BONE METASTASES

Bone  Metastases

     Preoperative  transarterial embolization of hypervascular bone metastases, most commonly  renal metastases, is a very useful and helps reduce  preoperative blood loss and surgical morbidity. As a technique this was first  described  by Feldman et al and there have been a number of subsequent studies with favorable results . Barton et al reported 500-1500 ml intraoperative estimated blood loss (EBL) in embolized patients as compared to 2000-18500 ml if no embolization was performed . Further, even  partial devascularization of the lesion is beneficial in reducing estimated  blood loss although complete  devascularization is ideal.

     Tumor  vessels can originate  directly from a main artery or from distal  2nd or 3rd order branches. Embolization of the  former carries a higher risk of embolising down the main artery and the latter comes with cannulation  problems with smaller calibre arterial branches. Successful cannulation of the smaller branches gives the freedom  of aggressive embolization whilst proximal tumor  branches require extra care.

     The technique involves vascular access via a suitable artery depending on the tumor location.  Initual angiography  should include detailed  demonstration of all  the feeding branches. The tumor  arteries should be cannulated and  catheter positioned beyond any major  arterial branches. Embolization is usually performed using polyvinyl alcohol (PVA)  particles. The particle size should be appropriate to the size of the arterial branches embolised. Other  agents including  gelatine  sponge and coils have been  used.

      Transarterial  embolization of bone tumors is usually  safe with a few potential  complications. Post  embolization syndrome is not unusual  and should be considered for  planning  both the embolization and the surgical procedure. A number of these  bone lesions involve  the appendicular  skeleton and  hence embolization down the femoral or brachial arteries can result in ischemic  symptoms. Similarly   skin necrosis  and nerve palsies have been reported.

DNA METHYLATION AND EPIGENETIC GENE SILENCING

DNA  METHYLATION AND EPIGENETIC GENE SILENCING

     DNA methylation is a reversible chemical modification of the cytosine in the CpG islands  of promoter sequences, catalyzed by a family of DNA methyltransferases. DNA  methylation does not change  the genetic information but it just alters the readability of the DNA  and results  in the  inactivation of gene by  subsequent transcript repression.  CpG island  are the regions  in DNA  that  contains  many adjacent cytosine and guanine nucleotides. The ''p '' in CpG  refers to the phosphodiester bond between  the cytosine   and  the guanine. These islands  occur  in  approximately  40% of the promoters  of human  genes. These  islands occur  in approximately 40%  of the promoters  of human genes. DNA methylation  plays  a critical  role in the control  of cellular  process  including  embryonic development , transcription, X- chromosome inactivation and  genomic imprinting. DNA  methylation occurs in the C5 positions of cytosines that precedes guanines and  are called dinucleotide CpGs. The CpG dinucleotides are not found frequently throughout the human genome and present 20 % of its  expected frequency. But approximately half of the human gene promoter regions have CpG rich areas of 0.5 to 2 kb in length. In which CpG

dinucleotide frequency are higher than expected . These CpG rich areas are often known  as CpG islands. . The majority (94%) of CpG island  remain  unmethylated  in normal cell. But particular subgroups of promoters CpG are  methylated  such as tissue  and germ line specific genes. In general , CpG  island methylation causes gene silencing. The  methylated CpG  island  also recruit   histone deacetylases  and other factor involved  in transcriptional silencing .  In activation  of tumor suppressor genes through  hypermethylation of CpG islands within promoters regions is a major event in carcinogenesis. Hypermethylation of CpG  islands within promoter regions  is a major  event in  carcinogenesis . Hypermethylation of CpG  island also has silencing effect on miRNA  in cancer. Micro RNA are short , 18-22  nucleotide, noncoding RNas that

regulate many cellular functions including cell proliferation, apoptosis and differentiation by silencing specific target  genes through translational repression or mrNa degradation.

COMPOSITE TISSUE ALLOTRANSPLANTATION

COMPOSITE  TISSUE  ALLOTRANSPLANTATION  

       

      

        After the report of the first microvascular tissue transfer  the free transfer of autologous tissue became the  mainstay for  treatment  of complex soft tissue defects and with reimplantation  of the  hand and digits, the modern era of replantation in reconstructive  surgery began in the  1960.

    

        Composite tissue allotransplantation (CTA)  is a term that includes transplantation of multiple tissues of ecodermal and mesodermal  origin. It  involves simultaneous transplantation  of tissue  components  involving  skin, muscle, nerve bone and tendons. Transplantation of hand is one of the best examples of CTA concept and it has  brought the  attention  of the  scientific  community and the public  to this new field of transplantation. The growth of solid organ transplantation also parallels the emergence of newer immunosuppressive drugs.

       The first hand transplant was performed in Lyon France in 1998, with eventual graft loss due to noncompliance with immunosuppression. The clinicopathological  freatures of rejection were largely confined to skin with milder involvement of muscle   and tendon and sparing of bone and joints.

     Louisville School of Medicine  in United  States has taken lead  in hand transplant surgery in the United  States. Of the approximately 30 hand transplants done worldwide, 3 have been done in Louisville. A hand  transplant protocol by the University  was drawn up. Patient recruitment  is rigid. The transplant protocol by the University  was drawn up. Patient  recruitment  is rigid. the pretransplant  psychiatric evaluation  screening tests are similar to solid organ transplantation  and include routine  blood work out. ABO  type, cancel reactive antibody, infection screen , chest X-ray, cardiac evaluation, etc .

      Decreased donor has to meet the standard criteria for determination of brain death. Donation after cardiac death is not  considered. All donors were from the jurisdiction of the  local organ procurement organization. ABO blood group compatibility and a negative  crossmatch with the recipient was necessary. Absolute contraindications included active  intravenous drug use. A detailed evaluation of the limbs of the potential donors included range of motion in all joints and absence of arthritis.

     The details  of the donor procedure is described briefly. A circumferential incision is made around the  distal arm with identification of underlying  veins and cutaneous  nerves. another longitudinal incision is made along  the medical side of the arm over the brachial vessels  to enable cannulation for cold perfusion of the limb with the University of Wisconsin  solution.

        The sequency of tissue repair proceeds in the following order: bony fixation, arterial revascularization, vein repair, tendon repair and nerve  repair. All  patients  received  heparin for 48 hours postoperatively.

       Immunosuppression   was induced with basiliximab , tacrolims, MMF  and steroids, The digits were fixed in metacarpophalangeal  fiexion.  The   wrist was in a dynamic brace. a transcutaneous electrical  nerve stimulation unit to decrease pain and  electric muscle stimulator were  used throughout the rehabilitation course. Skin biopsies were performed to monitor rejection.

       In  Malaysis, an upper extremity transplantation was performed at the level of the shoulder on a 28 day old neonate  born with congential absence of one arm.  The identical  twin had fatal brain anomaly and was the donor of  the limb. The  transplanted limb grew at the same rate as the native limb and after 7 years was  functional. One major controversy surrounding CTA is the  toxicity of immunosuppression with an increased risk of cancer, organ failure and opportunistic infections.

      Many other tissues have been successfully transplanted to restore tissue loss from trauma or tumor. Simultaneous and sequential abdominal wall transplantation  coincident with intestinal transplantation has been reported from University of Miami. A 40- year- old man received the  first  successful human laryngeal transplant in 1998. A human leukocyte antigen matched  laryngopharyngeal complex including  thyroid,prathyroids and five rings of trachea were transplanted  along with   anastomosis of both superior and one of the recurrent laryngeal nerves.

       At a follow- up of more than 7 years, the patient had excellent  function, normal swallowing and good phonation. Other workers have reported 13 laryngeal transplantations with 90 percent graft survival at 2 years using immunosuppression similar to renal transplantation . Patients with  severe disfigurement of face not amenable to reconstruction are likely to benefit from partial face transplantation. The first  facial transplant was in a 38- year- old woman, disfigured by a severe dog bite who received a  central and lower  facial transplant in 2005.  A sentinel skin graft was placed in the left inframammary area to monitor rejection.  Sensitivity to  light touch and temperature returned by 6 months , whereas  motor recovery allowing complete mouth closure was achieved at 10 months . Despite two episodes of acute rejection and renal  dysfunction requiring cessation of tacrolimus, the patient is satisfied with aesthetic result and  is maintained on sirolimus, MMF and prednisone.