 Dwi'n ei wneud i Lleisar, chi'n hyn yn ei brafio'r gweithio, ond hi'n dysgu'n mynd i chi'n meddwl mewn metastaseid trwy peth. Fo'r dyrfa, ac rwy'n i'n dweud i'n fwy yn y gweithgifeth a'n ddwy'n i'n brydwch ar ben-dwynt yn oed. Wrth i'n gweithio. Wrth ei gweithio... Rwy'n credu bod supports 30% unrhyw o夫 gysylltu metastaseid 구독 yn gweld bod y gwirionedd yw'u cyd-ddechrau o'r hynach yn ei chem i wneud yma'r hollhau hynny. Rwyda, snapuan, sy'n cael ei gwirionedd ar y sefydliad am conferenceau i yw eu hunain, ac yn gyfle i'r hollhau gwirionedd yma, mae'n gwirionedd ar hyn yn cael ei gofio arall yn eu fan ond ei'n gwirionedd ar hyn. Fi, rwy'n gwelsio ar y wneud, cyflym i'r hollhau cyfreidwyd, wrth gwrs, i'n ei cyfrnodau sydd, ac mae'n cyfrnodau sydd nhw ar gyfwetzaeth Mae gwahach i nad oherwydd ymarfer o catalansau brifatig iddyntor yn adrofenigolion. Mae rai gyda'i mae'n dod i bach ar gweithio drwy ddiogel. Ond yn dod, y cyflogs ymddech chi gael ar gyfer fy wneud a'r lleidiaethol erbyn i amlwg o'r gwahanol, byddai fydd newidol ysgolion yn creweisiau ddechrau mewn gwir. Fel iddynt yn phi ydych chi'n wych yn cerddau at y Byn Llywodraeth llyfr llawer y gallun dddangos ymrondig beth hynny. Mae'n gweithio gyda'r rheinswyr mae'r lleidwydau bywydol yn sgolwyddiol, ac yn ogylch o'n gwybod ei ddysgu'r lleidwydol, angen i'r lliwyrirau o'r rhai o'r holl ddadol, nad oedd o'r cyffredinol o'r cyfrannu oedd yn bwysig, o'r cyfrannu o'r yrhyw ymddiol, o'r cyfrannu o'r cyfrannu, o'r cyfrannu o'r cyfrannu oed yn bwysig. Mae'r lleidwydau sydd wedi bod cyffredinol yng nghyrch, yn ddiwethaf i'r ddiwylliant Rodd Coleman i'r barill, feirio'r ffordd gwawdd sgiliz. Roedd 80% esperfans wedi cyffredig o'r ffordd gwodydd yn fawr dechrau Dyfwyl Mhotasys wedi'u rai wathgrin gen nhw, felly rhai ffordd cyfraffol fwyaf i gyd-gain gŵur ythafod gan ddweud chyflwyntau gyda'r 1 ar 5 yn cysylltiad yr ystyried. Rwy'n mynd i gyd yn cael ei fod yn dweud, ond yw'n ddweud sydd yn cael ei gwyll void roedden nhw i wneud y cyfraffol, gyda hyn a'r cael wlad. Mae'r hyn yn hyn y cydweithio ffynol iawn knight yw Attila Bwll Allez, a rhaid i'w chlas cywlaethu dechydig ybu duol Canterbonei Llywodraeth wedi ychydig. Mae hyn ychydig yn angen i bobl'n mynd i hynny i fod yw hefyd yw meddwl meddwl jywodraeth, ac mae'r cychwyn ni'n meddwl sydd wedi dynnu'r problem. Mae'r cymdeithasur, a'rcheeringr, yn dweud cyfanc ferch mewn gwyrwyr, yn newid am y meddwl The imaging tool is currently utilised or have available, plane films, radio-nucleid bone scans and cross-sexual imaging with CT, MR and FGDPET, all of which have some sort of problems associated with them. Radio-nucleid bone scans are probably the most commonly used tool for staging bone metastases, but we know that the renal cancer bone metastases can look negative on bone scans and there's an example here of a patient who had a negative bone scan .. cautious scan that was found... ..having presented with pain to have a lytic bone metastasis.. ..requiring orthopedic surgery. Recognising that, this is a summary of the current guidelines for the recommendations... ..for staging bone metastases or bone disease in renal cancer. There is a consensus that actually radio-nucleide bone scans... ..are not a particularly good tool. All of these guidelines recommend that in the absence of specific symptoms... felly causen yn tynnu bod yn flwyddyn cymrydll, ac wrth gwrs, ym mlynedd yn y profiadau i gydlwn i'r dda ni at y ddeall fy hun oedd hwn yn blod yn ei gynnal. Ryn ni'n hyn, sy'n ddim yn ei gallu gilydd am ymddangos boughno'r bractios, felly ddim yn dwi'n cael y dweud y ffordd ei ddweud iawn. Ffftig gyda petau sy' wneud hynny yn cyflawnioli ein Garethunomol, ac y gallw'n mynd i fod yw'r funaid yr eich mynd. Mae'n rhaid i'r cyfrifiadau o'r unrhyw unrhyw yw y maeson o'ch gwrtho'u gyda 47 reidio ar gyfer y diwrnod a'r rhaid oherwydd ymgriffyrdd i'r unrhyw i'r bodi bodi bodi yn gyfrifiadau at y tiwn. Mae'n dweud o'r gyrffordd ymlaen i'r bodi'r bodi yn gyfrifiadau a'n ddylch i'r bodi'r gyrffordd, sy'n syniad. Yn rhaid, mae'r bodi'n gyrffordd i'r bodi yn gweithio'r amlwg. So we are currently looking to replicate this study in something we call the DOOMOR study, looking at extended CT scanning to include the humorium femora in additional to standard CT scanning of thorax, abdomen and pelvis. I'll get this in the end. Do the difficulty of imaging bone metastasis matter? I would suggest that they do matter if we are going to alter the management according to presence of bone metastasis. So thinking on that point, what happens to patient with Yr ystyried yn dod, dyma'r cyfnodd ddweud y bod yn bydd hynny yn ymgyrch gyda'r cyfnodd a'i hynny'n ddweud ymgyrch cyfnodd yma'r cyfnodd yw'r cyfnodd ymgyrch gyffredinol. Rydym wedi'i gael y Dany Heng yw'r cyffredinol am y cyfnodd ymgyrch yn rhinocharsanome i'r hyn o'r unrhyw ddych i'r rwyf wedi'i cyffredinol ar y cyfnodd ymgyrch ymgyrch ymgyrch yn ymgyrch yn unrhyw am wneud. ac yn y gweithio y nifer oedd yna hynny mae'n hynny mae yw'r amall feddwl gyrraeth sy'n deall i'r newid yn y cymuned Gwyrd. Felly, 102 o'r cerddydd, mae'n bwyd eich ddweud o'n dod o bwynt cyflogol gwahanol am gallu uchydigbanydd ym hynny yw bywyd mewn gweld mewn gweld mewn gweld mewn gweld mewn gweld ym hynny yn comod haywyr mewn gweld mewn gweld mewn gweld mewn gweld mewn gweld, eu cyfaint o fwy i'r gweld mewn gweld mewn gweld mewn gweld ym forum feel. ac rwy'r cyflogau unwaith yn ddysgu ymddangos yn ymgyrchredigol gyda'r cyflogau sydd y brawcoffodol o bethau gyflogau i ddod yn sus, yna? Felly, mae esbyg ddim o bach gofyn fydd y cwestiynau i thati mathafu gyflogau yn ymgyrch yn ymgyrch ac mae'r cyflogau sydd yn cyflogau sy'n cael ei hwn hynny ymgyrch iawn yn ymgyrch i ddiartond o ddim yn ymgyrch o bethau gyflogau a'r cyflogau i gael o latrfyn iawn hynny a'r diogel, y cyfnodig cymaint, y cyfnodig cyfarfod meistafol, a'r cyfnodig cyfnodig cyfnodig cyfnodig cyfnodig, sy'n byw'r llys ar gyfer y dyfodol gynnig beth o'r blaid. Ond, mae'n bwysig ar hyn o'r gwneud yn ffordd o gyfnodig cyfnodig yma, o'r cyfnodig cyffredinol yn y ffrif. A'r cyffredinol yn bwysig ar gyfer gyffredinol gyffredinol, oherwydd, mae'n bwysig ar gyfer cyffredinol yn ffawr, are quite low compared with primary and other metastatic sites. So, what do we do about this? And let's think about treatment. Of course, there are a number of different possible roles for surgery in the management of renal bone metastases and I just want to concentrate on the issue of limited or oligometastatic disease. There is evidence, that patients who have wide excision with debulking, there is retrospective evidence I should say, but there is retrospective suggestion the patients who have debulking and wide excision neu mae'r gweithio meddwl yn ystul고 o'r cynhyrch neu gweithio, pan yn staff o'r parw lleoedd ni, a yma, mae yma hwn yn defnyddio'r uryn ni allanau i'r atebydd cael ei gweithio beth y gallwn yma. Mae'nτοi'n mynd fi, nid yw'r cymdeithasol, ac mae'n amser yn ynnilladu y myd ac mae'n amserio. Mae'r drosbeth ei flyn i'r oesaf y gwirionedd i'r meddwl i'r etud i'r gweithio meddwl a'r adegau cerddio'u meddwl. Ac mae'n ddigon i'r gwybod gyda'r unrhyw unrhyw sy'n gyfrannu'r gyfrannu dylai'r digwydd, ac yna'r ddweud yw'r ddweud yw'r cyfrannu cynnigol wrth gwrs. A yna'r ddweud yw'r cyfrannu cynnigol yn ei ddweud hynny, ac mae'n dweud gyda'r syniadau sydd wedi gweld gyfaintol gyda'r radio-therapau o'r radio-therapau yn dod o erbyn y cyfrannu cyfrannu syniadol'. SC interesson, Roedd yn varnodol a Imberw. Aled yn hydafence investedau Cym Anylw i'r cyfrydd mwynhau o gyfar� level nifer cyfrydd ac yng nghydwahith gweld in bone metastases. The registration trials with which we're familiar don't report response in bone because bone is not measurable by resist so alluding to response in bone is quite challenging. This is a retrospective analysis from the MD Anderson group that was reported at GeoAskoo earlier this year and they simply reported on the median overall survival in patients with bone metastases from a historic era without TKIs compared with the same size group who had received TKIs. They showed that the bone metasis patients did have an improved survival in line with perhaps what we'd see in a generalised metastatic renal cancer population. The vicious cycle of bone metasis was described by Greg Mundy over 10 years ago now and it's a development or an extension of Stephen Padgett's seed and soil hypothesis, but particularly within bone. This gives us a number of possible targets for the management of bone disease in renal cancer. This describes that tumour cells within bone release cytokines and factors such as PTHRP, which stimulates osteoblast to produce rank ligand and the rank ligand in turn stimulates osteoclustogenesis. The osteoclast produces osteolysis releasing further growth factors such as TGF, beta and IGF1, which in turn promotes further tumour growth. This has given us a number of targets and a number of agents used to treat bone disease. The most well-known of course is Dologronic Acid, a potent nitrogen containing amino bisphosphonate. Bisphosphonate binds to areas of high mineralised bone at higher areas of high bone turnover, where they directly inhibit osteolysis by causing osteoclast apoptosis and they probably also have a number of direct cytotoxic effects within bone. This is a publication by Alan Lipton, which is a subset of a much larger study of 700 patients who had metastatic bone disease from a selection of solid tumours but excluding breast and prostate cancer. We're fortunate the 74 patients subset with renal carcinoma was published separately. This showed that those who had solidronic acid compared with placebo had a reduced skeletal-related event rate, reduced time-to-first bone event and reduced mean skeletal morbidity rate. As a consequence of this, solidronic acid started being quite widely used in the management of metastatic bone disease. More recently there has been this publication comparing denosumab with solidronic acid. This is a similarly designed trial in that it is a mixed group of patients with a number of different solid tumours. The total number of patients is just over 700 in each arm of whom 9% had renal carcinoma. However, we do not currently have the renal cancer specific information from this study. So all we have is the overall information, which is the group who did have neither non-soul cell lung cancer or myeloma, but another selection of solid tumours had a better result from denosumab with a prolonged time-to-first skeletal-related event and also not just the first event, but a prolonged time-to-first and subsequent skeletal-related event. Denosumab was also found to be superior to solidronic acid preventing skeletal-related events from other tumours including breast cancer, prostate cancer, and in a combined analysis of all of these three randomized controlled trials. So after the Liptim publication, solidronic acid was recommended for patients with bone metastases from renal cancer. But of course that's a publication from 2004, and so those patients would not have received the systemic therapy that we use today. So what do we know about the use of bone directed therapy in the current era and what are the particular toxicity issues? So there's an awful lot of information on this slide. And I draw attention first to the bottom two publications which have got huge numbers of patients in. The Mackay publication which is a collection of patients in a series of randomized controlled trials and Edward Rudoljack's recent poster, which is data from the Global Sunnysnip Expanded Access Programme. Now this is retrospective data, and so looking at the outcome with TKI alone or TKI plus bisphosphonate is clearly fraught with difficulties because as clinicians it's highly likely that we would choose to use bisphosphonates in the patients who we perceive somehow to have worse bone disease. Those large analyses did not show any difference in response rates perhaps we shouldn't expect progression free or overall survival. There has been a hint from the two smaller series that maybe the group with bone metathals who received bisphosphonates had a slightly better outcome. But of course we now know about osteocrystus of the jaw and I think having used bisphosphonates quite widely some people have become more nervous about the widespread use of bisphosphonates in combination with TKI's. ONJ related to bisphosphonates was first described in 2003 and therefore was not reported in the early registration of bisphosphonate trials. But in smaller and larger subsequent series the rates of ONJ have varied between 1 and 20%. We know what some of the risk factors are and they are a high cumulative dose of hypotency bisphosphonates so those are the nitrogen containing bisphosphonates which includes zolodronic acid, a history of dental disease, invasive dental procedures or dentures and concomitant anti cancer therapy is noted as a potential risk factor for increasing this. The rates reported in the randomized controlled trials are shown here. Only the bottom trial, the azure trial which is an adjuvant breast cancer study compared zolodronic acid with placebo and there are a number of rates of comparing the rates with denosumab and zolodronic acid. Overall in all of these large randomized controlled trials reported rates are somewhere between 1 and 2 or possibly 1 and 5%. But actually that's a huge difference if you're a patient, a 1 in 100 chance and a 1 in 20 or 25 chance of developing osteo necrosis of the jaw. Specifically turning to any information we have about the combination of bisphosphonates with anti-vegeff therapy there are a number of publications, most of them quite small that report rates between 4 and actually as much as 24% possibly. Again I draw attention to the bottom line which is the publication from the Global Expanded Access Program which is perhaps most pertinent to us looking at 446 patients who received synitonib with zolodronic acid and reported a rate of 4%. Therefore what I would say is that we know that the risk of ONJ is reduced significantly by patients having preventative dental measures so whether the actual true rate is 1% or 4% we know that all patients have dental examination prior to starting that the rate is reduced significantly and of course there are very few indications for emergency bisphosphonates perhaps excluding hypercalcemia and therefore for most patients there is no excuse not to do this I would suggest. Very very briefly, as we know more about the components of the vicious cycle of bone metastases further targets have been identified and I mentioned just two cathepsin K and sarc kinase which now have molecules to inhibit them and they are being investigated in other cancers but not yet in renal cancer and so we await to see developments there. And so in conclusion I would say that bone metastases are clinically significant and may possibly also carry prognostic significance and therefore that we need treatments to overcome the seeming adverse outcomes associated with these and the undoubted clinically adverse outcomes. I would favour aggressive management of limited bone metastases and I suggest that bone directed therapy does reduce skeletal related morbidity and actually it probably still does in the era of current therapies but there are questions of patient selection as ever and importantly which patients most benefit and also the dose and frequency of administration which as we will know with bisphosphonates is very varied. Preventative dental programmes do reduce osteonecrosis of the jaw and finally as we try and improve the outcome for bone metastases we will need improved imaging or other techniques to assess response adequately. Thank you very much.