that it the single freeze-thaw cycle was applied during selective vasodar inflow occlusion, the volume of the cryolesion was significantly increased compared to single freeze-Maw cycle (SF) and double freeze-thaw cyde(DF). More detaled analysis of the transition zones of the crydesions of each group revealed destruction of the intralobutar Irabeculer architecture in zone 1. which was slightly more donoenced n VO-SF-treated livers corrpared to OF-Mers. Importer*. destruction of hepatactie nuclear morphology in zone 1 was not complete in SF-treated livers. but was evident 0 DF- and VO-SF treated hepatic tissue. Accordingly. wain the tranation zone 1 Dr- and VO-SF livers showed a significanth- hgher score of destruction of hepatocyte nuclear morphology compared to SF-treated tissue. In zone 2. VO-SF resulted in comparable leukocyte intitraton as observed after SF. wile OF was associated with a significantly reduced leukocytic infiltrative response. In zone 3. We dual proliferation was associated with apoptotic cell death and eosinophlic infiltration. Bile duct proliferation was comparable n all three groups. Moreover. MD-SF-treated livers showed more pronounced apoplotic cell death. Mile OF-treatment increased the infiltration of ecanophilc cells. The petechia bleedings al the transition to the normal hepatic tissue in zone 4 did not differ in severity between the three different tresitntent groupstFigure 1-842) Figure 14512. Histomorphological characteristics 7 days after ayosurgery.NoSe the bile dud proliferation (A. after single reeze-thaw cycle of 15 mins). the accumulation of apoplolic cells (B. after single freeze-thaw cycle of 15 mins during selective vascular idiom occlusices (VO-SF)). and the infiltration of echnophlic cells (C. after double freeze Maw cycle of 2X7.5 inns) in zone 3 of the aansi0onal area within the margin of the cavlesch In addition. within the transition from tone 3 to the normal hepatic tissue of zone 4. petechal bleedings are observed (D. after VO-SF). From Kohnan O, of et Conboamy 2004; 48163-272 felate(28] studied the effect of vascular inflow occlusion Ice aydesons in pigs during hepatic freezing. Ice-ball volume was estimated by intraoperative magnetic resonance imaging Results showed that the median volume of ayalesiensmade during inflow occlusion was 195% larger than ayolesiens induced without occlusion. The gentry of the 'cabal's was more regular if produced during inflow occlusion than if not Seifert(10.29] showed that using 8 rembryoprobes in vivo placed in the pg liver. 3 20 mins single freeze cycle with additionel Pringle mananrrte. resisted in a safely margin of about 15-18 mm However, a significant ischaerria-reptifusion injury may result in addition to the liver Mury caused by Pringle manoeuvre. For this reason hepatic inflow occlusion during cryotherapy should be limited to special situations requring this technique (ter example lesions >3 cm in difficult locations dose to large vessels, which do not allow the placement of multiple probes) and not recommended as a routine procedure. The higher effectiveness achieved by aglow vascular occlusion has to be attributed to the abrogation of the "heat sink effect" due to the tack of miaosascular pedusion(1.8). Antifreeze proteins It have been shown that antifreeze proteins can enhance the destruction of cells frozen. MI Me AFFs. including AFP-I. share the ability to depress the freezing pant of body Odds noncolligatively. When the fluids eventually freeze. these proteins modify the structure of the ice cryslasf31T A more comprehensive study on antifreeze protein adjuvant cryosurgery for prostate. bread. and bier cancer was performed. Over 30 control studies compared the viability of postale cancer cells. bread cancer cells, and hepalocytes. To show that antifreeze pfdeins are effective during cryosurgery in vivo, Plea:n(31j performed experiments with human prose: do adenocarcinoma grown subcutaneously in nude mix. Fria to cryosurgery. the tumors of test mice were injected interstitially with Aral. In control mice. the terrors were injected with PBS in a similar manner or wet no injection at all. The results showed (Figure 115131the tissue frozen with AFPs has completely Iasi its suuderal integrfly. The cell merribiaries are not intact. the nuclei have become distorted. and. 0 particular. Pe corrective tissue surroundng the cells appears to be sheared. There is no continuity between the cells. and numerous bonne are evident between the cells. 2 Figure 14-13. Typical micrographs of the prostate cancer tissue before (a) and after cryosurgery (Wand (a) b. Obtained from prostate cancer tumors that were injected with phosphateduffered seine solution prim to freezing: ?c.? °Waned from tumors that were injected with a solution of PBS containing 10 mgaril AFP-I. The staining shows the cell nuclei. a. Illustrates the round shape of the nuclei in prostate cancer tumors and the normal tissue structure. b. Shows that atter freezing some of the nuclei have become distorted and have darkened while others (marked with arrows) appear Strad. c. Sham that after freezing with AFP the nuclei are dsforted and irregular in size. Furthermore, there are numerous tacunae in the tissue. Scale bar. 10mm Flom Priam L. et atChrobiotgy /99138:169175 Stud/met 32lhod a sinlar study. He used witheutaneous tumors of Denning AT-1 rat prostate cells grown in Copenhagen rats to detect adjuvant effect o/ AFP for chop:gay. and the cryoinjury was assessed with the alarms blue indcator of metabcdc activity. Results showed that a double-freeze procedure with AFFIl was found to give significantly better ablation than a doeble-freeze without AFP or a singe-freeze with or without AFP. The mechanism by which AFPs destroy cells and tissue was not yet understand. Them is a possiblity that AFPs modify the structure of ice crystals. The destruction occurs regardess of the thermal conditions during freezing and appears to be related only to the observed formation of the needlelike ice crystals. Histology suggests that this mode of freezng is associated with severe disruption of the celblar and connecbve Wincluies, including the nuclei membrane. A possble explanation for the damaging effect of the antifreeze proteins is mechanics. The small needle-like ice crystals propagate through the tissue in the direction of the temperature gradents and may shear the col and nuclei membrane and the connective tissue as they propagate through the tissue. Formation of the spades is concer*atsn dependent(32). EFTA00661251 Regardless of the mechanism by which antifreeze protein produce their destruction, the demonstration of the effectiveness of the AFPs in cryosurgery in omit important for clinical practice. Tumor necrosis fatten (771Fm) The cytokine TNF.a. while systerrically toxic. has shown benefit :Men locally administered to timers. This arluvant is known to promote inflarnmatice. endothelial injury and apoceteis. in addition to being cytotoxic to cancer cells and generally harmful to tumor rncrovascnature Because of the role of TNF-a in cellular (apoptotic and necrotic cell death) as well as vascular mechanisms of injury rented to endothelial cell activation and inflammation. TNFo may entiance coos:pion lesion in vivol33-35). Chac66] examined me effect of TNF-a on cryosurgery of an n vivo micrcreasoelar preparation in a nude mouse. A comparison of injury data to a thermal model indicated that the minimum temperature alto moderate cooling. thawing. and hold time required fa causing necrosis, shows? that the local use of TNF-a can dramatically ncrease me threshold temperature of cryodestruckei by more than 1070 ( Figure 1.8-14 ) . Figure 1b10. The minimum temperatures required to cause necrosis in different tissues following moderate cooling. thawing and hold time. 'Normal Skil" denotes normal skin tissues from Copenhagen rats (n- 8: while columni, nude mice (n • 9: litibt gray). or inflamed skin tissues from nude mice after INF.% treatment (n • 4: dark gray). 'Timor Tissues" denotes AT-1 Dunning fa: prostate hence (n while oakum). LNCaP Pro 5 human prostate cancer (n -8; fight gray). or inflamed LNCaP Pro 5 tissues alter TNF-a treatment (n wit: dark gray). A previous remits obtained using normal tissue and AT-I rat prostate tumor in the Copenhagen rat are listed for comparison ( Hoffmann NE. anchor IC. J Binger. Eng 2001: 123:310-316) . Error bars are standard deviations From Chao SH. ef atOryotaglogy 2004:49:10-27 However, neither normal nor tumor tissues showed necrosis after TNF-a treatment without cryosurgery. suggesting local application of 174F.a by itself al this dosage would not damage tissue. There is the hypothesis that ',ascot's-mediated injury is responsble la dolling the edge of the cryolesen n nicrovascularderfused tissue. and therefore the inearrimalico induced by local use of Third augments crytinjury. The effect may impact the rtionning of clnical cryosurgery. During cryosurgery of the nonce and other organs such as liver. kidney or ben. ultrasound. CT Of MRI can be used to monitor the extent of the cryosergical ioeball. HoweVer, this is not optimal with cryosurgery on some special sites such as prostate. since eve-freeze° into sensitive adjacent structures can cause complications. On the other hand. if the surgeon underfreeze by keeping the lethal solely warn, the tumor, cancer eitinng at the periphery of the coolesion may not be effectivety treated. which may lead to recurrence of disease. Local apploation of TNF-a to targeted tissue in nine woad decrease its cryenjury threshold. or increase its thermal threshold. to 3.5s6.9?C under rrioderate freeze 'Thaw condition. which are close to the temperature at the edge of the icelsall. Therefore. the combination of cryosurgery and local inflammation induced by TNF-a may improve the clinical application of cryosurgery. specifically n the prostate but also in o0er organ systems. by increasing the abfity of uerasound and other itebalimonitoring technologies to monitor and preckt injury. subsedeently reducing potential side elects from ayotherapy(37]. CONCLUSION MaO causes of tumor persistence or recurrence after cryosurgery at the site of cryoablabon are incomplete destruction due to inaccurate procedural mcoilaing and inadequate criteria fa treatment adequacy. The optimization of cryosurgery should consider crucial factors such as the timed freezing. freeze.thaw cycles. number of probes. probes' sizes, the spatial position of the probes. and shape and size of the tumor. The snatchya occlusion of vascular inflow and addition of molecular adjuvants. sod. as TNF-apha. can dramatically increase the threshold temperature of coo-destruction. REFERENCES (1) Lam CM. Shire SA. Needle implantation ayoprobet Biophysical and thermal characteristics. Semis Laparosc Surg 1997:4:89-95. (2) Lam CM. Shine SA. Cumberi A. Ultrasonographic characterization of hepatic ayolesions. Arch Sure 1995:130.1068-1072. (3) lam CM. Shimi SA. Cuschieh A. Thermal charm-nice= of a hepatic cryotesion formed in vitro by a 3 rmiimptsMable ay:probe. Cryobiology 1998:38: 158- 1St. (4) Baust JG. Gage AA. Ma H. el al. Minimally invaave ayosurgeo. technological advances. Cryobiology 1997:34.373-384. (5) Popken F. Seifert JK. Dutkowski P. el at Comparison of iceball diameter and temperature eceunbnion achieved with 3.rnrn aocuprobe orrice:nes in porcine and human liver tssue and human colorectal liver metastases in Mtn:. Cryobiology 2000:40:302-310. (8) Mala T. Satinet E. Atadal L et al. Magnetic resonance imaging estimated three dimensional temperature distribution in liver cryolesico A study of coalesce, characteristics assumed necessary for tumor ablation. Cryobiology 2001.43:268275. (7) Seifert JK. Gerharz CO. Mattes F. Mal A Mg model*: hepatic cryaherapy. In dm temperature elstibulice during freezing and histopalhologicol changes. Cryobiology 2003:47:214228. (8) Rti J. Talsulan KN. Dahiya R. el al. Effect of thermal variables on human beast cancer in cryosurgery. Breast Cancer Res Treat 1999:53:185-192. (9)Yang Wit Lao ST, Shen SY. et al. The speed of ice groMh as an important indicator in cryosiegery. J Urol 2004:172:345.348. (10) Seifert JK. Gerharz D. Hanes F.. et atA pig model of hepatic coolie-race. In vivo temperature distributice during freezing and histopalholopcal datives. Cryobiology 2003:47(3)214218. (11) Uttrup Pl. Freeman-Gibb L, Andea A. el al. Cryotherapy for Wean Motoceenemes. Radiology 2005234:63.72. 1121 Chua KJ. Chou SK. Ho JC. An analytical study on the thermal effects of cryosurgery on selective cell destruction. J Biomech 2007:40(1 k102118. (13) Reed KL. Brown TD. Conzemius MG. Focal cryogen insults for inducing segmental ostenonecrosis. computational and experceental assessments of thermal fields. J Biornech 2003:38:1317.1328. (14) Popken F. Seifert JK. Engelmann R. et al. Comparison of cobalt diameter and temperature distribution achieved with 3mm scour:robe crycpcees in porcine and human liver tissue and Moan colorectal fiver metastases in vitro. Cryobiology 2000:40.302.310. (15) Rennin& TS. Steele GJ. Kane R. et al. Experimental and clinical observations on hepatic cryosurgery for colorectal metastases. Cancer Res 1991:51: 83234327. (16) Baissalwe R. Sandison GA. Reynolds D. Mal. Simulaneous optimization of cryoprobe placement and thermal protocol for cryosurgery.Phys Med Blot 2001:48:179281. (17) Rewcastle JC, Sandison GA. Muidrew K. et al.Amodel for the lime dependent threedimensicoal thermal distribution with iceballs surrounding multiple coopittes. Med Phys 200128:11221137. (18) Miller WI Mama P. Survival frozea•thawed human red cells as a function of cooling and warning velocities. Cryobiology 1978:13:404-414. (19) Zacarian SA. The observation of freezolheet cydes won cancer-cell suspensions. J Dermatol Surg Oncol 1977:3(2):173.174. (20) Kalmar COMM.. S. Schillig MK. et al.Advanced hepatic tissue destruction in ablative cryosurgery: potentials of intemitlent freezing and selective vascular inflowa:duties Cryobiology 2004:48282272. (211 SchEoder G. Procrius G. Fehringer M. al al. Complete shutdown of microvascriar perfusion upon hepatic cryothermis is critically dependent on local tissue temperature. Br J Cancer 2030:82:794-799. PA Schuler G. Vollmer B. Richter S. et al. Epi-ituminalion fluorescent light microscopy fa the in vivo study of rat hepatic miaovascular response to cryothennia. Hepalceogy 199929:801-808. (231 Gage AA. Bausl J. Mechanisms of tissue injury in 0yr:surgery. Cryobiology 1998:37:171-1Ln. (241 Robinson D. Haberin N. New Z Two Freezing cycles ensure interface sterilization by cryosurgery during bone tumor resection. Cryobiology 2001.43:4. 10. (25) SchEuder G. Porno B. Richter S. et al. Epirllimination fluorescent fight microscopy for the in vivo study of rat hepatic microvascular response to ayothemiia. Hepalology 199929:801-808. EFTA00661252 [26] Segert JK Junghger T Morris °L.Acol/active review of the world literature on hepalie ayotherapy. J R Sung Edit* 1996:41141-154. [271 Olney AV. Dy DV. Wailers A. el al. Laboratory and animal model evaluation of the Ciyoteth LCS 2000 in heparseeryolherapy. Cryobiology 199330:T4-85. Sent from my iPhone NOTE: This e-mail message is subject to the Dubai World Group disclaimer see littp://www.dubaiworld.aekmail_disclaimer EFTA00661253