STEM CELL RESEARCH
Stem cells are the versatile cells that have the ability to grow into any kind of tissue. Certain features distinguish these from other cells. Firstly, they have the capacity of self-renewal. They can undergo endless division to sustain their population under appropriate conditions and still remain in an undifferentiated state. Secondly, they have the ability to differentiate into multiple lineages and this characteristic is termed as ‘plasticity.’ Thirdly, these cells can functionally repopulate the tissue of origin when transplanted into a damaged recipient.
The use of stem cell technology has generated a great deal of interest though controversy surrounds its use and is being debated in both public and political arena. This is, however, an exciting phase of development with potential to dramatically influence the study of human biology. An era seems to have arrived with a key to treatment of hitherto incurable complex disorders.
The stem cells may be divided into three types: (i) embryonic stem cells, (ii) adult stem cells, and (iii) other stem cells.
Embryonic Stem Cells
Though embryonic stem cells have been extensively studied in mice for over 20 years, the human embryonic cells were derived for the first time only in 1998.1 The cells of the inner cell mass (ICM) of the blastocyst are known as ‘embryonic stem cells.’ It is possible to remove these cells from the blastocyst and culture them in an undifferentiated state in the laboratory.
The fertilized human ovum begins a series of cell divisions which result in the formation of embryo and its membranes. The blastocyst is present by the seventh day and consists of a single layer of cells surrounding the contained fluid, with a collection of cells forming solid area on the inner aspect of the wall at one point. This is the inner cell mass (ICM) from which the fetus is formed. The cyst wall of flattened cells is the trophoblast. Immunosurgery involving complement-mediated destruction of trophoblast surrounding the ICM cells, allows selection of ICM cells, which are then propagated under appropriate growth conditions.2 Their pluripotent status is confirmed by expression of certain molecular markers. These then are grown continuously in an undifferentiated state on irradiated mouse embryonic fibroblast cells as a feeder layer and can be established as a cell line. These cell lines can act as a constant reservoir of stem cells. These, upon treatment with specific growth factors or agents, differentiate preferentially along a particular lineage. Embryonic stem cells can differentiate into cells of all three germ layers.3 A single cell line is capable of growing indefinitely in the uncommitted state while retaining its ability to give rise to all tissues of the body upon directed differentiation by various growth factors.4
The potential source of human embryonic stem cells is through therapeutic cloning or somatic nuclear transfer. It is basically the same concept that was used in generating Dolly, the sheep.* What is done is to obtain a somatic cell, for example a tail tip of a mouse. These are just the generic diploid cells (46 chromosomes). These are grown in a dish. We then obtain eggs (oocytes) from a donor mouse. We enucleate the oocyte (remove its nucleus) and transfer the nucleus of the somatic cell into oocyte, which is now tricked into believing that it is fertilized because it has this diploid genotype. Then the egg will go on to form a blastocyst, and at day 4, we remove the embryonic stem cells from the inner cell mass and then we generate an embryonic cell line that would have the same genotype as the tail tip donor.
Public concern, religious dictate and government control has however held back human embryonic stem cell research and it is considered by some unethical and morally unacceptable. One criticism is that stem cells are derived from embryos and retain ability to form a complete embryo. This is however, incorrect as once the embryonic cell is isolated from the cluster of cells, it loses any memory of axis formation and can no longer form a body plan.5
The other criticism is based on the harvesting procedure of embryonic stem cells which destroys the embryo and hence the research has got entangled into abortion debate. Human embryos used in such research are blastocysts of only about 100 cells, long before an abortion would be performed. Critics of embryo research, however, fear that man is getting a step closer to create a human clone.
The global policy towards embryo research and its control remains variable. Certain countries allow embryo research only for therapeutic purposes. In the UK, therapeutic cloning research has been legal since 2001 but it is under licence from Human Fertility and Embryology Authority (HFEA) of Great Britain.*
* The world's first cloned mammal. Dolly, the sheep was cloned by Professor Ian Wilmut at the Roslin Institute Edinburgh in 1996. —Editor.
In March 2002, US Federal Government allowed federal funding for human embryonic research on a limited basis and appointed an Advisory Council for Stem Cell Research. This Council and the National Institute of Health guidelines will ensure public scrutiny of research. About 60 cell lines are listed in NIH Cell Registry. Scientists can use these, but are not allowed to derive new ones. Moreover, accessing these cell lines may not be simple as some of these are the property of private companies and specific contract agreements need to be signed. It has now been clarified that any laboratory in the United States could do nuclear transfer research so long as it does not use any Federal funds in any part. The private companies doing stem cell research in the US are California-based Genetic Savings and Clone (GS & C)** and Texas A and M company and many others.
In December 2002 the Senate of Australian Federal Parliament approved a bill allowing the use of stem cells from 70,000 surplus IVF embryos held in Australian Fertility Clinics. This practice was however staunchly opposed by the Catholic Church and so called ‘Right to Life Advocates’ who believe that life begins at the moment of conception.
Breakthrough is now coming from Asia. The South Korean researcher Woo Suk Hwang and his team at Seoul National University have created a puppy whose entire genome came from a single cell from the ear of another hound.*** Hwang's team has also created eleven stem cell lines perfectly matched to the DNA of human patients.6 The skin cell (with nucleus) is injected into the emptied donor egg (the donor egg is emptied by squeezing out its nucleus through a tiny slit in its outer membrane). The skin cell (with nucleus) is injected into the emptied egg through the same tiny slit. The fused cell is stimulated electrically and chemically to get it to start dividing. After about 5 days, a blastocyst forms and stem cells emerge from the inner cell mass. The stem cells which are genetically identical to the patient are removed and grown in culture. Hwang calls this procedure “Nuclear Transfer” rather than “Cloning.” This development has brought us closer to creating customized stem cells for treatment.*
* In February 2005 HFEA of Great Britain gave licence to Professor Ian Wilmut of Roslin Institute Edinburgh, to clone human embryos for research. Professor Wilmut will collaborate with researchers from King's College University of London. They plan to extract stem cells from patients with motor neuron disease (MND) and implant these in unfertilized eggs to create cloned embryos. Later, harvesting of stem cells from embryos to grow motor neurons. The study of cells may help to develop future treatment for motor neuron disease. —Editor
** Little Nicky, the kitten died and from its DNA another kitten (its carbon copy) was created an year after in 2001 by the company Genetics Savings and Clone of Sausalito California. Dollar 32,000 was the charge for this service. This ignited fierce ethical and scientific debate over cloning technology. —Editor
*** At Seoul National University, Hwang and his team have recently created SNUPPY the pupy-an animal whose entire genome came from a single cell from the ear of a three year's old Afghan hound. SUNPPY's arrival announced in Nature in August 2005 earned grudging admiration from rival cloners in the US.Professor Ian Wilmut, Dolly's cloner also wants to work with South Koreans on Motor Neuron Disease.
The ability to have embryonic stem cells, without sacrificing conception human embryos, might be an answer to the debate generated by Catholic Church and Right to Life Advocates. Parthenogenesis is a reproductive means that is used by worms and some plants and the idea would be that an oocyte, instead of dividing by sexual division will reproduce itself and go on to become an embryo with its genetic material. The ability to create cloned 100 cells embryo from the maternal egg alone without the use of sperm, has been identified as a potential source for stem cells. Parthenogenesis-derived cells can serve as a novel source of multipotent stem cells.7**, ***
Adult Stem Cells
Ever since the development of human embryonic stem cell line there has been an extensive debate about the ethics of using embryos in research. In a situation when due to restriction, prejudice or mistrust scientists are being denied and perhaps kept starved of embyonic stem cells, there has progressed parallel research into the therapeutic potential of adult stem cells.
Stem cells have been identified in adult mammalian tissue like epithelia, germline and connective tissue such as blood, bone, muscle and cartilage. These cells can regenerate when lost due to injury or age. The previous notion that these cells are tissue specific and can only give rise to cells of the tissue from which they are originally derived has now been challenged.
* In May 2005 issue of US Journal Science, Woo Suk Hwang reported that he had successfully produced tailor made stem cells from eleven cloned human embryos. Though controversial, Hwang's research was hailed as a breakthrouigh because it appeared to move a step closer to being able to treat a variety of afflictions from spinal cord injuries to Alzheimer's by using a patient's own DNA to grow perfectly matched tissue to restore defective or damaged organs. However, Hwang's colleague Roh Sung II who collaborated on the groundbreaking study alleged that Hwang had faked research data and this prompted investigation by an expert panel at Seoul National University. It was found that the laboratory data for eleven stem cell lines as reported was the data made using two stem cell lines in total. The University panel found that Hwang's fabrication was a deliberate step and this undermined its credibility. Hwang has resigned from his position as a University Professor.
US Time Magazine, Dec 24, 2005
** At Professor Atala's Unit at Wake University School of Medicine at Winston, Salem NC, Chester Koh and colleagues have investigated whether multipotent cells could be isolated from parthenogenesis-derived cells for potential surgical applications.1 These cells have a high self-renewal rate. The cell type specific inductions result in fully-differentiated muscle, endothelial bone and fat cells. This is the first description in the literature that parthenogenesis derived cells can serve as a novel source of multipotent stem cells.
*** The Roslin Institute Edinburgh has sparked a new ethical row by creating so called parthenotes by stimulating human eggs to start dividing like an embryo without the addition of any genetic material from a male sperm cell. This would serve as a source of stem cells.2
1. Koh Chester, Lanza Robert, Soker Shay, et al. A novel source of stem cells for reconstruction. Abstract for 59th Annual Session of the Forum on Fundamental Surgical Problems. J Am Coll Surg 2004;199:S101.
They possess “plasticity” and are capable of differentiating into multiple tissue types upon induction of extracellular developmental signals of other lineages.
Stem cells with considerable plasticity are found in a variety of tissues including bone marrow, fat, liver and neuronal tissue. The identification of stem cells in the adult brain has challenged the prevailing dogma that the nervous system is rigidly and immutably constructed. Adult bone marrow, liver and pancreas have been reported to harbor stem cells with a differentiation potential for different lineage.
The best-characterized source of adult stem cells is the bone marrow. It has two populations of stem cells that exhibit distinct biological properties; (a) hematopoietic stem cells, which are non-adherent and circulating and (b) stromal stem cells, which are non-circulating, adherent and fibroblastic in nature.9 These cells are able to differentiate into multiple mesenchymal tissues including fat, bone, cartilage, epithelial cells of the liver, kidney, lung, skin, gastrointestinal tract and myocytes of heart and skeletal muscle.8
Hematopoietic stem cells from bone marrow have been used for treatment of leukemias, aplastic anemia, myelodysplastic syndrome and hemoglobinopathies using either autologous (from the patient) or allogeneic (from donor) stem cells. Use of peripheral blood-derived stem cells has now become more frequent. Today, these cells have largely replaced bone marrow as the preferred stem cell source.
In addition to hematopoietic stem cells, bone marrow also contains mesenchymal stromal cells. These cells, as mentioned earlier can differentiate into cells with properties characteristic of muscle, endothelium, liver, heart, neuronal tissue, bone and cartilage. Bone-like tissue has been synthesized in vitro and differentiated into osteoblast.10 These are capable of forming extracellular matrix consisting of hydroxyapatite comparable to natural bone mineral. This tissue engineered cultured bone has been used for large bone defects.11 The clinical trials show that allogeneic stromal cells offer a feasible transplantation therapy for osteogenesis imperfecta.12
Adult bone marrow, liver and pancreatic ducts have been reported to harbor stem cells with a broad differentiation potential for endothelial lineage, including hepatocytes and beta cells. Various groups have reported the ability of murine and human embryonic stem cells to differentiate into insulin secreting beta cells.13, 14 Islet like functional cells can also be differentiated from bone marrow stem cells. These cells have been shown to control blood glucose level in diabetic rats.15 However, the clinical impact of these results awaits further confirmation.
Liver transplantation has evolved over the past 20 years to a relatively standardized operation today with good survival rates. However, the donor shortfall presents a severe challenge worldwide. This has led to search for alternative options for transplantation. Liver repopulation with bone marrow derived hepatocytes has been shown to cure the genetic liver disease fumary lacetoacetate hydrolase (FAH) deficiency.16 Thus, this cell therapy can be used for treatment of inherited and acquired liver disease. In a report by Soriano et al subjects showed marked improvement in the clinical condition of fulminant hepatic failure following intraportal hepatocyte transfusion.17 Khan et al have reported on the peritoneal transplantation of human fetal hepatocytes for the treatment of acute fatty liver of pregnancy.18
Cardiac Regeneration with Adult Stem Cells
To compensate for cardiomyocyte loss after myocardial infarction the cells with the great therapeutic potential are the skeletal myoblasts and the autologous bone marrow cells. The initial clinical trials used skeletal myoblasts. A phase 1 clinical trial by Menasche in Paris19 included patients who had extensive infarct rendering that region nonfunctioning without any viable cardiomyocytes on PET scan. Muscle biopsy is performed from patient's thigh and myoblasts are expanded in culture and then injected in and around the infarct at the time of bypass surgery. At 1 to 2 years postoperatively, an improved function was noted on an echocardiogram suggesting return of function in the infarct region. The postoperative PET scan showed some viability in the infarct region that was not present preoperatively. Arrhythmias have however been noted in some patients and they required insertion of an implantable cardioverter defibrillator. This is because myoblasts, do not express gap junction proteins and remain electrically-insulated, suggesting that they may not beat with the host myocardium.20 The cellular engraftment with myoblasts, therefore, needed to be revised. A better alternative option has been the progenitor cells from patients's own bone marrow. These cells can be expanded in vitro to have a sufficient number of cells available to populate the infarct region. These cells can also be induced to beat when co-cultured with fetal cardiomyocytes or treated with 5-azacytidine. The cells are then injected in and around the infarct.21 The engrafted cells expressed muscle proteins and participated in the angiogenesis and in the vasculogenesis by forming endothelial cells and smooth muscle cells.
To determine the improvement in function, the animals underwent 99mTc sestamibi scanning. Before the transplant the infarct region had very little perfusion but after cell transplantation, the regional prefusion was improved. Clinical trials are now proceeding to determine the efficacy of this type of cellular transplantation.22, 23
Stem Cells and Brain Repair
In humans, there is sufficient data to confirm that there are stem cells in the adult brain. The cells perhaps line the ventricles, or exist in the hippocampus. The cells that can be isolated in large numbers from humans are the ones that can exist in white matter and there are cells that are largely committed to become oligoandrocytes or oligoprecursors.
Another potential tissue source is the non CNS stem cells. More specifically, perhaps the adult hematopoietic stem cells with the possibility of transdifferentiating from a potentially hematopoietic lineage to brain or neural lineage. The work on these cells with pluripotential ability however is still in infancy.
The main source at present of cells for brain or neural repair, is from embryonic stem cells. The loss of specific type of dopaminergic neurons in the substantia nigra, is a major feature of the pathology in Parkinson's disease. The midbrain dopamine neurons can be made available in vitro by directed differentiation of human embryonic stem cells into dopamine neurons.24 Clinical studies have demonstrated that dopamine neurons can survive and reinnervate the striatum for at least 10 years. Clinical trials showed partial recovery of motor function in patients with Parkinson's disease. These cell replacement procedures are, however, far from optimal. Some have exhibited major clinical improvement, others have shown no or only modest improvement.25
It has been suggested that embryonic stem cells be collected from inner cell mass developed through somatic nuclear transfer. These cells through a defined process are directed to generate into a specific type of neuron and to further generate dopaminergic neurons in great numbers.
Amyotrophic lateral sclerosis is a progressive fatal neurological disease. The loss of motor neurons in this disease cause the muscles under their control to weaken and waste, leading to paralysis. Recently, it has been in animal models that stem cells significantly slow the progress of disease and prolong survival.26
An inherited form of Alzheimer results from mutations in the beta amyloid precursor protein (APP) and presenilins which accelerate neuro-degenerative cascade by increased production and deposition of neurotoxic form of amyloid beta peptide and by disturbing calcium hemostasis. Administration of embyonic cells in mice model of Alzheimer, contributed to considerable improvement in animals. The embryonic cell source in this study was the human umbilical cord blood.27
Other Sources for Stem Cells
Umbilical cord blood is another rich source of hematopoietic cells and has been favored because of significantly decreased incidence of T cell-mediated graft versus host disease.28 There is no ethical dilemma in using cord blood stem cells as the blood is collected from discarded umbilical cords after child birth and collection of stem cells in this manner poses no danger to infant or mother and is simple and easy.
Due to decreased incidence of graft versus host disease, cord blood transplant can be used for HLA mismatched patients as well. But there are some disadvantages of cord blood (CB) transplantation. The engraftment is usually significantly delayed in CB transplantation as compared to peripheral blood stem cells. The number of cord blood stem cells may also be insufficient for engraftment in an adult. This has led to the establishment of cord blood banks throughout the world. Cord blood banks process cord blood and preserve it by freezing in liquid nitrogen at temperature of −195 degree celsius.
The umbilical cord blood banks in India are either public or private. In a private bank it is possible to store blood for up to two decades and it can be claimed by the donor or his/her family.* It is, however, not possible to stake claim from a public bank.
Problems with the Therapeutic Use of Stem Cell
Use of stem cells in treatment of various diseases is a new field of medicine which utilizes the inherent capacity of stem cells to renew and also differentiate to various lineage. There are, however, certain problems:
- Human stem cells proliferate more slowly than their murine counterpart. There is a definite need to improve cloning efficiency.
- At present there are limited number of human stem cell lines available. More cell lines need to be developed and there is need to produce sufficient number of desired cell types in a pure form.
- In cell cultures, spontaneous differentiation may occur and a wide variety of mixed cells may be there. Derivation of a relatively homogeneous cell population from the mixed cell population becomes necessary.
- Rejection of graft by the immune system may be a problem. The immunosuppressive drugs used today are far from ideal and have complications including opportunistic infections, drug-related toxicity, skin malignancy, low grade lymphoma, etc. The answer to this problem may lie in creating a large bank of stem cells with a wide variety of histocompatibility background or by knocking out MHC genes in the stem cells.
* The Indian Council of Medical Research, the Department of Biotechnology and the Drug Controller General of India (DCGI) are in the process of preparing guidelines for Umbilical Cord Blood Banking in India. The guidelines are being drafted in consultation with Chennai-based Asia Cryo Cell and Mumbai-based Reliance Life-Sciences. Asia Cryo Cell Pvt Ltd and Florida-based Cryo Cell International (CCI) have established Life Cell in India as a joint venture. Life Cell is the first private stem cell bank in India. The Apollo Group of Hospitals have also recently signed MoU with American Blood Bank Histostem Inc for establishing stem cell bank. At Life Cell, each client has to incur Rs. 27,000 (US $ 621) as enrollment and processing fee, Rs. 2,900 (US $ 66) every year as storage cost. For one time payment, the cost comes to Rs.59,900 *US $ 1,377).
- To understand what cell type needs to be provided to correct a specific pathology and how to deliver it may be another problems area.
- Whether the transplanted pluripotent cells will form tumors or otherwise differentiate improperly after transplantation is a difficult situation to envisage at times.
- The major milestone in stem cell research would be to see that the differentiated cellular derivatives would function in a normal physiological way. Some specialized cells like neurons and cardiomyocytes may, however require a complex structural integration in order to repair the tissue concerned.
An era has now arrived with a key to the treatment of hitherto incurable and complex disorders. Research into the use of stem cells is an exiciting development and has the potential to dramatically influence therapeutics. Stem cells can provide a way to repopulate damaged organs, to deliver genes or growth factors to required sites in the body and to reconstitute organs in vitro for transplantation.
- Thomson JA, Itskovitz Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived from human blastocysts. Science 1998;282:1145.
- Mitalipova M, Calhoun J, Shin S, et al. Human embryonic stem cell lines derived from discarded embryos. Stem Cells 2003;21:521.
- Zeng X, Miura T, Luo Y, et al. Properties of pluripotent human enbryonic stem cells BG01 and BG02. Stem Cells 2004;22:292.
- Reubinoff BE, Pera MF, Fong CY, et al. Embryonic stem cell lines from human blastocysts. Somatic differentitaion in vitro. Nat Biotechnol 2000;18:399.
- Trounson A, Pera M. Human embryonic stem cell: Fertil Steril 2001;76:660.
- US Time Magazine, May 30, 2005.
- Koh Chester, Lanza Robert, Soker Shay, et al. Parthogenesis, a novel source of stem cells for reconstruction. Abstract for 59th Annual Session of the Forum on Fundamental Surgical Problems. J Am Coll Surg 2004;199:S101.
- Herzog EL, Chai L, Krause Ds, et al. Plasticity of marrow derived stem cells. Blood 2003;102:3483.
- Friedenstein AJ, Petrakova KV, Kurolesova AI, et al. Heterotopic cells of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 1968;6:230.
- Maniatopoulos C, Sodek J, Melcheer AH, et al. Bone formation in vitro by stromal cells obtained from marrow of young adults. Cell Tissue Res 1988;254:317.
- Marcacci M, Kon E, Zaffagnini S, et al. New cell based technology in bone and cartilage tissue engineering. Chir Organi Mov 2003;88:33.
- Horwitz EM, gordon PL, Koo WK, et al. Allogeoneic bone marow derived mesenchymal cell engraft stimulates growth in children with osteogenesis imperfecta. Implications for cell therapy of bone. Proc Natal Acad Sci 2002;99:8932.
- Lumelsky N, Blondel O, Laeng P, et al. Differentiation of embryonic stem cells to insulin secreting structures similar to pancreatic islets. Science 2001;292:1389.
- Chen LB, Jian XB, Yang L. Differentiation of rat marrow mesenchymal stem cells into pancreatic islet beta cells. World J Gastroenterol 2004;10:3016.
- Willenbring H, Bailey AS, Foster M, et al. Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nat Med 2004;10:744.
- Soriano HE, Wood RP, Kang DC: Hepatocellular transplantation in children with fulminent hepatic failure (Abstr.) Hepatology 1977;26:39A.
- Khan AA, Habeeb A, Parveen N, Habibulla CM, et al. Peritoneal transplantation of human fetal hepatocytes for the treatment of acute fatty liver of pregnancy-a case report. Trop Gatroenterol 2004;25:141.
- Menasche P, Scorsin M, Hagege A, et al. Myoblast transplantation for heart failure. Lancet 2001;357:279.
- Murray CE, Whitney ML, Reinecke H. Muscle cell grafting for treatment and prevention of heart failure. J Card Fail 2002;8:5532.
- Weisel RD. Cardiac regeneration with adult stem cells: In: Symposium on Stem Cells in Clinical Practice. Moderator Evers BM, et al. J Am Coll Surg 2003;197:458.
- Hamano K, Nishida M, Hirata K, et al. Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patietns with ischaemic heart disease. Clinical trial and preliminary results. JPN Cirt J 2001;65:845.
- Stam C, Westphal B, Kleine HD, et al. Autologous bone marow stem cell transplantation for myocardial regeneration. Lancet 2003;361:45.
- Perrier AL, Taber V, Barberi T, et al. Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc Natl Acad Soc 2004;101:12543.
- Lindvall O, Hagell P. Cell therapy and transplantation in Parkinson's disease. Clin Chem Lab Med 2001;39:336.
- Silani V, Cova L, Corbo M. Stem cell therapy for amyotrophic lateral sclerosis. Lancet 2004;364:2000.
- Ende N, Chen R, Ende-Harris D. Human umbilical cord, blood cells ameliorate Alzheimer's disease in transgenic mice. J Med 2001;32:241.
- Cohen Y, Nagler A. Umbilical cord blood transplantation, how, when and for whom? Blood Rev 2004;18:167.
NON-HEARTBEATING KIDNEY DONORS
The distinction between heartbeating and non-heartbeating kidney donor lies in the mode of death. Heartbeating donors die because of intracranial catastrophe resulting in brain stem death and are on a life-support machine. Non-heartbeating donors (NHBD) are patients who die as a result of cardio-respiratory arrest. Following cardiac arrest, the kidneys remain viable for about 40 minutes and if these can be cooled rapidly they may remian suitable for subsequent transplantation. Most NHBD programs exclude kidneys that have suffered prolonged warm times, the usual cut off time being in the region of 30 to 45 minutes.
In the controlled situation, where warm time is commonly in the region of 10 to 15 minutes, initial function rates of over 50 percent can be achieved.1 In uncontrolled NHBD, where the warm time is usually more than 30 minutes, the initial graft function is rare and posttransplant dialysis is required for several weeks while the kidney recovers.2 From a young donor, even if the warm time has extended to 60 minutes the transplant results may be good.
In uncontrolled NHBD it is imperative to perform in situ organ cooling as soon as possible after death. The situation is straightforward if the next of kin is available at the time of death as consent for cannulation and in situ organ perfusion can be obtained quickly. Once in situ perfusion has been performed the family has much more time to think whether they wish organ retrieval to be performed. If the next of kin is not present at the time of death, it is a controversial situation. In the UK, Coroner's office may permit in situ perfusion without written consent from the next of kin (the situation in India is not clear on this point).
The kidney preservation by simple static cold storage in ice has been adopated widely. This has been successful for HBD kidneys as they suffer no warm ischemic damage. Pulsatile machine perfusion, though more expensive, more labor intensive and complicated has advantages for NHBD kidneys as they have suffered a greater ischemic insult.
After transplantation, NHBD kidneys have higher rates of primary non-function than HBD kidneys. Despite poorer initial graft function, there were no statistically significant differences in acturial graft survival rates at 5 years posttransplant (percent survival for living, HBD and NHBD= 78%, 75% and 79% respectively).3
- Nicholson ML, Wheatley TJ, Horsburgh T, et al. The relative influence of delayed graft function and acute rejection on renal transplant survival. Transplant International 1996;9:415.
- Gonzalez Segura C, Castelao AM, Torres J, et al. Long term follow-up of transplanted non-heart beating donor kidneys. Transplant Proc 1995;27:2948.
- Brook NR, Nicholson ML. Kidney transplantation from NHB donors. Surg JR Coll Surg Edin Irel 2003;1:311.
LIVE DONOR LIVER TRANSPLANTATION
The use of adult to child liver transplantation and split liver transplantation in which a left lateral segment services a pediatric recipient, has eliminated deaths of children awaiting liver transplantation. The excellent results encouraged expansion of living donor transplantation to adults using the entire right or the left hepatic lobe.1 At present most centers prefer right lobe grafts for adult recipients to ensure adequate hepatic mass in the recipient.
Right lobe liver living donor transplantation is an innovative and challenging surgical procedure that has become a viable alternative for adult patients with end-stage liver disease.2 The greater magnitude and complexity however of the right hepatectomy carries a corresponding increase in risk to donors. There are two different goals: first, to maximize the mass of optimally-vascularized right liver graft for the recipient and second, avoiding vascular and biliary injuries. An extensive preoperative imaging defines the vascular and biliary anatomy in donors. Anatomic variations in right lobe grafts are common. The classic anatomy is present in only 10 percent of patients. The most common anatomic variations are not considered to be contraindications for donation but surgeons should be prepared to recognize and manage them.
Unfortunately, two widely publicized deaths after living donation have been a sobering reminder that although mortality remains low (0.2% to 0.5%), donor partial hepatectomy is an operation of far greater magnitude than is living donation of other organs.3, 4
A study of adult to adult liver transplantation funded by the American Society of Transplant Surgeons and the National Institute of Diabetes and Digestive and Kidney Diseases is in progress. The efforts to better define parameters for safe application of living donor liver transplantation are ongoing, with the professional transplant organizations working closely with the government to lead the way. Results are not expected for a few years but the work is in progress. Clearly, much work lies ahead but the efforts are on.
- Roberts JP, Brown RS, Edwards EB, et al. Liver and intestine transplantation. Am J Transplant 2003;3 (Suppl 4):78.
- Marcos A. Right lobe living donor liver transplantation. Liver Transpl 2000;6:S59.
- Humor A. Donor and recipient outcomes after adult living donor liver transplantation. Liver Transpl 2003;9(Suppl 2):S42.
- Pomfret EA. Early and late complications in the right lobe adult living donor. Liver Transpl 2003;9(Suppl 2):S45.
Most surgeons base their practice on uncontrolled case series and uncontested expert opinion. There is lack of quality evidence on a wide variety of topics. They have little or no training in conducting an evidence-based literature search.
We must however convince the practicing surgeon that evidence-based surgery (EBS) can be practized efficiently. If however, he believes that integration of EBS in his practice will take more time than is available, then there will be little motivation to do so. Changing attitude is not an easy task. Surgeons working in teaching hospitals must set the standard for integrating evidence-based surgery in every day working life of their trainees. As Birch, et al1 comment. “It is no longer acceptable for a surgeon to be estranged from the current literature. The demands of colleagues, licensing bodies and patients necessitate satisfactory knowledge of the best available evidence for surgical care.” We cannot allow the surgical community at large to believe that the EBS is nothing more than doing randomized-controlled trials, and is not within the purview of the average attending surgeon.
Prof. Shrikhande, a senior surgeon with rich experience and an observant open mind, writes about EBS in this issue.1 He learnt surgery at the doorstep of master surgeons, much before the new technology brought ‘literature hunt’ to its present eminent position. The evidence-based-surgery espoused by him is based on basic, truthful and honest approach in treating disease.
- Birch DW, Eady A, Robertson D, et al. User's guide to the surgical literature: how to perform a literature search. Can J Surg 2003;46:136.
- Shrikhande VN: Evidence-based surgery. In: Roshan Lall Gupta (Ed). Recent Advances in Surgery No. 10. Jaypee Brothers, New Delhi: 2006.
ROBOTICS IN SURGERY
In conventional laparoscopy, the action of surgeon's hand is mediated by rigid unarticulated instruments and the visual access is not direct, but is mediated by a camera. Obviously, these limitations increase technical difficulties for the surgeon. To avoid some of these disadvantages, robotics have been introduced in surgery. The robotic surgery, however, has been slow to catch on. The various reasons are the cost of equipment and need for a new and specific training.
Until now, two robotic systems have been extensively tested in surgery: the Zeus (Computer Motion) and the Da Vinci (Intuitive Surgical) systems. Although both have shown to be effective and both are clinically promising, but the Da Vinci systems allow for shorter operating time and steeper learning curve.1 Now, Computer Motion (the manufacturer of Zeus robotic) has been acquired by its competitor Intuitive Surgical. Intuitive Surgical has selected to pursue the Da Vinci system and has discontinued manufacturing of the Zeus system2, though both were initially conceived to perform minimally-invasive cardiac procedures. The greatest innovation of Da Vinci system is the articulated arms. Whereas in open surgery the flexibility of wrist and hands inside the abdomen permits full and free movements, in laparoscopy, the presence of rigid, unarticulated instruments entering the abdomen through fixed openings (trocar sites) limits the degree of freedom. Additional articulations inside and outside the abdomen may help recover the degree of freedom that had been lost and regain some dexterity of the surgeon's hand in open surgery. A three-dimensional monitor allows the surgeon to obtain a more accurate visual control of the instruments and better motion co-ordination.3 Robotics offer many advantages, including magnification, increased sensitivity, increased precision and ambidexterity.
The first use of a robot in surgery in humans was for transurethral resection of prostate and was developed at Imperial College London in April 1991. Probot system has a transurethral ultrasonographic probe at its tip to measure the gland. A three-dimensional model of the prostate was built up. The surgeon can then mark which parts are to be removed. The robot then calculates trajectories of cutting and follows them.4
Robotic cardiac surgery has seen great advancement. For coronary artery bypass, a safe and reliable multiple vessel anastomosis can be performed without the use of cardiopulmonary bypass. The innovative technique, stabilizing platform and refined and intraoperative monitoring have brought good and safe results. A complex master-console system is used for replicating the arm and hand movements of the surgeon. The surgeon manipulates traditional surgical instrument handles at the interface device. His movements are relayed in real time by a computer to robotic arms which are attached to the operating room table. These robotic arms hold specially designed endoscopic instruments which are placed through small ports. By the use of computer elimination of tremor and motion scaling, robotics provide the precision necessary to perform total endoscopic coronary artery anastomosis.
The use of robotics has not only expanded rapidly in cardiac surgery but also other specialities as urology, gynecology and general alimentary surgery. Robot is composed of two units. The patient's station and the surgeon's station, united by a cable. The surgeon is allowed to work from a distance. Because the cable linking the surgeon's and patient's station can be substituted by a satellite transmission or by any vehicle performing digital data transmission, the surgeon can in fact operate from any distance, even thousand of miles away.5
There are certain disadvantages of integrating robotic assistance into the clinical arena. The major drawback is that the system is expensive, usually in excess of one million US dollars. Procedures take longer, are more costly to perform and have clinical outcome equivalent to those with standard minimally-invasive techniques. Now, a different role has been pursued for the robot: that of a surgical assistant working in concert with a primary surgeon operating with standard laparoscopic instruments.
- Sung GT, Gill IS. Robotic laparoscopic surgery: a comparison of the Da Vinci and Zeus systems. Urology 2001;58:893.
- Drasin T, Dutson E, Gracia C. Use of robotic system as surgical first assistance in advanced laparoscopic surgery. J Am Coll Surg 2004;199:368.
- Dion YM, Gaillard F. Visual integration of data and basic motor skills under laparoscopic. Influence of 2 D and 3 D videocamera system. Surg Endosc 2001;11:995.
- Satava RM. Surgical robotics: a personal historical perspective. Surg Laparosc Endosc Percutan Tech 2002;12:6.
- Marescauz J, Leroy J, Gagner M, et al. Transatlantic robot-assisted telesurgery. Nature 2001;413:379.
SURGERY FOR CONJOINED TWINS
The true incidence of conjoined twins is 1:200,000 live-births and females predominate in the ratio of 3:1. Conjoined twins are classified according to the most prominent site of fusion. Thoracopagus accounts for 40 percent of cases followed by omphalopagus (33%), pygopagus (9%), ischiopagus (6%) and craniopagus (2%). Parapagus term has been introduced to indicate side-to-side fusion.
The most celebrated pair was Chang and Eng born on a river boat in the Mekong river in Siam in 1811. They were joined at the xiphisternum by a short band (xiphopagus), which, over time, stretched so that they were able to stand side-by-side. They were discovered by a travelling Scottish merchant Robert Hunter, and taken to the US where they were displayed by showmen. They were seen by surgeons in the UK in 1829 and surgery was considered risky. They married sisters, lived in separate houses in North Carolina and had 22 children between them. During the last year of their life, Chang, who three years previously had suffered a stroke, expressed concern that they could not survive together much longer. They died in 1874.1
The diagnosis of conjoined twins can be made by the 12th week of gestation on prenatal ultrasonography. By 20 weeks of gestation, precise detail of shared organs can be determined on ultrasound scan. It is important to carry out chromosomal analysis and echocardiography. Prenatally, there is opportunity, for recommending to parents, for elective termination of pregnancy, particularly in the presence of a chromosomal abnormality, or cardiac fusion in thoracopagus twins or erebral fusion in craniopagus twins. The parents may elect for termination, if the deformity is so extensive as to be unacceptable to them. If however, the pregnancy is allowed to proceed, an elective cesarean section is planned at 38 weeks gestation. The birth should take place at, or close to, the surgical center where further management will be carried out.
Emergency separation may be performed soon after birth where one twin may be dead or dying and threatening the survival of the other twin. If, however, the infants are stable, it is prudent to allow them to thrive. This would permit time for detailed investigations to be carried out, such as CT, MRI, echocardiography, angiography, urography to plan the ‘operative’ procedure.
Success in the management of conjoined twins demands an experienced team and resources, only available in a tertiary referral center, where the full range of medical, nursing and surgical specialities are present. Advances in diagnostic techniques particularly imaging modalities are of value in planning the separation procedure.2 The operation requires two sets of experienced anesthetists, with individual monitoring of each twin separately as they may require different volume replacement and drug dosage. The separation may involve a variety of specialists, depending on the area of union.
Separation is recommended in all cases where this is feasible with the anticipated survival of both twins. Where there is complex cardiac or cerebral fusion, survival is unlikely. However, a successful separation in craniopagus twins has been attempted with dedicated planning.* Benjamin Carson from Johns Hopkins Baltimore is also in the midst of planning separation in 10 years old craniopagus twins in India.**
* Swift, et al1 published a remarkable summary of the successful separation of twins described as “total vertex craniopagus.” These 28 months old twins had discrete brains, incompletely separated dural sinuses, and shared arachnoid. A careful use of extensive neuroradiologic evaluation included 3D reconstructions of the venous system and creation of life-sized physical models. These twins had crossed venous drainage, i.e. reciprocal drainage of one twin's hemisphere into the other twin's dural venous system. The surgical decision making for separation of the venous system was complex. The planning for this operation extended over 16 months.
** Benjamin Carson, Director Neurosurgery Johns Hopkins Baltimore, has extensive experience of separating craniopagus twins. He successfully separated 11 month old twins in a 28 hour operation in South Africa. Carson and his team are now planning to separate 10 years old craniopagus twins at New Delhi, India.2 A detailed neuro-radiologic evaluation in 3 D simulation will be carried out. The venous system will need to be adjusted in a way that both brains have a parallel drainage system. A saphenous vein segment from thigh will be grafted into the brain of one of the twins who does not have the superior sagittal sinus. The circumference of the fused portion of the skull will be divided and a 5 mm gap created. The skulls will be kept apart using a bone graft. In about two months time, the brains are expected to ease away from each other and brains will later be separated. One of the twins has no kidney and will require peritoneal dialysis and after successful cranial separation, kidney transplantation will follow. The entire procedure will be in multiple stages and would take about 9 months.
1. Swift DM, Weprin B, Sklar F, et al. Total vertex craniopagus with crossed venous drainage: case report of a successful surgical separation. Childs Nerv Syst 2004;20:607.
Where one twin is dead or has lethal abnormality and cannot survive independently and if unoperated, both twins would die, separation to save the healthy twin should be attempted.3
- Hunter K. Duet for a Lifetime. Michael Joseph, London: 1964.
- Mackenzie, TC, Cromblehome TM, Johnson MP, et al. The natural history of prenatally diagnosed conjoined twins. J Ped Surg 2002;37:303.
- Spitz L. Surgery for conjoined twins. Ann R Coll Surg Engl 2003;85:230.
SURGERY FOR FACIAL PALSY
A new technique known as Facial Reanimation can restore function to the muscles of facial expression in unilateral facial palsy.1
The surgery is performed in two stages. The first stage involves harvesting the sural nerve from the calf and exposing the facial nerve on the unaffected side of the face, using a face lift incision. The sural nerve is grafted from the facial nerve and tunnelled under the top lip to the preauricular region of the affected side.
The second stage, after 6 months, involves removing pectoralis minor in the axilla. The facial artery and vein on the affected side is anastomosed to the arterial and venous supply of the pectoralis minor muscle, using microvascular anastomosis. The pectoralis minor muscle is divided into three slips and each one is sutured above the top lip, the corner of the mouth and below the bottom lip. The nural nerve graft is then grafted to the nerves of pectoralis minor muscle. The surgery is fairly successful with good results.
Obesity is an increasingly serious health problem. It is termed morbid obesity when the body mass index (BMI) exceeds 35, a value usually equivalent to an individual exceeding the ideal body weight by about 45 kg or more. Morbid obesity is associated with several fold increase in mortality.
Surgical therapy for morbid obesity known as bariatric surgery, is through either restricting food intake or decreasing absorption from the intestinal tract. In this issue, Chowbey and his team present an illustrative display of laparoscopic bariatric surgery.1 They have preferred minimally-invasive technique because the co-morbid health conditions may contribute to development of postoperative complications. A long laparotomy incision in the morbidly obese not only results in short-term (wound infection or would dehiscence) and long-term (ventral hernia) morbidity, it also greatly limits postoperative respiratory function which contributes to postoperative pulmonary complications. The other advantages of laparoscopic approach, as for other intra-abdominal conditions, include less postoperative pain and faster convalescence.
- Pradeep K Chowbey. Bariatric surgery. In: Roshan Lall Gupta (Ed). Recent Advances in Surgery No. 10; Jaypee Brothers, New Delhi: 2006.
Laparoscopic Surgery for Colorectal Cancer
In this issue Shukla and his team1 at the Tata Memorial, present a lucid account of laparoscopic resection for colorectal cancer as an alternative to open resection with equivalent oncologic outcome and even better postoperative recovery. It is one of the most complex intervention to accomplish laparoscopically and currently only available to a small percentage of patients. A structured approach to training, which would include case selection, preoperative tumor localization, reorganization of theater environment and operative technique, should make surgery safe. Higher conversion rates in patients with adhesions or in obese or for rectal cancer may be acceptable and these are better avoided in the earlier stage of training. Shukla and his team have shown that laparoscopic surgery for colorectal cancer is safe and confers significant benefits when used in appropriate patients with a willingness to readily convert.
CHEMOPREVENTION OF CANCER
Role of Certain Natural Products
The chemotherapeutic agents though used widely for cancer have the drawback of high toxicity and are costly. Recently, natural products are receiving detailed attention by the scientific community towards treatment of cancer.
Certain natural agents possess a chemopreventive role.1 These either inhibit, reverse or halt the process of carcinogenesis. The agents studied in various clinical trials are retinoids, B carotene, calcium, alpha-tocopherol (vitamin E), curcumin, selenium, green tea and soyabean, etc.
The main sources of natural products are vegetables, fruits, spices and plants. The various mechanisms of chemoprevention are: induction of apoptosis, inhibition of metabolic activation of carcinogen; inhibition of free radical mediated damage to cellular environment; inhibition of angiogenesis interaction with signal transduction mechanism and modulation of immune response, etc.
It has been demonstrated that hydroalcoholic root extract of Withania somnifera (Ashwagandha) and seed oil of Ocimum sanctum (Tulsi) exerts significant antiproliferative activity. The chemoprevention activity was shown in mice when it prevented and delayed fibrosarcoma incidence.
Carotenoids are the chemical compounds occurring widely in fruits, green and yellow leafy vegetables. Vitamin C, a water-soluble antioxidant is present in fruits and vegetables and exerts its chemopreventive effect in stomach and pancreatic cancer. Vitamin E, a fat-soluble vitamin having potent free radical scavenging activity prevents cancer in lung, skin and liver. Soyabean is the source of naturally-derived phytoestrogens. The chief constituent of soyabean are isoflavones and it is chemopreventive against breast cancer.2
Alpha-linolenic acid is present in vegetable oils and other omega 3 fatty acids in fish and sea foods. There is strong epidemiological and experimental evidence to suggest its chemotherapeutic role in breast, colon and possibly prostate cancer.3
Green tea is a popular beverage in China and Japan and epidemiological studies suggest that the incidence of prostate cancer is lower in Japanese and Chinese population. Its usefulness has been validated scientifically4, however, clinical studies are required to verify its chemopreventive role.
Anthrocyanins occur in colored fruits and vegetables (blue berries, red cabbage, sweet potatoes and grapes). They are the flavonoids and possess antioxidant property and have been shown to inhibit tumor promotion in mice. The grape seeds have been reported to have colon cancer preventive agent. Turmeric (Curcuma longa) has been shown to have effect against mammary epithelial cell lines.5
The natural products though not absolutely safe are relatively safer, though caution needs to be exercized in their use.
- Reddy L, Odhav B, Bhoola KD. Natural products for chemoprevention. A global perspective. Pharmacol Ther 2003;19:1.
- Adlercreutz H. Phytoestrogens and cancer. Lancet Oncol 2003;3:364.
- Rose DP, Connolly JM. Omega 3 fatty acids as cancer chemopreventive agents. Pharmacol Ther 1999;83:217.
- Adhami VM, Ahmed Mukhtar H. Molecular targets for green tea in prostate cancer prevention. J Nutr 2003;133:2417.
- Ramachandran C, Fonseca HB, Jhabrala P, et al. Inhibition of human telomerase reverse transcriptase and telomerase activity by curcumin in human mammary epithelial and breast carcinoma cell lines. Scientific World J 2002;54:430.
TREATMENT OF ANEMIA FOR PATIENTS RECEIVING RADIOTHERAPY
Tumor hypoxia is related to two factors, the oxygen carrying capacity of blood and presence of poorly-perfused areas in the tumor. Hypoxia is an important factor in poor response to radiotherapy and increasing hemoglobin levels will be able to take care of the oxygen carrying capacity. Conventionally, blood transfusions have been the means to increase hemoglobin levels. There are, however, theoretical reservations with its use, i.e. the immunosuppressive effect of blood transfusion which may be detrimental in certain cancers and fear of transfusion associated infections such as hepatitis, HIV, etc.
With the availability of recombinant human erythropoietin, it is possible to increase hemoglobin levels and thus avoid blood transfusions. It has been shown that the quality of life improves significantly in patients treated with erythropoietin to maintain or increase hemoglobin levels during chemotherapy or radiotherapy.1 However, increasing hemoglobin levels alone will not be able to take care of poorly-perfused areas in the tumor. A combination of erythropoietin therapy and hypoxic cell-sensitizers is therefore recommended and specially for the large bulky tumors that have a high likelihood of poorly-perfused areas.2
- Littlewood TJ, Bafetta E, Nortier JW, et al. Effects of epoietin alpha on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double blind, placebo-controlled trial. J Clin Oncol 2001;19:2865.
- Henk M, Laszig R, Rube C, et al. Erythropoietin for prevention or treatment of anemia in cancer patients undergoing radiotherapy. Lancet 2003;362:1255.
POSITRON EMISSION TOMOGRAPHY (PET)
Cancer Imaging of The Future
This technology is based on the observation that cancer cells demonstate an increased uptake of a glucose analogue, 18-fluoro-2-deoxy-D-glucose (18-FDG) compared with that of normal cells because of increased glycolysis. Unfortunately, increased 18-FDG uptake is not exclusive to tumor cells. All metabolically active cells can take up the tracer, and this enhanced activity is normally seen in brain, myocardium,* spleen, liver, kidney and bone marrow. This “functional imaging” initially used for central nervous system tumors1, 2 can help detect neoplastic cells at an earlier stage as compared to other cross-sectional imaging techniques (i.e. CT scan, MRI or ultrasonography.3
PET has a limited role in initial diagnosis but it can be helpful to localize a primary focus in cases of metastasis of unknown origin. In thyroid cancer, PET is useful for detecting site of non-iodine concentrating metastasis in a clinical setting of high thyroglobulin levels and a negative radioiodine scan. These patients are candidates for either surgery or external beam radiotherapy.
There are patients with rising CEA during follow-up, but with no evidence of recurrent disease by conventional cross-imaging modalities and may have areas of increased 18-FDG uptake during PET scan, representing recurrent or metastatic disease.4, 5 In breast cancer PET does not replace surgical staging of the axilla, however, it can give clinically important information about the locoregional metastatic spread to supraclavicular or internal mammary lymph nodes. Identification of these metastases may have implications for local treatment. Gynecological malignancy and head and neck malignancy are other areas where PET imaging is useful in various stages of the disease.
- Francavilla TI, Miletich RS, Chiro G, et al. Positron emission tomography in the detection of malignant degeneration of low grade gliomas. Neurosurgery 1989;24:1.
- Alavi JB, Alavi A, Chawluk J, et al. Positron emission tomography in patients with glioma. A predictor of prognosis. Cancer 1988;61:1074.
- Som P, Atkins HL, Bandoypadhyay D, et al. A fluorinated glucose analog, 1-fluoro-deoxy D glucose (F-18): Non-toxic tracer for rapid tumor detection. J Nucl Med 1980;21:670.
- Boykin KN, Zibar GB, Lilien DL, et al. The use of FDG-positron emission tomography for the evaluation of colo rectal metastases of the liver. Ann Surg 1999;65:1183.
- Flanagan FL, Dehdashti F, Ogunbiyi OA, et al. Utility of FDG-PET for investigating unexplained plasma CEA elevation in patients with colorectal cancer. Ann Surg 1998;227: 319.
- PET/CT Scan. US Times, September 5, 2005.
PET SCAN IN CARCINOMA ESOPHAGUS
CT scan and endoscopic ultrasonography have been the modalities for assessing the local extent and spread of carcinoma esophagus. Positron emission tomography with fluorodeoxyglucose (FDG-PET) is playing an increasing role in esophageal cancer management.
* PET/CT Scan: A hybrid machine can provide structural and functional information about the heart in a single scan. The contrast CT of the heart locates narrowed regions along arteries and PET shows the areas that are deprived of blood flow as a result.6
Vrieze et al1 reviewed data from 30 patients with advanced esophageal carcinoma. Prior to radiotherapy planning, the degree of spread was found different in 47 percent of cases when assessed with CT, endoscopic US and FDG-PET. Based on PET findings, the clinical tumor volume needed to be increased. The authors recommend that for accurate radiotherapy planning, PET scan is far superior to CT or endoscopic US.
Before a curative esophagectomy in 69 patients Choi et al at the Samsung Medical Center in Seoul, Korea2 found that the prognostic implications were the length of the tumor and the number of positive lymph nodes and these were best-determined by PET. The authors even suggest revision of the TNM classification system considering tumor length and the number of positive nodes.
Heeren, et al3 studied 74 patients who underwent FDG-PET and CT as initial staging modalities. Fifty-two also had endoscopic ultrasonography. In 24 patients with pathologic distant nodal disease, PET identified 71 percent compared with 29 percent by combined CT and endoscopic US. The sensitivities to detect distant nodal or metastatic disease were 78 percent with PET and 37 percent with CT. PET correctly upstaged 20 percent, falsely upstaged 7 percent and falsely downstaged 4 percent.
- Vrieze O, Haustermans K, De Wever W, et al. Is there a role for FDG-PET in radiotherapy planning in esophageal carcinoma. Radiotherapy Oncol 2004;73:269.
- Choi JY, Jang HJ, Shim YM, et al. 18F-FDG PET in patients with esophageal squamous cell carcinoma undergoing curative surgery: prognostic implications. J Nucl Med 2004; 45:1843.
- Heeren PA, Jager PL, Bongaerts F, et al. Detection of distant metastases in esophageal cancer with (18) F-FDG PET. J Nucl Med 2004;45:980.
Ultrasonography (USG) is the first-line imaging modality in the radiological work up of hepatic disease. It helps in categorizing the lesion as hepatic, biliary, or pancreatic and thereby guides the need for further investigation by CT and MRI. In some, it shows lesions such as cysts, either simple or complex, thereby obviating the need for any further investigation. USG, however, has marked limitations, such as low specificity for characterizing liver lesions, and poor beam penetration in the obese and a hindered visualization in patients with air-filled bowel anterior to the liver.
With the advent of CT, the entire abdomen can be scanned. Perfusion CT is a dynamic technique used to study liver perfusion. CT cholangiography uses either oral/intravenous agents to opacify the biliary tree prior to scanning or no contrast agent (bile acts as an inherent low density contrast media).
MRI is utilized as a problem-solving technique when other modalities have failed to provide definitive diagnosis. The major advantage of MRI is the absence of ionizing radiation, a good soft tissue contrast, inherent multiplanar capability and high temporal resolution in dynamic gadolinium-enhanced imaging. Developments in MR cholangiopancreatography (MRCP) have played an important clinical role in evaluating patients with known or suspected hepatobiliary disease.1 MRI probably has greater potential in detecting small HCCs in the setting of cirrhosis.2
Clinical applications for FDG—positron emission tomography (PET) have been introduced for the diagnosis, staging and metastatic survey of various types of cancers in the past few years.
Advances in imaging have greatly improved our understanding of hepatic problems. However, there is worrisome issue of cost-effectiveness of the newer procedures. The cost needs to be assessed in the context of extra-expense involved in patient management if the newer investigations are not used or are not accessible.
- Schnieder G, Grazioli L, Saini S (Eds): MRI of the Liver. Springer-Verlag Italia. Milano: Techniques for Liver MR Imaging 1–5, 2003.
- Martin J, Puig J, Darnell A, Donoso L: Magnetic resonance of focal liver lesions in hepatic cirrhosis and chronic hepatitis. Semin US CT MRI 2002;23:62.
CANCER ESOPHAGUS – SINGLE CENTER EXPERIENCE
Southern Hebei Province of China has the highest incidence of esophageal cancer in the world. The largest single center experience on the subject of esophagectomy between September 1952 and December 2000 for 15,500 patients (a rate of over 300 per year) performed at one hospital is interesting.1 It is a fusion of data from six papers published in the past 25 years.
Technical results are outstanding. The operative mortality rate for the first reported cohort between 1952 and 1978 was only 4.6 percent. The importance of ligating the thoracic duct and the futility of resuturing a leaking intrathoracic anastomosis remain lessons that some surgeons have still to learn.
The resectability rate over the time, increased from 78.8 to 96 percent for esophageal cancer and from 69.6 to 94.8 percent for cancer of the cardia. The surgical mortality rate also decreased from 4.6 to 1.1 percent. There was however little change in the overall 5 year survival rate. It increased from 21.2 to 23.9 percent for patients with esophageal carcinoma and from 15.2 to 17.6 percent for those with cancer of the cardia.
With overall improvement in surgical technology and care, the postoperative complications and deaths following esophagectomy for cancer have fallen steadily over the past five decades, but long-term survival remains disappointing. Improved survival is likely to depend on earlier diagnosis and adjunctive therapy.
CYFRA 21-1: A SENSITIVE TUMOR MARKER FOR ESOPHAGEAL SQUAMOUS CELL CANCER
CYFRA 21-1 is a sensitive tumor marker for lung and head and neck carcinoma. Several reports have suggested this as a useful tumor marker for esophageal squamous cell cancer. These reports, however, have included only a small number of patients and did not examine the prognostic value in an indepth manner.1, 2
Shimada, et al3 measured CYFRA 21-1 levels in 157 patients with primary esophageal squamous cell carcinomas before surgery and prospectively determined not only the clinicopathologic, but also the prognostic importance of CYFRA 21-1 levels. In their study, an elevated level was found with esophageal squamous cell carcinoma and notably increased levels were associated with tumor progression resulting in poor prognosis. Measuring its levels serially after resection, in order to determine if recurrent disease is present is a useful means of an accurate follow-up.
- Kawaguchi H, Ohno S, Miyazaki M, et al. CYFRA 21-1 determination in patients with esophageal squamous cell carcinoma. Clinical utility for detection of recurrences. Cancer 2000;89:1413.
- Brockmann JG, St. Nottberg H, Glodny B, et al. CYFRA 21-1 serum analysis in patients with esophageal cancer. Clin Cancer Res 2000;6:4249.
- Shimada H, Nabeye Y, Shin-ichi Okazumi, et al. Prognostic significance of CYFRA 21-1 in patients with esophageal squamous cell carcinoma. J Am Coll Surg 2003;196:573.
FINE NEEDLE ASPIRATION BIOPSY OF NECK LUMPS
Fine needle aspiration biopsy (FNAB) has become established as an investigation of choice in the diagnosis of neck lumps. It is minimally-invasive, does not violate the neck and is very accurate in most cases. In addition, it allows for the rapid diagnosis of malignant pathology and enables the initiation of prompt and appropriate treatment.
The accuracy is dependent on obtaining an adequate specimen for examination by the cytopathologist. The presence of a cytopathologist at the time that the procedure is being performed enhances the likelihood of obtaining an adequate specimen.
The difficulty in distinguishing between benign cysts and cystic carcinoma on the fine needle aspiration biopsy has been documented by several workers.1, 2 It is therefore wiser to consider any cystic neck mass in an older adult as malignant until proven otherwise. Repeating FNAB leads to increased sensitivity for FNAB in detection of cystic carcinomas.
Lymphoma cannot be accurately diagnosed by FNAB. Diagnosis may be suspicious but not diagnostic of lymphoma. In some, the aspirate may closely resemble that from a reactive lymph node. Conversely, aspirate from reactive lymph nodes may closely resemble lymphoma.3 It is suggested that an open biopsy of a neck lump should be performed in any case where FNAB is suggestive of lymphoma or the lump persists, even if the FNAB is not suspicious.
- Gourin CG, Johnson JT. Incidence of unsuspected metastases in lateral cervical cysts. Laryngoscope 2000;110:1637.
- Sheham P, Fitzgibbon J, O'Leary G, et al. Efficacy and pitfalls of fine needle aspiration in the diagnosis of neck masses. Surg JR Coll Surg Edinb Irel 2004;2:152.
- Amedee RG, Dhurandhar NR. Fine needle aspiration biopsy. Laryngoscope 2001;111:1551.
SENTINEL NODE BIOPSY IN OPERABLE BREAST CANCER
Sentinel node biopsy (SNB) promises to avoid treatment of the axilla when nodes are negative for metastasis. It has however not been able to achieve its objective. The world literature quotes a false-negative rate of 4.7 to 12.5 percent on immuno-histochemistry. Leaving behind untreated positive non-sentinel nodes in axilla is a potential risk for axillary recurrence. The axillary sampling may be a simpler alternative to SNB and it is important especially in developing countries with limited resources as it does not require any expensive gadgetry like radio-localization gamma probe or the procedure of injection of vital blue dye.1, 2 The Nottingham Group3 have published the results of a prospective study to find out the value of adding SNB to 4-node axillary sampling within the same patient. Two hundred patients were accrued and 4 node axillary sampling was found to have a lower false-negative rate compared to SNB.
- Parmar V, Badwe RA, Mittra I, et al. Sentinel node biopsy in operable breast cancer. Ind J Surg 2003;65:361.
- Badwe RA, Mittra I. Sentinel node biopsy in breast cancer. Lancet 2001;357:2054.
- Macmilln RD, Barbera D, Hadjiminas DJ, et al. Sentinal node biopsy for breast cancer may have little to offer for node samplers. Results of a prospective comparison study. Eur J Cancer 2001;37:1076.
MULTIPLE MYELOMA—THALIDOMIDE-DEXAMETHASONE AS A PRIMARY THERAPY
Thalidomide was first used as a sedative in late 1950s and subsequently withdrawn because of its teratogenicity. Despite its tragic past, thalidomide has now reentered the clinical scene.
In a landmark trial at the University of Arkansas, thalidomide was given for relapsed refractory myeloma1 at a dose of 200 mg/day orally for two weeks and then increased by 200 mg/day every 2 weeks up to a maximum daily dose of 800 mg. An overall response rate of 32 percent was obtained with a median time to response being one month. An update of this study on 169 patients confirmed the results, demonstrating 2-year overall and event-free rates of 48 percent and 20 percent respectively.2 These results have been confirmed by several other workers.3
The current treatment for myeloma, for less than 65 years of age includes VAD chemotherapy (Vincristine, doxorubicin and dexamethasone) for 4 to 6 months followed by high dose therapy with autologous stem cell transplantation.4 The response rate is 55 to 65 percent, however, VAD administration requires central venous access for continuous infusion and has toxicity in the form of infection, sepsis, thrombosis and cardiac complications.
Several trials have shown that thalidomide and dexamethasone combination can achieve similar or better results compared with chemotherapy as initial therapy for multiple myeloma.5–7 The high response rate seen with thalidomide combination suggests a synergy between the two. Both agents inhibit angiogenesis, in addition, the effects of thalidomide are mediated through its effect on the microenvironment.8
There are, however, a variety of side effects of thalidomide like peripheral neuropathy, deep vein thrombosis, constipation and somnolence. Deep vein thrombosis has emerged as the single most serious complication and therapeutic anticoagulation with warfarrin or with low molecular weight heparin can abrogate the excess risk of DVT with thalidomide. Recently, newer and safer immunomodulatory derivatives of thalidomide such as lenalidomide (CC-5013) that exert similar or higher efficacy without the toxicity profile of thalidomide have shown promising results.9
- Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999;341:1565.
- Barlogie B, Desikan R, Eddlemon P, et al. Extended survival in advanced and refractory multiple myeloma after single agent thalidomide. Identification of prognostic factors in a phase 2 study of 169 patients. Blood 2001;98:492.
- Weber D, Rankin K, Gavino M, et al. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 2003;21:16.
- Alexanian R, Barlogie B, Tucker S. VAD based regimes as primary treatment of multiple myeloma. Am J Hematol 1990;33:86.
- Rajkumar SV, Hayman S, Gertz MA, et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed multiple myeloma. J Clin Oncol 2002;20:4319.
- Cavo M, Zamagni E, Tosi P, et al. Combined thalidomide dexamethasone as first-line therapy for newly diagnosed multiple myeloma. Hematol J 2002;45:244, (Abstr 309 Suppl).
- Rajkumar SV, Blood E, Vesole DH, et al. Combined thalidomide plus dexamethasone versus dexamethasone alone in newly diagnosed multiple myeloma: results of phase III trial coordinated by the Eastern Cooperative Oncology Group (Abstract). Blood 2004;104:63a,(Abstract 205).
- Majumdar S, Lamthe B, Aggarwal BB: Thalidomide suppresses NF kappa B activation induced by TNF and H2O2 but not that activated by ceramide, lipopolysaccharides or phorbol ester. J Immunol 2002;168:2644.
In the era of gastrointestinal endoscopy, the awareness regarding gastric carcinoids has become relatively more common. In patients undergoing gastroscopy, polyps may be found in the parietal gland area and the probability of carcinoids needs to be kept in mind. The gastric carcinoids can be categorized into three types.1
Type 1: Arise in the setting of hypergastrinemia and chronic atrophic gastritis. It has a benign clinical behavior. About 60 percent appear as multiple nodules.
Type 2: Occur in patients with multiple endocrine neoplasia type 1. They are composed of enterochromatin like cells and are typically benign. These patients have concomitant Zollinger-Ellison syndrome.
Type 3: These are malignant. They feature poorly differentiated endocrine and exocrine cells. Metastasis is common at the time of diagnosis.
For type 1, somatostatin may be prescribed and this may be useful in reducing the progression of enterochromatin like cells to hyperplasia and carcinoids.2
A reasonably-sized carcinoid in the stomach can be removed endoscopically and smaller lesions, if there are not too many, can be ablated and the patient monitored for recurrence. If this method of treatment is chosen, it is important to follow these patients because as many as 23 percent of carcinoids can metastasise to lymph nodes.3
Endoscopic or surgical removal of a few small lesions is a reasonable first treatment step followed by antrectomy if the number increases.4 Surgical treatment of gastric carcinoids includes antrectomy or total gastrectomy. Currently, most gastric carcinoids associated with hypergastrinemia are best treated by antrectomy.
It is dangerous to assume that all gastric carcinoids in patients with pernicious anemia, achlorhydria, and hypergastrinemia are benign. These lesions are indolent but can progress in size and become malignant.
- Schindl M, Kaserer K, Niederle B. Treatment of gastric neuro-endocrine tumors. The necessity of a type-adapted treatment. Arch Surg 2001;136:49.
- Modulin IM, Lye KD, Kidd M. Carcinoid tumors of the stomach. Surg Oncol 2003;12:153.
- Kenz SE, Yardley JH, Lazenby AJ, et al. Reversal by antrectomy of endocrine cell hyperplasia in the gastric body in pernicious anemia: A morphometric study. Mod Path 1990;3:561.
- Ahlman H, Kolby LM, Lundell L, et al. Clinical management of gastric carcinoids. Digestion 1994;55(Suppl 3):77.
The widespread use of abdominal ultrasound has led to increasing detection of clinically unsuspected gallstones. The decision to treat is not an easy one. There is no way of knowing which gallstones would remain silent and which would create problems.
If stones remain within the gallbladder confines, the course is usually benign. The longer the stones remain, the more are the chances of complications. Migration to common bile duct may lead to suppurative cholangitis or gallstone pancreatitis.
In a study which followed up 123 persons for 24 years, 16 developed symptoms, while only 3 developed a biliary complication.1 The cumulative probability of the development of biliary pain and its complications over a period of 15 years was only 18 percent.
It may not be prudent to operate on every case of incidental gallstones as it may be an unnecessary drain on medical facilities available. Surgery is however desirable in the following situations:
- Nonfunctioning gallbladder in a diabetic.
- Gallstones are very small or very large.
- Calcified gallbladder.
- Patient is a candidate for organ transplant.
- Grady WA, Ransom DF: The natural history of silent gallstones. The innocent gallstone is not a myth. N Eng J Med 1982;307:798.
MIRIZZI SYNDROME—A DIAGNOSTIC AND OPERATIVE CHALLENGE
Mirizzi, the great advocate of operative cholangiography described the syndrome in 1948.1 It is an unusual complication of gallstone disease. The majority of cases are not identified preoperatively, despite advances in imaging techniques and constitute a high-risk of intraoperative damage to the common bile duct.
Abdominal ultrasound and CT scan lack sensitivity and ERCP has been used successfully to detect Mirizzi syndrome in some but at times it may be difficult to cannulate CBD and complications like sepsis and pancreatitis can occur. MRCP may be as good as ERCP in diagnosis of biliary strictures and to detect cholecystocholedochal fistula. Some authors consider preoperative diagnosis essential in avoiding CBD injuries; 2, 3 others suggest that with a cautious intraoperative approach to periductal inflammation and judicious dissection, it is not necessary for successful management.4, 5
McSherry et al proposed a classification of Mirizzi syndrome6 (MS) into type 1, with external compression of the common hepatic duct (CHD) by a calculus impacted in the cystic duct and type 2 where the calculus had eroded into the bile duct creating a cholecystocholedochal fistula. Csendes et al7 in a series of 219 patients further sub-classified McSherry type II into type II to IV, according to the increasing size of the fistula, relative to the diameter of the CBD.7 In type II, a cholecystobiliary fistula is present with erosion of less than 1/3 of the circumference of the bile duct. In type III, there is cholecystobiliary fistula with erosion of the wall of the common bile duct that involves up to two-thirds of its circumference. In type IV lesion there is a cholecystobiliary fistula with complete destruction of the entire wall of the common bile duct.
The surgical strategy aims at tackling the difficult problems of MS. During cholecystectomy, the fundus first approach is favoured over the conventional Calot's first dissection. In acute cholecystitis or when the gallbladder is distended and tense, decompressing can facilitate dissection. A cholangiogram via the gallbladder may display the location and size of the fistula as well as to exclude the presence of stones or stricture in the bile duct. In type I MS, the minimum necessary surgery (a cholecystectomy) is adequate. When the gallbladder is found densely adherent to the dilated common bile duct. Partial cholecystectomy is a prudent approach using the gallbladder cuff for choledochoplasty in type II and III MS.8 Routine CBD exploration is not necessary unless stones are noted preoperatively or on intraoperative cholangiogram. For type IV MS, Roux-en-y hepatico-jejunostomy is the procedure of choice.9
Surgical therapy in MS has a high morbidity and mortality rate which in a large series is reported as 23 percent and 4 percent respectively for type 2 MS.7
- Mirizzi PL. Syndrome del conducto hepatico. J Int Chir 1948;8:731.
- Baer HU, Matthews JB, Schweitzer WP, et al. Management of Mirizzi syndrome and the surgical implications of cholecystocholedochal fistula. Br J Surg 1990;77:743.
- Dewar G, Chung SCS, Li AKC. Operative strategy in Mirizzi syndrome. Surg Gynecol Obstet 1990;171:157.
- Curet MN, Rosendale DE, Congilosi S. Mirizzi syndrome in a native American population. Am J Gastroenterol 1994;168:616.
- Vezakis A, Davides D, Birbas K, et al. Laparoscopic treatment of Mirizzi syndrome. Surg Endosc 2000;10:15.
- McSherry CK, Ferstenberg H, Vishup M. The Mirizzi syndrome: suggested classification and surgical therapy. Surg Gastroenterol 1982;1:219.
- Csendes A, Diaz JC, Burdiles P, et al. Mirizzi syndrome and cholecystobiliary fistula: A unifying classification. Br J Surg 1989;76:1139.
- Sandblom P, Tabrizian M, Rigo M, et al. Repair of common bile duct defects using the gallbladder or cystic duct as pedicle graft. Surg Gynecol Obstet 1975;140:425.
- Johnson IW, Schon JK, Lee WC, et al. Mirizzi syndrome. Experience from a multi-institutional review. Am Surg 2001;1:11.
EARLY POSTOPERATIVE SMALL BOWEL OBSTRUCTION
A literature search in early postoperative small bowel obstruction by Sajja and Schein1 reveals that in most cases it can be treated expectantly. Many episodes of postoperative obstruction resolve without the cause being elucidated. Majority resolve spontaneously and are most probably caused by adhesion. Some causes of obstruction (e.g., herniation at a laparoscopic trocar site) require early reintervention, whereas in other cases (such as radiation enteritis, carcinomatosis) reintervention may be deferred indefinitely.
In a multicenter study from France2 the prevalence of small bowel obstruction after laparotomy procedure was 0.2 percent with episodes of early small bowel obstruction representing 88 percent of all obstructions.
If a patient still presents features of obstruction on the 5th day after laparotomy, diagnostic steps are taken in parallel with therapy. Plain abdominal radiography is done. When clinical picture suggests ileus or if strangulation is suspected, abdominal CT combined with oral gastrografin is indicated.
A nasogastric tube if not already in situ should be inserted to decompress the stomach, prevent aerophagia, relieve nausea and vomiting and measure the volume of the effluent. Electrolyte imbalances which promote ileus should be measured and corrected. As opiates are the most common promoters of ileus, their use should be restricted and specific antagonists considered.3 Significant hypoalbuminaemia may lead to generalized oedema that also involves the intestine, such oedematous and swollen bowel termed hypoalbuminaemic enteropathy, does not move well. Parenteral nutrition support should be initiated according to the nutritional status of the patient but not later than one week after the start of starvation.
Assuming that persistent ileus and its causes have been ruled out, and there is no clinical and radiological evidence of strangulating obstruction, for how long should non-operative management be continued? Because the risk of strangulation in the setting of early postoperative small bowel obstruction is small, the consensus is that non-operative management should be attempted initially in every patient. There is disagreement however when to operate. Ellozy et al4 recommend reexploration when symptoms fail to resolve within 1 week.
Resolution of the condition without operation usually occurs within 2 weeks as was the case in 96 percent of patients in Pickleman series.5 However, spontaneous resolution beyond 10 days after operation is unlikely.
- Sajja SBS, Schein M. Early postoperative small bowel obstruction. Br J Surg 2004;91:683.
- Duron JJ, Hay JM, Msika S, et al. Prevalence and mechanism of small intestinal obstruction following abdominal surgery in a retrospective multicenter study. Arch Surg 2000;135:208.
- Taguchi A, Sharma N, Saleem RM, et al. Selective postoperative inhibition of gastrointestinal opioid receptors. N Engl J Med 2001;345:935.
- Ellozy SH, Harris MT, Bauer JJ, et al. Early postoperative small bowel obstruction in a prospective evaluation of 242 consecutive abdominal operations. Dis Col Rectum 2002;45:1214.
- Pickleman J, Leo RM. The management of patients with suspected early postoperative small bowel obstruction. Amer Surg 1989;210:216.
For many years, parathyroid surgery has been entirely exploratory relying on experienced surgeons to distinguish an adenoma from hyperplasia of all glands. Bilateral neck exploration has cure rates exceeding 95 percent.1 Despite these excellent results, surgeons continue to explore newer ways to treat in the hope of improving cosmesis, shortening hospital stay, hastening return to work and reducing postoperative pain.2
During the last decade, several developments have brought change in the traditional approach. The advent of more reliable preoperative imaging techniques, including sestamibi scanning, as well as intraoperative PTH measurement and the use of a hand-held gamma probe and video-endoscopy, have become increasingly popular. In addition, minimally invasive parathyroidectomy has now been described for patients with primary hyperparathyroidism, thought to have a single adenoma on preoperative imaging.3
Professor Bhansali has described his extensive experience of primary hyperparathyroidism in this issue of Recent Advances. The management has been mostly exploratory. He has kept the newer knowledge as a firm background and used it in suitable cases.4
- Chen H, Zeiger MA, Gordon TA, et al. Parathyroidectomy in Maryland. Effects of an endocrine center. Surgery 1996;120:948.
- Prager G, Passler C, Scheuba C, et al. Minimally invasive open parathyroidectomy. A review. Acta Chir Austriaca 1999;31:221.
- Udelsman R, Donovan PO, Sokoll LJ. One hundred consecutive minimally invasive parathyroid explorations. Ann Surg 2000;232:331.
- Bhansali SK: Management of primary hyperparathyroidism. In: Roshan Lall Gupta (Ed) Recent Advances in Surgery No. 10. Jaypee Brother, New Delhi: 2006.
THYROID EYE DISEASE
Thyroid eye disease is also known as Graves' ophthalmopathy and is usually associated with autoimmune hyperthyroidism (Graves' disease). Once a patient has Graves' disease, the major risk factor for developing eye disease is smoking.1 Strong evidence exists that radioiodine used to treat hyperthyroidism can cause a flare in thyroid eye disease.2
The accompanying signs include edema of the conjunctiva and eyelid, proptosis and diplopia owing to involvement of extraocular muscles. High vigilance for many features of possible optic neuropathy is important.
Most patients experience mild disease that requires only symptomatic measures. A sizable minority require medical treatment.3, 4 This is aimed at modulating the immune response and consists of steroids at high dosage and orbital radiotherapy.
Orbital decompression surgery can be used in the acute phase to treat compression of the optic nerve. The usual procedure is an inferior orbital decompression during which a defect is created in the floor and medial wall of the orbit, allowing some of the orbital contents to prolapse down into the maxillary sinus, so reducing the tissue volume within the orbit. Although this improves proptosis, a need for eyelid surgery often arises at a later date, to improve appearance and function.
Recent work shows that there is increased adipogenesis in the orbit of these patients and a subpopulation of orbital fibroblasts can differentiate into adipose cells with appropriate stimulation. Interestingly, peroxisome proliferator activated receptor gamma (PPAR gamma) agonists (such as the thiazolidinediones) have been shown in vitro to stimulate orbital adipogenesis and increase orbital expression of TSH receptors.5
With the observed experimental and clinical findings of PPAR gamma agonists worsening adipogenesis in thyroid eye disease, it may be that antagonists of PPAR gamma may present another future therapeutic avenue for thyroid eye disease5 but any such agent would have to be judged in the light of what detrimental metabolic effects it might have.
- Vestergaard P. Smoking and thyroid disorders a meta-analysis. Eur J Endocrinol 2002;146:153.
- Bartalena L, Marcocci C, Bogazzi F, et al. Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy. N Eng J Med 1998;338:73.
- Perros P, Crombie AL, Kendall-Taylor P. Natural history of thyroid associated ophthalmopathy. Clin Edocrinol (Oxf) 1995;42(1):45.
- Noth D, Gebauer M, Muller B, et al. Graves' ophthalmopathy: Natural history and treatment outcomes. Swiss Med Wkly 2001;131:603.
- Starky K, Heufelder A, Baker G, et al. Peroxisome proliferator-activated receptor gamma in thyroid eye disease: contraindication for thiazolidinedione use? J Clin Endocrinol Metab 2003;88(1):55.
SURGICAL CARE PRACTITIONERS
The medical services and training in India have been mostly designed by the British and this design continues to be followed. The Fellows of the Royal Colleges in Great Britain and Ireland have been occupying most surgery chairs in India and the surgical trainee in India still covets to be a Fellow of the Royal College of Surgeons.
In this issue, there is a chapter on newer trends in surgical training in the UK1 and this concerns our younger trainees who intend to train in a NHS Trust Hospital in the UK. The trainee may now need to work with, coexist, co-operate and even learn from newly appointed surgical care practitioners in British hospitals.
In 1991, the National Health Service Management Executive published the New Deal to limit the number of hours worked by junior doctors2 and this provided opportunity for nonmedical professionals (mostly nurses) to undertake tasks formerly performed by junior doctors. The European Working Time Directive (EWTD) has also reduced the time available for surgical trainee to be exposed to hospital (ward, OPD and operating department) work. It has also hindered the experience obtained from continuity of care gained by “seeing the job through” as by traditional on-call rota system. The limitation on hours has led to the shift system whereby the trainee gets to rest after night duty.
Due to reduction in junior doctors' hours there has been an increasing trend to devolve tasks and responsibilities, that were previously in the domain of medically-qualified professionals, to trained nurses. The origin of this idea in the UK can be traced to a pilot project in Oxford in 1989 when a cardiac surgeon's assistant was appointed to harvest long saphenous veins for coronary artery bypass. The pilot scheme for the new appointments was approved by the Royal College of Surgeons of England and the Department of Health.3 There has been strong criticism from the medical profession, but the surgeon's assistant's role has continued to extend to other specialities and areas of surgical care.
As stated earlier, the total training time for junior doctors has shrunk with the aim of providing more trained surgeons at an average younger age and EWTD has brought further reduction in junior doctor hours. The void in hospital work due to loss of junior doctors had to be filled and trained nurses under a new label of surgical care practitioner was the answer. The National Health Service Plan launched in July 2000 addressed the need for increase in number of such jobs with redesign of role which may supplement the traditional doctor's duties. The role includes that of a theater assistant, also encompassing outpatient and ward-based activities. It provides valuable assistance to the consultant surgeon when the junior doctor is absent.
Throughout the development of surgical assistant's role the job title and its nomenclature has been vague. Clarification was necessary as the scheme is still receiving opposition from the medical profession. There were concerns that the title “Surgical Practitioner” could be considered as a doctor and the “Surgical Care Practitioner” is now the more favored title.
It is important that the regulatory authorities should see that the role of a nonmedical professional who is designated as “Surgical Care Practitioner” has an appropriate training program. The Royal College of Surgeons in England is in the process of assessing the academic and nonacademic training pathways for these practitioners and this presages the manner in which the new profession may work within the National Health Service in future.
General Medical Council in Great Britain provides clear guidelines for delegation of duties and tasks to other members of the surgical team. This delegation is permissible provided it is in the best interest of the patient and the competence of the person involved is assured. Surgical care practitioners are also covered for liability whilst performing duties for their NHS trust. Furthermore, they may have additional indemnity insurance through their trade union. The consultant, however, remains responsible for managing patient care.4
An umbrella organization, National Association of Assistants in Surgical Practice (NAASP) was formed in October 2001 to ensure appropriate standard of training and care in these new posts. The curriculum development for training of surgical care practitioners (SCP) was devised jointly by the NAASP and the Royal College of Surgeons. The SCP is required to undertake theoretical courses in anatomy, health, technology and basic surgical skills5.
Todate, the role of nurses taking over the duties of junior doctors in surgical practice has not been subjected to detailed analysis and quality control. Perhaps the time will tell and if these efforts succeed, the medical profession may have to reconsider its oppositional stand.
- Lee C, Vohra RK. Surgical education and training—Newer trends. In: Roshan Lall Gupta (Ed). Recent Advances in Surgery No. 10. Brothers, New Delhi: 2006.
- NHS Management Executive—Junior Doctors New Deal. Department of Health, London: 1991.
- Society of Cardiothoracic Surgeons. Cardiac Surgeon's Assistant. Guidelines for Heads of Departments. Society of Cardiothoracic Surgeons, London: September 1994.
- Good Medical Practice, 2nd Edition. General Medical Council, London: 1998.
- De Cossart L, Graham R: Curriculum development for surgical care practitioners. Ann R Coll Surg Engl 2005;86(Suppl):354.
SURGICAL TRAINING IN THE UK
Higher professional training in the UK in our time was a long and arduous apprenticeship. You really became an independent surgeon at the end of your apprenticeship, not afraid of whatever came through the door in your speciality. The longer period spent in training ensured that just about anything had been seen, done and taught. No doubt the system was open to abuse, but it produced surgeons who were able to cope!
The position of a Registrar in the National Health Service however got changed and the training was replaced by apprenticeship. We now have a generation of trainees who will have to be trained within the so-called “working hours” and may even need to be spoonfed.
The result is that there will be loss of quality of diagnostic, operative and patient management skills. There is no doubt that trainees will be able to gain knowledge needed to pass their fellowship examination. Unfortunately, operative skills can only be mastered by daily repetition of a sequence of motor skills. Some trainees are gifted and will take less time to learn, some may take longer.
The implementation of the Calman report in 1993 brought UK medical training into line with Europe.1 The number of years spent in the training grades got reduced. The political drive to reduce the length of higher surgical training, to as little as four years in some specialities, and at a time when the European Working Time Directive is starting to have an impact, will have a dramatic effect on the type and competency of surgeons produced.
One would therefore bemoan the passage of a traditional stand-alone consultant surgeon, with wide experience in a variety of elective and emerging procedures. However, time and event are moving on and we should look forward to days with higher standards of health care. Naturally, the future role of the consultant surgeon is bound to vary from the way it has been.
- Department of Health. Hospital doctors: training for the future. Department of Health, London: 30 April 1993.
INTERNATIONAL PROSTATE SYMPTOM SCORE (IPSS): ITS ROLE IN PREDICTING POSTOPERATIVE ACUTE URINARY RETENTION IN MALE PATIENTS UNDERGOING MAJOR SURGERY
Increasing age and the severity of obstructive symptoms are the most reliable factors in predicting acute retention of urine in males undergoing major surgery.1 International Prostate Symptom Score (IPSS) was developed by the WHO and has been widely accepted as a reliable method of detecting and categorising the severity of lower urinary tract symptoms with the risk of retention increasing in older patients.
IPSS consists of seven items, each of which is rated from 0 to 5. The total score is the sum of seven and a range of 0 to 35. The greater the score, the more severe are the symptoms (Table 1.1). It categorises patients into three symptom groups: mild (0-7), moderate (8-18), and severe (more than 18). The likelihood of postoperative retention is depicted in Table 1.2.
Patients with moderate symptoms should have elective perioperative catheterization. This would reduce bladder distension with faster return of normal bladder function after surgery. In patients with severe symptoms, there is high risk of acute retention postoperatively and they should be seen by a urologist before surgery.
- Barry M, Fowler F, O'Leary M, et al. The American Urological Association Symptom Index for BPH. J Urol 1992;148:1549.
MANNED MISSION TO MARS
NASA is preparing for a trip out of low Earth Orbit for an exploratory mission, perhaps to Mars. A possible window for such a trip would be in 2014, but with the problems with the shuttle program, 2020 is a more likely date. One of the first project is to design and train medical personnel who will be on the trip to provide medical care for 30 to 36 months with precondition of no return and no resupply. The initial design was undertaken in the spring of 2003. several surgeons participated in the exercise.
Long-duration space flights present a unique paradigm, being the remote medical care setting, an experienced medical person (surgeon or physician) offering traditional intervention is highly desirable but mission requirements may preclude this. Even in low Earth Orbit, the International Space Station has only 50 percent to 70 percent real time communication coverage. A Mars expedition would further confront the issue of communication delay of 8 to 50 minutes depending on the orbital configuration.
Communication delays will make telemonitoring impractical for a Mars mission.1
The International Space Station represents the most complicated multinational project in history that could provide a unique medical research platform to address surgical issues related to long duration space flight. On the International Space Station, medical care has largely focused on patient's stabilization and evacuation. Medical specifications mandate the following abilities at the station:
- Initiating an intravenous infusion.
- Performing endotracheal intubation.
- Placing a chest tube.
These have been found technically within the skill levels of On-board Crew Medical Officer (CMO) and have been found feasible in the temporary weightlessness of parabolic flight.
In weightlessness, several physiological changes occur that are likely to impair the ability to withstand injury.1 These include reduction in circulating blood volume, reduced red cell mass, cardiac atrophy and reduced cardiac output, alteration in vascular tone, loss of protective bony mass and possible immune suppression.
On-board Crew Medical Officers (CMO) are not required to be surgeons or even physicians and currently receive only 34 hours of medical training. The International Space Station has only minor surgical capabilities and can only use local anaesthetics.2 With greater commitment to CMO surgical training, surgical capability can be provided aboard a new class of space exploration vehicle. Although it could be daunting for a non-surgeon to perform a laparotomy, the actual technique of standard midline incision has been performed successfully by specially trained paramedics in dire circumstances. It is what to do after opening the abdomen that constitutes the real challenge. Any procedure beyond the capability of the CMO could be managed in staged or minimalist approach rather than committing irreversible anatomic alterations. The goal of any intervention must be focused and simplified. A damage control laparotomy constitutes control of hemorrhage, prevention of enteric spillage and a ready acceptance of planned secondary or tertiary reoperations.
For long-duration space flights, the medical care system will need to be fairly autonomous and self sufficient and such an undertaking will require the ability to diagnose and treat serious life threatening injuries. Mars mission being man's great challenge, further development is crucial to support and sustain a very vulnerable crew.
- Davis JR. Medical issues for a mission to Mars. Aviat Space Environ Med 1998;70:162.
- Barratt M. Medical support for the international space station. Aviat Space Environ Med 1998;70:155.
SARS AND THE BIRD FLU
In March 2003, during the outbreak of Severe Acute Respiratory Syndrome (SARS) in Hong Kong due to corona virus, a patient with SARS was admitted to Prince of Wales Hospital. Within the next week, 18 health care workers and 16 medical students developed fever, chills and malaise.1 The use of nebulized bronchodilator for the index patient, with increase in droplet load, was believed to be the route by which the disease spread.2 It has been reported that all 156 patients with the diagnosis of SARS in late March 2003 were traceable to this index case. The bird flu virus became more deadly than the strain found in 1997. If the virus mutates and becomes more contagious, the health impact in terms of death and sickness may be enormous.*
* The bird flu killed thousands of chickens and six people in Hong Kong in 1997. In response Hong Kong destroyed all of its chickens, millions of them. It stopped the outbreak but the strain known as H5N1 continued. H5N1, a deadly avian flu virus has ravaged the South East Asia's poultry flocks and infected about 100 people since the end of 2003. In May 2005, thousands of migratory birds died in few weeks at Qunghai Lake in Northwest China. Each year in the late spring, hundreds of thousands of wild birds of almost 200 different species land at the lake to lay eggs and hatch their youg before departing for wintering grounds in Europe and South Asia. The viral study from the outbreak site has not yet been made available but this certainly raises the prospect that migratory birds may bring H5N1 virus to Europe and from there to India and adjoining densely populated parts of the world. H5N1 though highly contagious in birds, is not much contagious between birds and humans or from human to human. Chances of mutation, however, raise the possibility of a deadlier form. The 1918 flu pandemic killed up to 50 million people in 24 weeks. Now, public health officials are worried that avian flu pandemic could even be worse. Vaccine against H5N1 virus is under preparation and several countries are planning to stockpile Tamiflu, the antiviral drug—US Times, September 26, 2005.
* The National Institute for Tropical Medicine in Hanoi's Bach Mai Hospital has treated human cases of H5N1 since the end of 2003. H5N1 is unusually lethal. It ravages the lungs of healthy young patients in a matter of days. Roughly half of those who have contracted the disease have died despite the use of artificial respirators and antiviral drugs. This compares with the 10 percent mortality rate among those who contracted SARS due to corona virus—US Times, September 26, 2005.
All health care workers attending to severe acute respiratory syndrome (SARS) patients need to have a high degree of awareness and adequate self protection should be adopted while attending to new patients. Strict infection control measures have to be followed while performing endotracheal intubation, tracheostomy or bronchoscopy.
Innes Wan and Song Wan, two cardiothoracic surgeons at the Prince of Wales Hospital Hong Kong also contracted SARS in early March 2003.1–3 Both surgeons developed fever and watery diarrhea after contact with the SARS patient. Although there were no respiratory symptoms initially, the oxygen saturation dropped significantly within the next few days, with increased respiratory distress and persistent high fever. Chest X-ray and CT showed features of consolidation. Both surgeons were transferred to an intensive care unit. Intravenous ribavirin and methyl prednisolone were given. Their respiratory functions slowly improved and they were eventually discharged from ICU. Although still dependent on nasal oxygen supplement, active rehabilitation was started on the isolation ward and they were sent home 27 days after the onset of illness.
It is always difficult for surgeons and physicians to accept the sick role. Most are reluctant to abandon their role as a doctor and care providers have difficulty in treating doctor patients. A judicious careful approach and patients having trust in their care providers has been the key to successful treatment in this case. Many of their colleagues continued to volunteer to work in the SARS wards and many of them stayed within the hospital compound without going home. Their selflessness needs appreciation but our surgical practice needs to be modified while treating a new disease with a novel virus and with forewarning of the H5N1 pandemic ringing the bell.*
- Lee N, Hui D, Wu A, et al. A major outbreak of SARS in Hong Kong. N Engl J Med 2003;348:1986.
- Tomlinson B, Cockram C. SARS. experience at the Prince of Wales Hospital Hong Kong. Lancet 2003;361:1486.
- Innes VP Wan, Song Wan, Ahmed A Arif, et al. When surgeons become SARS patients. Letter to editor, Ann R Coll Surg Engl 2004;86:144.
CREUTZFELDT-JAKOB DISEASE (CJD)
The epidemic of bovine spongioform encephalopathy (BSE) in cattle in the UK also known as Mad Cow Disease, was shown to be due to transmission of an abnormal prion protein in meat and bone meal feeding products. This feeding practice was banned in 1988, but by that time the infected cattle had entered the human food chain. It was subsequently shown that CJD was produced by an identical agent to BSE, thus providing the first example of zoonotic transfer of prion disease to man. This discovery stimulated an intense research into the understanding of the molecular biology of human prion disease.
A number of government measures were taken to control BSE and from the outset of the CJD epidemic there has been concern on possible transmission of infection through blood or blood products. In December 2003, the death of the first probable victim of CJD was announced by the Secretary of Health in UK and it had followed blood transfusion in 1996 from a donor who later died of the disease. This has led to an extensive debate on the use of blood or blood products and surgeons should pay heed as to how the use of blood could be optimized.
The resistance of prion protein to standard sterilizing techniques has markedly influenced the management of at-risk and infected individuals. Surgeons must ensure that all instruments are traceable from every operative procedure. Instruments used for CJD patients must be destroyed and those from suspected cases, cleaned and placed in quarantine until a diagnosis is made. The instruments are only returned to service if a negative diagnosis of CJD has been made. This has happened in only half of the quarantined group so far.1 To date there have been 139 cases of CJD identified.1
- Lumley JSP. Creutzfeldt-Jakob Disease (CJD) in surgical practice. The CJD incidence panel. Ann R Coll Surg Engl 2004;86(Suppl):86.