De Souza is a fellow of the  American College of Surgeons ,  Royal College of Surgeons of England  and the  Royal College of Surgeons of Edinburgh  and a life member of the  Indian Medical Association , Association of Surgeons of India, Indian Association for the Study of Liver Diseases, Indian Society of Gastroenterology, Indian Society of Oncology and the Indian Association of Palliative Care. [ 10 ]  He is the vice president of the Ostomy Association of India since 1990 and is the director of the International Psycho-Oncology Society since 1992. [ 6 ]  He is also a member of several medical associations such as Indian Cancer Society and International Hepato-Pancreato-Biliary Association. [ 6 ]


The Government of India included De Souza in the 1992  Republic Day honours  list for the civilian award of the Padma Shri. [ 3 ]  The same year, he received three more awards, Fr. Maschio Platinum Jubilee Humanitarian Award, Vasantrao Naik Pratishtan Award, and the Rotary Club of Mumbai Public Award and was felicitated by the Mumbai chapter of the Indian Medical Association. [ 1 ]  He received the Suvidha Trust Award in 1993 and Goa Hindu Association made him their honorary member the next year. [ 1 ]  Ramniklal Kinariwal Cancer Research Award of the Gujarat Cancer Society and the Dr. Manoel Agostinho de Heredia Award reached him in 1996. He received three awards in 1998, Diwaliben Mohanlal Mehta Award, Old Campionites Association Award and Rotary Club of Bombay South Vocational Excellence Award. [ 1 ] [ 6 ]  Mumbai Medical Aid Association awarded him the  Karmayogi Puraskar  in 2010. [ 11 ]  The next year, he was selected as the  QIMPRO Platinum Standard 2011 . [ 8 ]  He is also a recipient of the Scroll of Honour from the Breast Cancer Conference of 2000, NATCON-ISO Award and Appreciation Award for Services to Humanity from St. Elizabeth Hospital. [ 1 ] [ 6 ]


Debulking  is the reduction of as much of the bulk ( volume ) of a  tumour  without the intention of a complete eradication. It is usually achieved by  surgical  removal. [ 1 ] [ 2 ]  When performed for curative intent, it is a different procedure, which is called surgical debulking of tumors is known as  cytoreduction  or  cytoreductive surgery [ 3 ]  ( CRS ); "cytoreduction" refers to reducing the number of tumor cells. Debulking is used with  curative intent  in only some types of  cancer , as generally partial removal of a  malignant  tumor is not a worthwhile intervention for curative purposes (because malignant cells left behind soon multiply and renew the threat).  Ovarian cancer [ 4 ]  and some types of  brain tumor [ 5 ]  are debulked before  radiotherapy  or  chemotherapy  begin, making those therapies more effective. It may also be used in the case of slow-growing tumors  to shift tumor cells from phase of cell cycle to replicative pool [ clarification needed ] .


In other types of cancer where debulking is not curative, it is sometimes done with  palliative intent  to relieve  mass effect . For example, tumors whose bulk presses on the lungs or esophagus can impair breathing or swallowing, in which case debulking can improve  quality of life [ 1 ]  and extend  survival [ 1 ]  regardless of not curing the cancer.


Debulking procedures are usually long and often complicated, taking several hours or more to perform, depending on internal involvement and location.


An  esophageal stent  is a  stent  (tube) placed in the  esophagus  to keep a blocked area open so the patient can  swallow  soft food and liquids.  They are effective in the treatment of conditions causing intrinsic esophageal obstruction or external esophageal compression.  For the  palliative  treatment of esophageal cancer most esophageal stents are  self-expandable metallic stents .  For benign esophageal disease such as refractory esophageal strictures, plastic stents are available.  Common complications include chest pain, overgrowth of tissue around the stent and stent migration. [ citation needed ]  Esophageal stents may also be used to staunch the bleeding of  esophageal varices . [ 1 ]


Esophageal stents are placed using  endoscopy  when after the tip of the endoscope is positioned above the area to be stented, then guidewire is passed through the obstruction into the stomach. The endoscope is withdrawn and using the guidewire with either  fluoroscopic  or endoscopic guidance the stent is passed down the guidewire to the affected area of the esophagus and deployed. [ 2 ]   Finally, the guidewire is removed and the stent is left to fully expand over the next 2–3 days.


In one study of 997 patients who had self-expanding metal stents for  malignant  esophageal obstruction it was found that esophageal stents were 95% effective. [ 3 ]


Pros of Esophageal Stent


There are several potential benefits of an esophageal stent procedure:


Cons of Esophageal Stent


There are also several potential drawbacks to an esophageal stent procedure:


Esophagectomy  or  oesophagectomy  is the surgical removal of all or parts of the  esophagus .


The principal objective is to remove the esophagus, a part of the  gastrointestinal tract . This procedure is usually done for patients with  esophageal cancer . It is normally done when esophageal cancer is detected early, before it has  spread to other parts of the body .  Esophagectomy of early-stage cancer represents the best chance of a cure.  Despite significant improvements in technique and postoperative care, the long-term survival for esophageal cancer is still poor. Multimodality treatment ( chemotherapy  and  radiation therapy ) is needed for advanced tumors. Esophagectomy is also occasionally performed for benign disease such as  esophageal atresia  in children,  achalasia , or  caustic  injury. [ citation needed ]


In those who have had an esophagectomy for cancer, omentoplasty (a procedure in which part of the greater omentum is used to cover or fill a defect, augment arterial or portal venous circulation, absorb effusions, or increase lymphatic drainage) appears to improve outcomes. [ 1 ]


There are two main types of esophagectomy.


In most cases, the  stomach  is transplanted into the neck and the stomach takes the place originally occupied by the esophagus.  In some cases, the removed esophagus is replaced by another hollow structure, such as the patient's  colon .


Another option that is slowly becoming available is minimally invasive surgery (MIS) which is performed  laparoscopically  and thoracoscopically.


After surgery, patients may have trouble with a regular diet and may have to consume softer foods, avoid liquids at meals, and stay upright for 1–3 hours after eating.  Dysphagia  is common and patients are encouraged to chew foods very well or grind their food.  Patients may complain of substernal pain that resolves by sipping fluids or regurgitating food.   Reflux -type symptoms can be severe, including intolerance to acidic foods and large, fatty meals.   Jejunal   feeding tubes  may be placed during surgery to provide a temporary route of nutrition until oral eating resumes. [ citation needed ]


Esophagectomy is a very complex operation that can take between 4 and 8 hours to perform. It is best done exclusively by doctors who specialise in  thoracic surgery  or  upper gastrointestinal surgery .  Anesthesia  for an esophagectomy is also complex, owing to the problems with managing the patient's  airway  and  lung  function during the operation. [ 3 ]  Lung collapse is highly probable, as well as loss of diaphragmatic function, and possible injury to the spleen.


Average mortality rates (deaths either in hospital or within 30 days of surgery) for the operation are around 10% in US hospitals. Recognized major cancer hospitals typically report mortality rates under 5%. Major complications occur in 10–20% of patients, and some sort of complication (major and minor) occurs in 40%. Time in hospital is usually 1–2 weeks and recovery time 3–6 months. It is possible for the recovery time to take up to a year.


Forequarter amputation  is  amputation  of the  arm ,  scapula  and  clavicle . It is usually performed as a last resort to remove a cancer, but decreasingly so as  limb-sparing operations  improve. [ 1 ]


The rhomboid muscles, trapezius, levator scapulae and latissimus dorsi are transected. The  neurovascular bundle  consisting of the  axillary artery ,  axillary vein  and  brachial plexus  is ligated and cut. The area of the chest left exposed is then normally covered with a split-thickness  skin graft . [ 1 ]


In 2008, David Nott, a British vascular surgeon in the  Democratic Republic of the Congo  with  Médecins Sans Frontières , performed a forequarter amputation to save the life of a 16-year-old boy, whose arm had been severed by an injury. He was left with a  gangrenous  stump and had a few days to live.


"The first thing I realised when I saw J was that he was dying. All that remained of this 16-year-old's arm was six inches of skin; the rest had been shot off when he became caught in gunfire between the Congolese army and rebel forces. A further amputation had left him open to infection, and now he was facing the prospect of an awful, agonising death over a period of several days – hallucinations, dehydration, his kidneys packing up, his breathing going and then, finally, his heart." [ 2 ]


It made the news because his colleague, Joseph Meirion Thomas, sent pointers via  SMS text message . [ 3 ]  The text message included 10 steps to be followed and finished by saying, "Easy! Good luck." [ 4 ]


The text David Nott received:


"Start on clavicle. Remove middle third. Control and divide subsc art and vein. Divide large nerve trunks around these as prox as poses. Then come onto chest wall immed anterior and divide Pec maj origin from remaining clav. Divide pec minor insertion and (very imp) divide origin and get deep to serrates anterior. Your hand sweeps behind scapula. Divide all muscles attached to scapula. Stop muscle bleeding with count suture. Easy! Good luck. Meirion" [ 2 ]


The  frozen section procedure  is a  pathological   laboratory  procedure to perform rapid  microscopic  analysis of a specimen. It is used most often in  oncological surgery . [ 1 ]  The technical name for this procedure is  cryosection . The  microtome  device that cold cuts thin blocks of frozen  tissue  is called a  cryotome . [ 2 ]


The quality of the slides produced by frozen section is of lower quality than formalin fixed paraffin embedded tissue processing. While diagnosis can be rendered in many cases, fixed tissue processing is preferred in many conditions for more accurate diagnosis.


The  intraoperative consultation  is the name given to the whole intervention by the  pathologist , which includes not only frozen section but also  gross  evaluation of the specimen, examination of  cytology  preparations taken on the specimen (e.g. touch imprints), and aliquoting of the specimen for special studies (e.g. molecular pathology techniques, flow cytometry). The report given by the pathologist is often limited to a "benign" or "malignant" diagnosis, and communicated to the surgeon operating via intercom. When operating on a previously confirmed malignancy, the main purpose of the pathologist is to inform the surgeon if the  resection margin  is clear of residual cancer, or if residual cancer is present at the resection margin. The method of processing is usually done with the  bread loafing  technique. But margin controlled surgery ( CCPDMA ) can be performed using a variety of tissue cutting and mounting methods, including  Mohs surgery .


The frozen section procedure as practiced today in medical laboratories is based on the description by Dr  Louis B. Wilson  in 1905. Wilson developed the technique from earlier reports at the request of Dr  William Mayo , surgeon and one of the founders of the  Mayo Clinic   [ 3 ]  Earlier reports by Dr  Thomas S. Cullen  at  Johns Hopkins Hospital  in  Baltimore  also involved frozen section, but only after formalin fixation, and pathologist Dr William Welch, also at Hopkins, experimented with Cullen's procedure but without clinical consequences. Hence, Wilson is generally credited with truly pioneering the procedure (Gal & Cagle, 2005). [ 4 ]


The key instrument for cryosection is the  cryostat , which is essentially a  microtome  inside a freezer. The microtome can be compared to a very accurate "deli" slicer, capable of slicing sections as thin as 1 micrometre. The usual histology slice is cut at 5 to 10 micrometres. The surgical specimen is placed on a metal tissue disc which is then secured in a chuck and frozen rapidly to about –20 to –30 °C. The specimen is placed in a gel-like embedding medium, usually  OCT  which consists of  polyethylene glycol  and  polyvinyl alcohol ; this compound is known by many names and when frozen has the same density as frozen tissue. At this temperature, most tissues become rock-hard. Usually a lower temperature is required for fat or lipid rich tissue. Each tissue has a preferred temperature for processing. Subsequently, it is cut frozen with the microtome portion of the cryostat, the section is picked up on a glass slide and stained (usually with  hematoxylin  and  eosin , the  H&E stain ). The preparation of the sample is much more rapid than with traditional  histology  technique (around 10 minutes vs 16 hours). However, the technical quality of the sections is much lower. The entire laboratory can occupy a space less than 9-square-foot (0.84 m 2 ), and minimal ventilation is required compared to a standard wax embedded specimen laboratory. [ citation needed ]


Steps of cryotomy:


The principal use of the frozen section procedure is the examination of tissue while surgery is taking place. This may be for various reasons. In the performance of  Mohs surgery , it is a simple method for real-time margin control of a surgical specimen. If a tumor appears to have  metastasized , a sample of the suspected metastasis is sent for cryosection to confirm its identity. This will help the surgeon decide whether there is any point in continuing the operation. Usually, aggressive surgery is performed only if there is a chance to cure the patient. If the tumor has metastasized, surgery is usually not curative, and the surgeon will choose a more conservative surgery, or no resection at all. If a tumor has been resected but it is unclear whether the resection margin is free of tumor, an intraoperative consultation is requested to assess the need to make a further resection for clear margins. In a  sentinel node procedure , a sentinel node containing tumor tissue prompts a further lymph node dissection, while a benign node will avoid such a procedure. [ citation needed ]


If surgery is explorative, rapid examination of a lesion might help identify the possible cause of a patient's symptoms. It is important to note, however, that the pathologist is very limited by the poor technical quality of the frozen sections. A final diagnosis is rarely offered intraoperatively. [ citation needed ]


Rarely, cryosections are used to detect the presence of substances lost in the traditional histology technique, for example lipids. They can also be used to detect some  antigens  masked by formalin. The cryostat is available in a small portable device weighing less than 80 lb (36 kg), to a large stationary device 500 lb (230 kg) or more. The entire histologic laboratory can be carried in one portable box, making frozen section histology a possible tool in primitive medicine.


A Cochrane systematic review published in 2016 analysed all studies that reported diagnostic accuracy of frozen sections in women undergoing surgery for suspicious tumor in ovary. The review concluded that for tumors that were clearly either benign or malignant on frozen section, the accuracy of the diagnosis was good, as confirmed later by regular biopsy. On the contrary, where the frozen section diagnosis was a borderline tumor, neither confirming not ruling out cancer, the diagnosis was less accurate. The review suggests that in such situations of uncertainty, surgeons may choose to perform additional surgery in this group of women at the time of their initial surgery in order to reduce the need for a second operation, as on an average one out of five of these women were subsequently found to have cancer. [ 5 ]


An  ultracryotome , which is a very similar device to crytome, can cut ultrathin blocks of tissue, and that tissue can be observed by  transmission electron microscopy . The cutting thickness of ultracryotome is about dozens of nanometers. The  ultrastructural  properties can be studied without embedding of the tissue, and so the molecular conservation is better. [ 6 ]


A  proctosigmoidectomy ,  Hartmann's operation  or  Hartmann's procedure  is the surgical  resection  of the  rectosigmoid colon  with closure of the anorectal stump and formation of an end  colostomy . It was used to treat  colon cancer  or  inflammation  (proctosigmoiditis, proctitis,  diverticulitis ,  volvulus , etc.). Currently, its use is limited to emergency surgery when immediate  anastomosis  is not possible, or more rarely it is used  palliatively  in patients with colorectal tumours. [ 1 ]


The Hartmann's procedure with a proximal end  colostomy  or  ileostomy  is the most common operation carried out by general surgeons for management of malignant obstruction of the distal colon. During this procedure, the lesion is removed, the distal bowel closed intraperitoneally, and the proximal bowel diverted with a  stoma .


The indications for this procedure include:


Use of the Hartmann's procedure initially had a mortality rate of 8.8%. [ 3 ]  Currently, the overall mortality rate is lower but varies greatly depending on indication for surgery. One study showed no statistically significant difference in morbidity or mortality between laparoscopic versus open Hartmann procedure. [ 4 ]


The procedure was first described in 1921 by French surgeon  Henri Albert Hartmann . [ 5 ]  The original two-paragraph article in French together with an English translation by Thomas Pézier [ 6 ]  and a modern commentary is available. [ 7 ]  The procedure is described in detail in his book,  Chirurgie du Rectum , which was published in 1931 and constituted volume 8 of his  Travaux de Chirurgie . [ 8 ]


Hematopoietic stem-cell transplantation  ( HSCT ) is the  transplantation  of  multipotent hematopoietic stem cells , usually derived from  bone marrow ,  peripheral blood , or  umbilical cord blood , in order to replicate inside a patient and produce additional normal blood cells. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]  HSCT may be  autologous  (the patient's own stem cells are used),   syngeneic  (stem cells from an  identical twin ), or  allogeneic  (stem cells from a donor). [ 4 ] [ 5 ]


It is most often performed for patients with certain  cancers  of the  blood  or bone marrow, such as  multiple myeloma ,  leukemia , some types of  lymphoma  and  immune deficiencies . [ 5 ]  In these cases, the recipient's immune system is usually suppressed with  radiation  or  chemotherapy  before the transplantation. Infection and  graft-versus-host disease  are major complications of allogeneic HSCT. [ 5 ]


HSCT remains a dangerous procedure with many possible complications; it is reserved for patients with life-threatening diseases. As survival following the procedure has increased, its use has expanded beyond cancer to  autoimmune diseases [ 7 ] [ 8 ]  and hereditary  skeletal dysplasias , notably  malignant infantile osteopetrosis [ 9 ] [ 10 ]  and  mucopolysaccharidosis . [ 11 ]


Indications for stem-cell transplantation are:


Many recipients of HSCTs are  multiple myeloma [ 15 ]  or  leukemia  patients [ 16 ]  who would not benefit from prolonged treatment with, or are already resistant to,  chemotherapy . Candidates for HSCTs include  pediatric  cases where the patient has an inborn defect such as  severe combined immunodeficiency  or  congenital neutropenia  with defective stem cells, and also children or adults with  aplastic anemia [ 17 ]  who have lost their stem cells after birth. Other conditions [ 18 ]  treated with stem cell transplants include  sickle cell disease ,  myelodysplastic syndrome ,  neuroblastoma ,  lymphoma ,  Ewing's sarcoma ,  desmoplastic small round cell tumor ,  chronic granulomatous disease ,  Hodgkin's disease  and  Wiskott–Aldrich syndrome . Non-myeloablative, so-called  mini transplant (microtransplantation)  procedures, have been developed requiring smaller doses of preparative chemotherapy and  radiation therapy , allowing HSCT to be conducted in the elderly and other patients who would otherwise be considered too weak to withstand a conventional treatment regimen. [ 19 ]


In 2006, 50,417 first HSCTs were recorded worldwide, according to a global survey of 1,327 centers in 71 countries conducted by the Worldwide Network for Blood and Marrow Transplantation.  Of these, 28,901 (57%) were autologous and 21,516 (43%) were allogeneic (11,928 from family donors and 9,588 from unrelated donors).  The main indications for transplant were lymphoproliferative disorders (55%) and leukemias (34%), and many took place in either Europe (48%) or the Americas (36%). [ 20 ]


The Worldwide Network for Blood and Marrow Transplantation reported the millionth transplant to have been undertaken in December 2012. [ 21 ]


In 2014, according to the  World Marrow Donor Association , stem-cell products provided for unrelated transplantation worldwide had increased to 20,604 (4,149 bone-marrow donations, 12,506 peripheral blood stem-cell donations, and 3,949 cord-blood units). [ 22 ]


Autologous HSCT requires the extraction ( apheresis ) of hematopoietic stem cells (HSCs) from the patient and storage of the harvested cells in a freezer. The patient is then treated with high-dose  chemotherapy  with or without  radiotherapy  with the intention of eradicating the patient's malignant cell population at the cost of partial or complete  bone marrow  ablation (destruction of patient's bone marrow's ability to grow new blood cells).  The patient's own stored stem cells are then transfused into his/her bloodstream, where they replace destroyed tissue and resume the patient's normal blood-cell production. [ 2 ]  Autologous transplants have the advantage of lower risk of infection during the immune-compromised portion of the treatment, since the recovery of immune function is rapid. Also, the incidence of patients experiencing rejection is very rare (and graft-versus-host disease impossible) due to the donor and recipient being the same individual. These advantages have established autologous HSCT as one of the standard second-line treatments for such diseases as  lymphoma . [ 23 ]


For other cancers such as  acute myeloid leukemia , though, the reduced mortality of the autogenous relative to allogeneic HSCT may be outweighed by an increased likelihood of cancer relapse and related mortality, so the allogeneic treatment may be preferred for those conditions. [ 24 ]


Researchers have conducted small studies using nonmyeloablative HSCT as a possible treatment for  type I (insulin dependent) diabetes  in children and adults. Results have been promising, but as of 2019 [update] , speculating whether these experiments will lead to effective treatments for diabetes is premature. [ 25 ] [ 26 ] [ 27 ]  Autologous HSCT is an effective treatment against aggressive Multiple Sclerosis. [ 28 ]  The type of autologous HSCT used as a Multiple Sclerosis treatment is considered safe and the serious adverse events rare. [ 29 ]


Allogeneic HSCT involves two people – the (healthy) donor and the (patient) recipient. Allogeneic HSC donors must have a tissue ( human leukocyte antigen , HLA) type that matches the recipient. Matching is performed on the basis of variability at three or more  loci  of the HLA gene, and a perfect match at these loci is preferred. Even if a good match exists at these critical  alleles , the recipient will require  immunosuppressive  medications to mitigate graft-versus-host disease. Allogeneic transplant donors may be related (usually a closely HLA-matched sibling), syngeneic (a  monozygotic  or identical twin of the patient – necessarily extremely rare since few patients have an identical twin, but offering a source of perfectly HLA-matched stem cells), unrelated (donor who is not related and found to have very close degree of HLA matching), or, as in the case of Haploidentical Transplantation, a half-matched relative such as a parent, child, or sibling. Unrelated donors may be found through a registry of bone-marrow donors, such as the  National Marrow Donor Program  (NMDP) in the U.S.  A " savior sibling " may be intentionally selected by  preimplantation genetic diagnosis  to match a child both regarding HLA type and being free of any obvious inheritable disorder. Allogeneic transplants are also performed using umbilical  cord blood  as the source of stem cells. In general, by transfusing healthy stem cells to the recipient's bloodstream to reform a healthy immune system, allogeneic HSCTs appear to improve chances for cure or long-term remission once the immediate transplant-related complications are resolved. [ 30 ] [ 31 ] [ 32 ]


A compatible donor is found by doing additional HLA testing from the blood of potential donors. The HLA genes fall in two categories (types I and II). In general, mismatches of the type-I genes (i.e.  HLA-A ,  HLA-B , or  HLA-C ) increase the risk of graft rejection.  A mismatch of an HLA type II gene (i.e.  HLA-DR  or   HLA-DQB1 ) increases the risk of graft-versus-host disease.  In addition, a genetic mismatch as small as a single  DNA   base pair  is significant, so perfect matches require knowledge of the exact DNA sequence of these genes for both donor and recipient.  Leading transplant centers currently perform testing for all five of these HLA genes before declaring that a donor and recipient are HLA-identical. [ citation needed ]


Race  and  ethnicity  are known to play a major role in donor recruitment drives, as members of the same ethnic group are more likely to have matching genes, including the genes for HLA. [ 33 ]


As of 2013 [update] , at least two commercialized allogeneic cell therapies have been developed,  Prochymal  and  Cartistem . [ 34 ]   Omidubicel  was approved for medical use in the United States in April 2023. [ 35 ]


To limit the risks of transplanted stem-cell  rejection  or of severe graft-versus-host disease in allogeneic HSCT, the donor should preferably have the same HLA-typing as the recipient. About 25 to 30% of allogeneic HSCT recipients have an HLA-identical sibling. Even so-called "perfect matches" may have mismatched minor alleles that contribute to graft-versus-host disease. With recent advances in  T-cell -depleting therapies such as post-transplant  cyclophosphamide ,  haploidentical  (half-matched) transplants have permitted successful transplantation of many patients who would otherwise have lacked a donor. [ 36 ]


In the case of a bone-marrow transplant, the HSCs are removed from a large bone of the donor, typically the  pelvis , through a large  needle  that reaches the center of the bone. The technique is referred to as a bone-marrow harvest and is performed under  local  or  general anesthesia . [ 37 ]


Peripheral blood stem cells [ 38 ]  are now the most common source of stem cells for HSCT. They are collected from the blood through a process known as  apheresis . The donor's blood is withdrawn through a sterile needle in one arm and passed through a machine that removes  white blood cells . The  red blood cells  are returned to the donor. The peripheral stem cell yield is boosted with daily  subcutaneous injections  of  granulocyte-colony stimulating factor , serving to mobilize stem cells from the donor's bone marrow into the peripheral circulation. [ 39 ]


Extracting stem cells from  amniotic fluid  is possible and may have applications for  autologous  and  heterologous  use. [ 40 ]


Unlike other organs, bone-marrow cells can be frozen ( cryopreserved ) for prolonged periods without damaging too many cells. This is a necessity with autologous HSCs because the cells must be harvested from the recipient months in advance of the transplant treatment. In the case of  allogeneic transplants , fresh HSCs are preferred to avoid cell loss that might occur during the freezing and thawing process. Allogeneic cord blood is stored frozen at a  cord blood bank  because it is only obtainable at the time of  childbirth . To cryopreserve HSCs, a preservative,  dimethyl sulfoxide , must be added, and the cells must be cooled very slowly in a controlled-rate freezer to prevent  osmotic  cellular injury during ice-crystal formation. HSCs may be stored for years in a cryofreezer, which typically uses  liquid nitrogen . [ 41 ]


The chemotherapy or irradiation given immediately prior to a transplant is called the conditioning regimen, the purpose of which is to help eradicate the patient's disease prior to the infusion of HSCs and to suppress immune reactions. The bone marrow can be ablated (destroyed) with dose-levels that cause minimal injury to other tissues. In allogeneic transplants, a combination of  cyclophosphamide  with  total body irradiation  is conventionally employed. This treatment also has an  immunosuppressive  effect that prevents rejection of the HSCs by the recipient's  immune system . The post-transplant prognosis often includes acute and chronic graft-versus-host disease that may be life-threatening. In certain leukemias, though, this can coincide with protection against cancer relapse owing to the  graft-versus-tumor effect . [ 42 ]  Autologous transplants may also use similar conditioning regimens, but many other chemotherapy combinations can be used depending on the type of disease.


A newer treatment approach, nonmyeloablative allogeneic transplantation, also termed reduced-intensity conditioning (RIC), uses doses of chemotherapy and radiation too low to eradicate all the bone-marrow cells of the recipient. [ 43 ] : 320–321   Instead, nonmyeloablative transplants run lower risks of serious infections and transplant-related mortality while relying upon the graft versus tumor effect to resist the inherent increased risk of cancer relapse. [ 44 ] [ 45 ]  Also significantly, while requiring high doses of  immunosuppressive agents  in the early stages of treatment, these doses are less than for conventional transplants. [ 46 ]  This leads to a state of mixed  chimerism  early after transplant where both recipient and donor HSC coexist in the bone marrow space. [ 47 ]


Decreasing doses of immunosuppressive therapy then allow donor  T-cells  to eradicate the remaining recipient HSCs and to induce the graft-versus-tumor effect. This effect is often accompanied by mild graft-versus-host disease, the appearance of which is often a surrogate marker for the emergence of the desirable graft versus tumor effect, and also serves as a signal to establish an appropriate dosage level for sustained treatment with low levels of immunosuppressive agents. [ 48 ]


Because of their gentler conditioning regimens, these transplants are associated with a lower risk of transplant-related mortality, so allow patients who are considered too high-risk for conventional allogeneic HSCT to undergo potentially curative therapy for their disease. The optimal conditioning strategy for each disease and recipient has not been fully established, but RIC can be used in elderly patients unfit for myeloablative regimens, for whom a higher risk of cancer relapse may be acceptable. [ 43 ] [ 45 ]


After several weeks of growth in the bone marrow, expansion of HSCs and their progeny is sufficient to normalize the blood cell counts and reinitiate the immune system. The offspring of donor-derived HSCs have been documented to populate many different organs of the recipient, including the  heart ,  liver , and  muscle , and these cells had been suggested to have the abilities of regenerating injured tissue in these organs.  However, recent research has shown that such lineage infidelity does not occur as a normal phenomenon. [ 49 ]


Chimerism  monitoring is a method to monitor the balance between the patient's own stem cells and the new stem cells from a donor. In cases where the patient's own stem cells are increasing in number after treatment, the treatment may potentially not have worked as intended. [ 50 ]


HSCT is associated with a high treatment-related  mortality  in the recipient, which limits its use to conditions that are themselves life-threatening. (The one-year survival rate has been estimated to be roughly 60%, although this figure includes deaths from the underlying disease, as well as from the transplant procedure.) [ 51 ]  Major complications include  veno-occlusive disease ,  mucositis , infections ( sepsis ), graft-versus-host disease, and the development of new  malignancies . [ 52 ]


Bone-marrow transplantation usually requires that the recipient's own bone marrow be destroyed (myeloablation). Prior to the administration of new cells (engraftment), patients may go for several weeks without appreciable numbers of white blood cells to help fight  infection . This puts a patient at high risk of infections, sepsis, and  septic shock , despite  prophylactic   antibiotics . However,  antiviral   medications , such as  acyclovir  and  valacyclovir , are quite effective in prevention of HSCT-related outbreak of  herpetic  infection in  seropositive  patients. [ 53 ]  The immunosuppressive agents employed in allogeneic transplants for the prevention or treatment of graft-versus-host disease further increase the risk of  opportunistic infection . Immunosuppressive drugs are given for a minimum of six months after a transplantation, or much longer if required for the treatment of graft-versus-host disease. Transplant patients lose their acquired immunity, for example immunity to childhood diseases such as  measles  or  polio . So, transplant patients must be retreated with childhood  vaccines  once they are off immunosuppressive medications. [ 54 ]


Severe liver injury can result from hepatic veno-occlusive disease (VOD), newly termed sinusoidal obstruction syndrome (SOS). [ 55 ]  Elevated levels of  bilirubin ,  hepatomegaly , and fluid retention are clinical hallmarks of this condition. The appreciation of the generalized cellular injury and obstruction in  hepatic vein  sinuses is now greater. Severe cases of SOS are associated with a high mortality rate.  Anticoagulants  or  defibrotide  may be effective in reducing the severity of VOD but may also increase bleeding complications.  Ursodiol  has been shown to help prevent VOD, presumably by facilitating the flow of  bile .


The injury of the mucosal lining of the mouth and throat is a common regimen-related toxicity following ablative HSCT regimens. It is usually not life-threatening, but is very painful, and prevents eating and drinking. Mucositis is treated with pain medications plus intravenous infusions to prevent dehydration and malnutrition. [ 56 ]


The mucosal lining of the bladder is affected in about 5% of children undergoing HSCT. This causes  hematuria  (blood in urine), frequent urination, abdominal pain and  thrombocytopenia . [ 57 ]


Graft-versus-host disease (GvHD) is an inflammatory disease that is unique to allogeneic transplantation. It is an attack by the "new" bone marrow's immune cells against the recipient's tissues. This can occur even if the donor and recipient are HLA-identical because the immune system can still recognize other differences between their tissues. It is named graft-versus-host disease because the transplanted cells must accept the body rather than the body accepting the new cells. [ 58 ]


Acute GvHD typically occurs in the first three months after transplantation and may involve the  skin ,  intestine , or  liver . High-dose  corticosteroids , such as  prednisone , are a standard treatment, but this immunosuppressive treatment often leads to deadly infections. Chronic GvHD may also develop after allogeneic transplant. It is the major source of late treatment-related complications, although it less often results in death. In addition to inflammation, chronic GvHD may lead to the development of  fibrosis , or scar tissue, similar to  scleroderma ; it may cause functional disability and require prolonged immunosuppressive therapy. GvHD is usually mediated by T cells, which react to foreign peptides presented on the  major histocompatibility complex  of the host. [ 59 ]


Further research is needed to determine whether mesenchymal stromal cells can be use for prophylaxis and treatment of GvHD. [ 60 ]


Graft-versus-tumor effect (GVT), or "graft versus leukemia" effect, is the beneficial aspect of the GvHD phenomenon. For example, HSCT patients with either acute, or in particular chronic, GvHD after an allogeneic transplant tend to have a lower risk of cancer relapse. [ 61 ] [ 42 ]  This is due to a therapeutic immune reaction of the grafted donor T lymphocytes against the diseased bone marrow of the recipient. This lower rate of relapse accounts for the increased success rate of allogeneic transplants, compared to transplants from identical twins, and indicates that allogeneic HSCT is a form of immunotherapy. GVT is the major benefit of transplants that do not employ the highest immunosuppressive regimens.


Graft versus tumor is mainly beneficial in diseases with slow progress, e.g. chronic leukemia, low-grade lymphoma, and in some cases multiple myeloma, but is less effective in rapidly growing acute leukemias. [ 62 ]


If cancer relapses after HSCT, another transplant can be performed, infusing the patient with a greater quantity of donor white blood cells ( donor lymphocyte infusion ). [ 62 ]


Patients after HSCT are at a higher risk for  oral   carcinoma . Post-HSCT  oral cancer  may have more aggressive behavior with poorer prognosis, when compared to oral cancer in non-HSCT patients. [ 63 ]


A meta-analysis showed that the risk of secondary cancers such as  bone cancer ,  head and neck cancers , and  melanoma , with standardized incidence ratios of 10.04 (3.48–16.61), 6.35 (4.76–7.93), and 3.52 (2.65–4.39), respectively, was significantly increased after HSCT. So, diagnostic tests for these cancers should be included in the screening program of these patients for the prevention and early detection of these cancers. [ 64 ]


Prognosis  in HSCT varies widely dependent upon disease type, stage, stem-cell source, HLA-matched status (for allogeneic HSCT), and conditioning regimen. A transplant offers a chance for cure or long-term remission if the inherent complications of graft versus host disease, immunosuppressive treatments and the spectrum of opportunistic infections can be survived. [ 30 ] [ 31 ]  In recent years, survival rates have been gradually improving across almost all populations and subpopulations receiving transplants. [ 65 ]


Mortality for allogeneic stem cell transplantation can be estimated using the prediction model created by Sorror  et al ., [ 66 ]  using the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI). The HCT-CI was derived and validated by investigators at the  Fred Hutchinson Cancer Research Center  in the U.S. The HCT-CI modifies and adds to a well-validated comorbidity index, the  Charlson Comorbidity Index  (CCI) (Charlson,  et al .) [ 67 ]  The CCI was previously applied to patients undergoing allogeneic HCT, but appears to provide less survival prediction and discrimination than the HCT-CI scoring system.


Patients who were successfully treated with HSCT and total body irradiation in childhood were found to have increased fat mass percentage, leading to significantly decreased exercise capacity in adulthood. This suggests patients who underwent successful treatment with HSCT have an increased predisposition to cardiovascular disease later in life. [ 68 ]


The risks of a complication depend on patient characteristics, health care providers, and the apheresis procedure, and the colony-stimulating factor used ( G-CSF ). G-CSF drugs include  filgrastim  (Neupogen, Neulasta), and  lenograstim  (Graslopin).


Filgrastim is typically dosed in the 10 microgram/kg level for 4–5 days during the harvesting of stem cells. The documented adverse effects of filgrastim include  splenic rupture ,  acute respiratory distress syndrome , alveolar hemorrhage, and allergic reactions (usually experienced in first 30 minutes). [ 69 ] [ 70 ] [ 71 ]  In addition, platelet and hemoglobin levels dip postprocedurally, not returning to normal until after a month. [ 71 ]


The question of whether geriatrics (patients over 65) react the same as patients under 65 has not been sufficiently examined.  Coagulation issues and inflammation of atherosclerotic plaques are known to occur as a result of G-CSF injection. G-CSF has also been described to induce genetic changes in  agranulocytes  of normal donors. [ 70 ]  There is no statistically significant evidence either for or against the hypothesis that myelodysplasia (MDS) or acute myeloid leukaemia (AML) can be induced by G-CSF in susceptible individuals. [ 72 ]


Blood is drawn from a peripheral vein in a majority of patients, but a central line to the jugular, subclavian, and femoral veins may be used. Adverse reactions during apheresis were experienced in 20% of women and 8% of men, these adverse events primarily consisted of numbness/tingling, multiple line attempts, and nausea. [ 71 ]


A study involving 2,408 donors (aged 18–60 years) indicated that  bone pain  (primarily back and hips) as a result of filgrastim treatment is observed in 80% of donors. [ 71 ]  Donation is not recommended for those with a history of back pain. [ 71 ]  Other symptoms observed in more than 40 percent of donors include muscle pain, headache, fatigue, and difficulty sleeping. [ 71 ]  These symptoms all returned to baseline 1 month after donation in the majority of patients. [ 71 ]


In one meta-study that incorporated data from 377 donors, 44% of patients reported having adverse side effects after peripheral blood HSCT. [ 72 ]  Side effects included pain prior to the collection procedure as a result of G-CSF injections, and postprocedural generalized skeletal pain, fatigue, and reduced energy. [ 72 ]


A study that surveyed 2,408 donors found that serious adverse events (requiring prolonged hospitalization) occurred in 15 donors (at a rate of 0.6%), although none of these events was fatal. [ 71 ]  Donors were not observed to have higher than normal rates of cancer with up to 4–8 years of follow-up. [ 71 ]
One study based on a survey of medical teams covered about 24,000 peripheral blood HSCT cases between 1993 and 2005, and found a serious cardiovascular adverse reaction rate of about one in 1,500. [ 70 ]  This study reported a cardiovascular-related fatality risk within the first 30 days of HSCT of about two in 10,000. [ 70 ]


In 1939, a woman with aplastic anaemia received the first human bone marrow transfusion. This patient received regular blood transfusions, and an attempt was made to increase her leukocyte and platelet counts by intravenous bone marrow injection without unexpected reaction. [ 73 ]


Stem-cell transplantation was pioneered using bone marrow-derived stem cells by a team at the  Fred Hutchinson Cancer Research Center  from the 1950s through the 1970s led by  E. Donnall Thomas , whose work was later recognized with a  Nobel Prize in Physiology or Medicine . Thomas' work showed that bone-marrow cells infused intravenously could repopulate the bone marrow and produce new blood cells. His work also reduced the likelihood of developing a life-threatening graft-versus-host disease. [ 74 ]  Collaborating with  Eloise Giblett , a professor at the  University of Washington , he discovered genetic markers that could confirm donor matches.


The first physician to perform a successful human bone-marrow transplant on a disease other than cancer was  Robert A. Good  at the  University of Minnesota  in 1968. [ 75 ]
In 1975, John Kersey, also of the University of Minnesota, performed the first successful bone-marrow transplant to cure lymphoma. His patient, a 16-year-old-boy, is today the longest-living lymphoma transplant survivor. [ 76 ]


At the end of 2012, 20.2 million people had registered their willingness to be a bone-marrow donor with one of the 67 registries from 49 countries participating in  Bone Marrow Donors Worldwide . Around 17.9 million of these registered donors had been ABDR typed, allowing easy matching.  A further 561,000 cord blood units had been received by one of 46 cord blood banks from 30 countries participating.  The highest total number of bone-marrow donors registered were those from the U.S. (8.0 million), and the highest number per capita were those from Cyprus (15.4% of the population). [ 77 ]


Within the U.S., racial minority groups are the least likely to be registered, so are the least likely to find a potentially life-saving match.  In 1990, only six African Americans were able to find a bone-marrow match, and all six had common European genetic signatures. [ 78 ]


Africans are more genetically diverse than people of European descent, which means that more registrations are needed to find a match. Bone marrow and cord blood banks exist in  South Africa , and a new program is beginning in  Nigeria . [ 78 ]  Many people belonging to different races are requested to donate as a shortage of donors exists in African, mixed race, Latino, aboriginal, and many other communities.


Two registries in the U.S. recruit unrelated allogeneic donors: NMDP or Be the Match, and the  Gift of Life Marrow Registry .


In 2007, a team of doctors in Berlin, Germany, including  Gero Hütter , performed a stem-cell transplant for  leukemia  patient  Timothy Ray Brown , who was also  HIV -positive. [ 79 ]  From 60 matching donors, they selected a  [CCR5]-Δ32 homozygous  individual with two  genetic copies  of a rare variant of a  cell surface receptor . This genetic trait confers resistance to HIV infection by blocking attachment of HIV to the cell. Roughly one in 1,000 people of European ancestry have this inherited  mutation , but it is rarer in other populations. [ 80 ] [ 81 ]  The transplant was repeated a year later after a leukemia relapse. Over three years after the initial transplant, and despite discontinuing  antiretroviral therapy , researchers cannot detect HIV in the transplant recipient's blood or in various biopsies of his tissues. [ 82 ]  Levels of HIV-specific antibodies have also declined, leading to speculation that the patient may have been functionally cured of HIV, but scientists emphasise that this is an unusual case. [ 83 ]  Potentially fatal transplant complications (the "Berlin patient" developed graft-versus-host disease and  leukoencephalopathy ) mean that the procedure could not be performed in others with HIV, even if sufficient numbers of suitable donors were found. [ 84 ] [ 85 ]


In 2012,  Daniel Kuritzkes  reported results of two stem-cell transplants in patients with HIV.  They did not, however, use donors with the Δ32 deletion. After their transplant procedures, both were put on antiretroviral therapies, during which neither showed traces of HIV in their blood plasma and purified  CD4 +  T cells  using a sensitive culture method (less than 3 copies/ml). The virus was once again detected in both patients some time after the discontinuation of therapy. [ 86 ]


In 2019, a British man became the second to be cleared of HIV after receiving a bone-marrow transplant from a virus-resistant (Δ32) donor. This patient is being called "the London patient" (a reference to the famous Berlin patient). [ 87 ]


Since McAllister's 1997 report on a patient with  multiple sclerosis  (MS) who received a bone-marrow transplant for chronic myelogenous leukemia (CML), [ 88 ]  over 600 reports have been published describing HSCTs performed primarily for MS. [ 89 ]  These have been shown to "reduce or eliminate ongoing clinical relapses, halt further progression, and reduce the burden of disability in some patients" who have aggressive, highly active MS, "in the absence of chronic treatment with disease-modifying agents". [ 89 ]  A randomized clinical trial including 110 patients showed that HSCT significantly prolonged time to disease progression compared to disease-modifying therapy. [ 90 ]  Long-term outcome in patients with severe disease has showed that complete disease remission after HSCT is possible. [ 91 ]


HSCT can also be used for treating selected, severe cases of other autoimmune neurological diseases such as  neuromyelitis optica ,  chronic inflammatory demyelinating polyneuropathy , and  myasthenia gravis . [ 92 ]


Peripheral blood stem cell transplantation  ( PBSCT ), also called "Peripheral stem cell support", [ 1 ]  is a method of replacing  blood-forming   stem cells . Stem cells can be destroyed through cancer treatments such as chemotherapy or radiation, as well as any blood-related diseases, such as  leukemia ,  lymphoma ,  neuroblastoma  and  multiple myeloma . [ 2 ]  PBSCT is now a much more common procedure than its  bone marrow harvest  equivalent due to the ease and less invasive nature of the procedure. [ 3 ] [ 4 ]  Studies suggest that PBSCT has a better outcome in terms of the number of  hematopoietic stem cell  ( CD34+ cells ) yield. [ 5 ]


Immature  hematopoietic stem cells  in the circulating  blood  that are similar to those in the  bone marrow  are collected by  apheresis  from a donor (PBSC collection). The product is then administered  intravenously  to the patient after treatment. The administered  hematopoietic stem cells  then migrate to the recipient's bone marrow, through a process known as  stem cell homing , where the transplanted cells override the previous  bone marrow . This allows the  bone marrow  to recover, proliferate and continue producing healthy  blood cells . [ citation needed ]


The transplantation may be  autologous  (an individual's own blood cells),  allogeneic  (blood cells donated by someone else with matching  HLA ), or  syngeneic  (blood cells donated by an  identical twin ). The apheresis procedure typically lasts for 4–6 hours, depending on the  blood volume  of the donor. [ 6 ]


Granulocyte colony stimulating factor  (GCSF) are naturally occurring  glycoproteins  that stimulate white blood cell proliferation.  Filgrastim  is a synthetic form of GCSF produced in  E.coli . [ 7 ]  PBSC donors are given a course of GCSF prior to PBSC collection. The increase in white blood cell proliferation as a result of the Filgrastim ensures a better results from the donation. The course is usually given over a 4-day period prior to PBSC collection. [ 8 ]  The most common side effects of Filgrastim are bone, joint, back, arm, leg, mouth, throat, and muscle pain. [ 9 ]  Additionally, headache, nausea, vomiting, dizziness, fatigue, rash, loss of appetite, and difficulty falling or staying asleep are common. [ 9 ]


Since  allogeneic  PBSCT involves transformation of blood between different individuals, this naturally carries more complications than  autologous  PBSCT. [ 10 ]
For example, calculations must be made to ensure consistency in the amount of total blood volume between the donor and recipient. If the total blood volume of the donor is less than that of the recipient (such as when a child is donating to an adult), multiple PBSCT sessions may be required for adequate collection. Performing such a collection in a single setting could result in risks such as  hypovolemia , which could lead to  cardiac arrest  and death. Health care providers must exercise careful precaution when considering donor-recipient matching in  allogeneic  PBSCT. [ 11 ]


An early example of a successful peripheral stem cell transplant was carried out in the wake of the  1999 Tokaimura nuclear accident . Hisashi Ouchi, who received the highest dose of  radiation  was treated with PBSCT in an attempt to restore his destroyed immune system. Cells from the patient's sister's bone marrow were administered, and in the following weeks successfully began dividing and differentiating into  white blood cells . However, several weeks later, the cells were found to have been mutated by the radiation still present within the patient's body, and were observed carrying out  autoimmune responses . [ 12 ]  Later studies on the incident and subsequent use of PBSCT found that the transplant had also induced  neoendothelialization  of the aortic  endothelium . [ 13 ]


Hemicorporectomy  is a  radical surgery  in which the body below the  waist  is amputated, transecting the  lumbar spine . This removes the  legs , the  genitalia  (internal and external),  urinary system ,  pelvic  bones,  anus , and  rectum . [ 1 ] [ 2 ]  It is a major procedure recommended only as a last resort for people with severe and potentially fatal illnesses such as  osteomyelitis ,  tumors , severe  traumas  and intractable  decubiti  in, or around, the  pelvis . [ 3 ]  By 2009, 66 cases had been reported in medical literature. [ 4 ]


The operation is performed to treat spreading cancers of the spinal cord and pelvic bones. Other reasons may include  trauma  affecting the pelvic girdle (" open-book fracture "), uncontrollable  abscess  or  ulcers  of the pelvic region (causing  sepsis ) or other locally uncontainable conditions. [ 2 ]   It is used in cases wherein even  pelvic exenteration  would not remove sufficient tissue. [ citation needed ]


The surgical procedure is typically done in two stages, but it is possible to conduct the surgery in one stage. The first stage is the discontinuation of the waste functions by performing a  colostomy  and  ileal conduit  in the upper abdominal quadrants. The second stage is the amputation at the  lumbar spine . [ 5 ] [ 6 ]


With the removal of almost half of the circulatory system,  cardiac  function needs to be closely monitored while a new  blood pressure  set-point develops. [ citation needed ]


Removal of large parts of the  colon  can lead to loss of  electrolytes . Similarly, calculated measurements of  renal function  (such as the  Cockcroft-Gault formula ) are unlikely to reflect actual activity of the  kidney , as these calculations were developed for patients in whom the circulatory system correlates with the body weight; this relation is lost in a post-hemicorporectomy patient. [ citation needed ]


Extensive  physiotherapy  and  occupational therapy  are necessary after the procedure. A return to mobility generally involves the use of a  wheelchair  and potentially a prosthetic. Designing a  prosthesis  for the removed body parts is difficult, as there is generally no remaining  pelvic girdle  musculature (unless this has been spared expressly).


Individuals sustaining a severe bisection injury that is essentially a  de facto  hemicorporectomy rarely reach a hospital before dying. Apart from the very low likelihood of surviving such an injury, even an operative hemicorporectomy is unlikely to be successful unless the patient has "sufficient emotional and psychological maturity to cope" and "sufficient determination and physical strength to undergo the intensive rehabilitation". [ 7 ]


Emergency rooms  and ambulance service policies advise against the resuscitation of such patients. The UK's  National Health Service , for example, in its "Policy and Procedures for the Recognition of Life Extinct" describes traumatic hemicorporectomy (along with  decapitation ) as "unequivocally associated with death" and that such injuries should be considered " incompatible with life " in patients under 18. [ 8 ]  The National Association of EMS Physicians (NAEMSP) and the American College of Surgeons Committee on Trauma (COT) have also released similar position statements and policy allowing on-scene personnel to determine if patients are to be considered unresuscitatable. [ 9 ]


In one case documented by the  Archives of Emergency Medicine  in 1989, a woman who sustained a complete corporal transection (hemicorporectomy) after being struck by a train arrived at a hospital in a "fully conscious" state and "was aware of the nature of her injury and wished for further treatment." Although the patient was initially stabilized and underwent three hours of emergency surgery, she died approximately two hours later due to " hypovolemia ,  cardiac arrhythmia  and biochemical imbalance." [ 10 ]


Following a hemicorporectomy, patients are fitted with a socket-type prosthesis often referred to as a bucket. Early bucket designs often presented significant pressure problems for patients, but new devices have incorporated an inflatable rubber lining composed of air pockets that evenly distributes pressure based on the patient's motions. Two openings at the front of the bucket create space for the  colostomy bag  and the  ileal conduit . [ citation needed ]


The development of  surgical medicine  was vastly accelerated during, and following, the  Second World War . Rarely-experienced traumas were made more common by new weaponry. This required decisive surgical action as well as the development of new techniques. As B. E. Ferrara stated in his summative article on hemicorporectomy,


Lessons learned from battle field injuries quickened innovative treatment of congenital and acquired conditions ... [the general surgeon] devised extensive cancer operations including extended radical  mastectomy , radical  gastrectomy  and  pancreatectomy ,  pelvic exenteration , the ' Commando Operation ' (tongue, jaw and neck dissection), bilateral back dissection,  hemipelvectomy , and then hemicorporectomy or translumbar amputation, referred to as the most revolutionary of all operative procedures. [ 1 ]


It was into this environment that Frederick E. Kredel first proposed the operation in February 1951 while discussing a paper on pelvic exenteration. [ 1 ]


Hemipelvectomy , also known as a  pelvic resection , is a surgical procedure that involves the removal of part of the  pelvic girdle . This procedure is most commonly performed to treat  oncologic  conditions of the pelvis. [ 1 ] [ 2 ]  Hemipelvectomy can be further classified as  internal  and  external  hemipelvectomy. [ 1 ] [ 2 ]  An  internal  hemipelvectomy is a  limb-sparing procedure  where the  innominate bone  is  resected  while preserving the  ipsilateral  limb. [ 1 ] [ 2 ]  An  external  hemipelvectomy involves the resection of the innominate bone plus  amputation  of the ipsilateral limb. [ 1 ] [ 2 ]


Hemipelvectomy is generally reserved for the treatment of pelvic  neoplasms . [ 1 ] [ 2 ]  Examples of malignancies that are treated with hemipelvectomy include  osteosarcoma ,  chondrosarcoma , and  Ewing's sarcoma . [ 1 ]  Rarely, hemipelvectomy is performed in settings of  traumatic injury  and  osteomyelitis . [ 1 ]  Indications for  external  hemipelvectomy include neoplastic extension into the  sciatic nerve , where loss of function of the lower extremity is anticipated. [ 1 ]   Internal  hemipelvectomy is preferred when complete resection of the tumor is possible without sacrificing the lower extremity. [ 1 ]  If  external  hemipelvectomy cannot provide a greater degree of tumor resection compared to  internal  hemipelvectomy,  internal  hemipelvectomy is recommended. [ 1 ]   Internal  hemipelvectomy must only be considered when the surgical approach can ensure the preservation of critical  neurovascular structures  in the region. [ 1 ]


As with any surgical procedure, risks include infection, blood loss, damage to surrounding structures, cardiac/pulmonary complications, and adverse reactions to anesthesia.


Complications of  external  hemipelvectomy include: [ 1 ] [ 2 ]


Complications of  internal  hemipelvectomy include: [ 1 ] [ 2 ]


Prior to performing a hemipelvectomy, surgeons must possess detailed knowledge of the pelvic anatomy and its relation to the pelvic tumor. [ 1 ]  Imaging studies such as  conventional radiography ,  computed tomography , and  magnetic resonance imaging  help the surgeon visualize the anatomy and its relationship to the local pathology. [ 1 ]   Surgical oncology  techniques are utilized when resecting tumors of the pelvis. [ 1 ]  Such techniques ensure that adequate  resection margins  are obtained at the time of surgery to minimize tumor recurrence. [ 1 ]


The Enneking and Dunham classification system was developed in 1978 to aid surgeons in characterizing pelvic resections. [ 1 ] [ 3 ] [ 4 ]  This classification scheme breaks down pelvic resections into 3 subtypes: Type I, Type II, and Type III. [ 1 ] [ 3 ] [ 4 ]  Type I resections involve removal of the  ilium . [ 1 ] [ 3 ] [ 4 ]  Type II resections involve removal of the  peri-acetabular  region. [ 1 ] [ 3 ] [ 4 ]  Type III resections involve removal of the  ischial  and/or  pubic  region. [ 1 ] [ 3 ]


Resection of pelvic bone typically requires subsequent reconstruction to ensure stability of the hip joint, particularly in  internal  hemipelvectomy. [ 1 ]  Examples of pelvic reconstruction include the use of an  allograft ,  autograft , or  prosthesis  to bridge the remaining ends of pelvic bone following resection. [ 1 ] [ 4 ]   Arthrodesis  is a technique that can be used in  internal  hemipelvectomy to fix the proximal  femur  to a segment of pelvic bone for the purposes of stabilizing the lower extremity. [ 1 ] [ 4 ]


Hepatectomy  is the surgical resection (removal of all or part) of the  liver . While the term is often employed for the removal of the liver from a  liver transplant  donor, this article will focus on  partial resections  of hepatic tissue and  hepatoportoenterostomy .


The first hepatectomies were reported by Dr. Ichio Honjo (1913–1987) of ( Kyoto University ) in 1949, [ 1 ]  and Dr. Jean-Louis Lortat-Jacob (1908–1992) of France in 1952. [ 2 ]  In the latter case, the patient was a 58-year-old woman diagnosed with  colorectal cancer  which had  metastasized  to the liver. [ citation needed ]


Most hepatectomies are performed for the treatment of hepatic  neoplasms , both benign or malign. Benign neoplasms include  hepatocellular adenoma , hepatic  hemangioma  and  focal nodular hyperplasia . The most common malignant neoplasms (cancers) of the liver are  metastases ; those arising from colorectal cancer are among the most common, and the most amenable to surgical resection. The most common primary malignant tumour of the liver is the  hepatocellular carcinoma . Another primary malignant liver tumor is the  cholangiocarcinoma . Hepatectomy may also be the procedure of choice to treat intrahepatic  gallstones  or  parasitic  cysts of the liver. [ citation needed ]  Partial hepatectomies are also performed to remove a portion of a liver from a living donor for transplantation. [ 3 ]


A hepatectomy is considered a major surgical procedure performed under  general anesthesia . Access is accomplished by  laparotomy , historically by a bilateral subcostal ("chevron") incision, possibly with midline extension (Calne or "Mercedes-Benz" incision). Nowadays a broadly used approach for open liver resections is the J incision, consisting in a right subcostal incision with midline extension. [ 4 ]  The anterior approach, one of the most innovative, is made simpler by the liver hanging maneuver. [ 5 ]
In most recent years the minimal invasive approach, consisting in laparoscopic and then robotic surgery, has become increasingly common in liver resective surgery.
Hepatectomies may be anatomic, i.e. the lines of resection match the limits of one or more functional segments of the liver as defined by the  Couinaud  classification (cf.  liver#Functional anatomy ); [ 6 ]  or they may be non-anatomic, irregular or "wedge" hepatectomies. Anatomic resections are generally preferred because of the smaller risk of bleeding and biliary fistula; however, non-anatomic resections can be performed safely as well in selected cases. [ 7 ]


The  Pringle manoeuvre  is usually performed during a hepatectomy to minimize blood loss - however this can lead to  reperfusion injury  in the liver due to  Ischemia . [ citation needed ]


Bleeding  is a feared technical complication and may be grounds for urgent reoperation. It has been demonstrated that the intraoperative blood loss during liver resections affects the outcome in terms of postoperative morbidity and mortality. [ 8 ]   Biliary   fistula  is also a possible complication, albeit one more amenable to nonsurgical management. Pulmonary complications such as  atelectasis  and  pleural effusion  are commonplace, and dangerous in patients with underlying lung disease.  Infection  is relatively rare. [ citation needed ]


Liver failure  is the most serious complication of liver resection; this is a major deterrent in the surgical resection of hepatocellular carcinoma in patients with  cirrhosis . It is also a problem, to a lesser degree, in patients with previous hepatectomies (e.g. repeat resections for reincident  colorectal cancer  metastases). [ citation needed ]


Liver surgery is safe when performed by experienced surgeons with appropriate technological and institutional support. As with most major surgical procedures, there is a marked tendency towards optimal results at the hands of surgeons with high caseloads in selected centres (typically cancer centres and transplantation centres). [ citation needed ]


For optimal results, combination treatment with systemic or regionally infused chemo or biological therapy should be considered.  Prior to surgery, cytotoxic agents such as oxaliplatin given systemically for colorectal metastasis, or chemoembolization for hepatocellular carcinoma can significantly decrease the size of the tumor bulk, allowing then for resections which would remove a segment or wedge portion of the liver only.  These procedures can also be aided by application of liver clamp (Lin or Chu liver clamp; Pilling no.604113-61995) in order to minimize blood loss. [ citation needed ]


The word "hepatectomy" is derived from Greek. In Greek liver is  hepar  and -ectomy comes from the Greek  ektomē , "to remove." [ citation needed ]


Hypophysectomy  is the surgical removal of the  hypophysis  (pituitary gland). It is most commonly performed to treat tumors, especially  craniopharyngioma  tumors. [ 1 ]  Sometimes it is used to treat  Cushing's syndrome  due to  pituitary adenoma [ 2 ]  or  Simmond's disease [ 3 ]  It is also applied in  neurosciences  (in experiments with lab animals) to understand the functioning of hypophysis.  There are various ways a hypophysectomy can be carried out.  These methods include transsphenoidal hypophysectomy, open craniotomy, and stereotactic radiosurgery.


Medications that are given as  hormone replacement therapy  following a complete hypophysectomy (removal of the pituitary gland) are often  glucocorticoids . [ 4 ]  Secondary Addison's and hyperlipidemia can occur. Thyroid hormone is useful in controlling cholesterol metabolism that has been affected by pituitary deletion. [ 5 ]


Hypophysectomies can be performed in three ways. These include transsphenoidal hypophysectomy, open craniotomy, and stereotactic radiosurgery.  Each of these methods differ in the method in which the pituitary gland is removed. [ citation needed ]


In a transsphenoidal hypophysectomy, the pituitary gland or section of the pituitary gland is removed through the  sphenoid sinus  and out through the nose. [ 6 ]


In an open  craniotomy , a cavity is opened within the skull to reach the pituitary gland. [ 4 ]   Once the cavity is open, the pituitary gland is removed through the cavity.


in stereotactic radiosurgery, a headframe is applied to a patient. [ 7 ]   MRI  or  CT scans  are then administered on the patient to allow a map of the head/brain to be formed.  This map will then be used as a guide to allow correct orientation of the lasers administering radiation to specifically destroy the pituitary gland or part of the pituitary gland.


Hypophysectomy performed at any age causes atrophy of the  thyroid  and  adrenal glands  as well as  asthenia  and  cachexia . When the procedure is performed before sexual maturity, the reproductive tract remains undeveloped and non-functional. There is also a general lack of growth.  If performed after sexual maturity, there will be a loss of reproductive function along with atrophy of gonads and accessory reproductive structures.


There is a risk of cerebral spinal fluid leak due to penetration of the basal skull and risk of increased cerebral spinal fluid pressure that may lead to central nervous system changes. Post surgery, patients may have a severely altered  self-image  that may lead to an increased risk of suicide. There is also an increased risk of hemorrhage and infection secondary to the surgical procedure. [ 8 ]


Hysterectomy  is the surgical removal of the  uterus  and  cervix . Supracervical hysterectomy refers to removal of the uterus while the cervix is spared. These procedures may also involve removal of the  ovaries  ( oophorectomy ),  fallopian tubes  ( salpingectomy ), and other surrounding structures. The term “partial” or “total” hysterectomy are lay-terms that incorrectly describe the addition or omission of oophorectomy at the time of hysterectomy. These procedures are usually performed by a  gynecologist . Removal of the uterus renders the patient unable to bear children (as does removal of  ovaries  and  fallopian tubes ) and has surgical risks as well as long-term effects, so the surgery is normally recommended only when other treatment options are not available or have failed. It is the second most commonly performed  gynecological surgical procedure , after  cesarean section , in the United States. [ 1 ]  Nearly 68 percent were performed for conditions such as  endometriosis ,  irregular bleeding , and  uterine fibroids . [ 1 ]  It is expected that the frequency of hysterectomies for non-malignant indications will continue to fall given the development of alternative treatment options. [ 2 ]


Hysterectomy is a major surgical procedure that has risks and benefits.  It affects the hormonal balance and overall health of patients. Because of this, hysterectomy is normally recommended as a last resort after pharmaceutical or other surgical options have been exhausted to remedy certain intractable and severe uterine/reproductive system conditions. There may be other reasons for a hysterectomy to be requested. Such conditions and/or indications include, but are not limited to: [ 3 ]


In 1995, the short-term mortality (within 40 days of surgery) was reported at 0.38 cases per 1000 when performed for benign causes. Risks for surgical complications were presence of fibroids, younger age (vascular pelvis with higher bleeding risk and larger uterus), dysfunctional uterine bleeding and parity. [ 12 ]


The mortality rate is several times higher when performed in patients who are pregnant, have cancer or other complications. [ 13 ]


Long-term effect on all case mortality is relatively small. Women under the age of 45 years have a significantly increased long-term mortality that is believed to be caused by the hormonal side effects of hysterectomy and prophylactic oophorectomy. [ 14 ] [ 15 ]  This effect is not limited to pre-menopausal women; even women who have already entered menopause were shown to have experienced a decrease in long-term survivability post-oophorectomy. [ 16 ]


Approximately 35% of women after hysterectomy undergo another related surgery within 2 years. [ 17 ]


Ureteral injury is not uncommon and occurs in 0.2 per 1,000 cases of vaginal hysterectomy and 1.3 per 1,000 cases of abdominal hysterectomy. [ 18 ]  The injury usually occurs in the distal ureter close to the  infundibulopelvic ligament  or as a ureter crosses below the uterine artery, often from blind clamping and ligature placement to control hemorrhage. [ 19 ]


Hospital stay is 3 to 5 days or more for the abdominal procedure and between 1 and 2 days (but possibly longer) for vaginal or laparoscopically assisted vaginal procedures. [ 20 ]  After the procedure, the American College of Obstetricians and Gynecologists recommends not inserting anything into the vagina for the first 6 weeks (including inserting tampons or having sex). [ 21 ]


Removal of one or both ovaries is performed in a substantial number of hysterectomies that were intended to be ovary sparing. [ 22 ]


The average onset age of  menopause  after hysterectomy with ovarian conservation is 3.7 years earlier than average. [ 23 ]  This has been suggested to be due to the disruption of blood supply to the ovaries after a hysterectomy or due to missing endocrine feedback of the uterus. The function of the remaining ovaries is significantly affected in about 40% of people, some of them even require  hormone replacement therapy . Surprisingly, a similar and only slightly weaker effect has been observed for  endometrial ablation  which is often considered as an alternative to hysterectomy. [ 24 ]


A substantial number of women develop benign ovarian cysts after a hysterectomy. [ 25 ]


After hysterectomy for benign indications the majority of patients report improvement in sexual life and pelvic pain. A smaller share of patients report worsening of sexual life and other problems. The picture is significantly different for hysterectomy performed for malignant reasons; the procedure is often more radical with substantial side effects. [ 26 ] [ 27 ]  A proportion of patients who undergo a hysterectomy for chronic pelvic pain continue to have pelvic pain after a hysterectomy and develop  dyspareunia  (painful sexual intercourse). [ 28 ]


Estrogen levels fall sharply when the ovaries are removed, removing the protective effects of estrogen on the cardiovascular and skeletal systems. This condition is often referred to as "surgical menopause", although it is substantially different from a naturally occurring menopausal state; the former is a sudden hormonal shock to the body that causes rapid onset of menopausal symptoms such as hot flashes, while the latter is a gradually occurring decrease of hormonal levels over a period of years with uterus intact and ovaries able to produce hormones even after the cessation of menstrual periods. [ 29 ]


One study showed that risk of subsequent cardiovascular disease is substantially increased for women who had hysterectomy at age 50 or younger. No association was found for women undergoing the procedure after age 50. The risk is higher when ovaries are removed but still noticeable even when ovaries are preserved. [ 30 ]


Several other studies have found that  osteoporosis  (decrease in bone density) and increased risk of  bone fractures  are associated with hysterectomies. [ 31 ] [ 32 ]  This has been attributed to the modulatory effect of estrogen on calcium metabolism and the drop in serum estrogen levels after menopause can cause excessive loss of calcium leading to bone wasting.


Hysterectomies have also been linked with higher rates of heart disease and weakened bones. Those who have undergone a hysterectomy with both ovaries removed typically have reduced  testosterone  levels as compared to those left intact. [ 22 ]  Reduced levels of testosterone in women are predictive of height loss, which may occur as a result of reduced bone density, [ 33 ]  while increased  testosterone  levels in women are associated with a greater sense of sexual desire. [ 34 ]


Oophorectomy before the age of 45 is associated with a fivefold mortality from neurologic and mental disorders. [ 35 ]


Urinary incontinence and  vaginal prolapse  are well known adverse effects that develop with high frequency a very long time after the surgery. Typically, those complications develop 10–20 years after the surgery. [ 36 ]  For this reason exact numbers are not known, and risk factors are poorly understood. It is also unknown if the choice of surgical technique has any effect. It has been assessed that the risk for urinary incontinence is approximately doubled within 20 years after hysterectomy. One long-term study found a 2.4 fold increased risk for surgery to correct urinary stress incontinence following hysterectomy. [ 37 ] [ 38 ]


The risk for vaginal prolapse depends on factors such as number of vaginal deliveries, the difficulty of those deliveries, and the type of labor. [ 39 ]  Overall incidence is approximately doubled after hysterectomy. [ 40 ]


The formation of postoperative  adhesions  is a particular risk after hysterectomy because of the extent of dissection involved as well as the fact the hysterectomy wound is in the most gravity-dependent part of the pelvis into which a loop of bowel may easily fall. [ 41 ]  In one review,  incidence  of  small bowel obstruction  due to intestinal adhesion was found to be 15.6% in non-laparoscopic total abdominal hysterectomies vs. 0.0% in laparoscopic hysterectomies. [ 42 ]


Wound infection  occurs in approximately 3% of cases of abdominal hysterectomy. The risk is increased by obesity, diabetes, immunodeficiency disorder, use of systemic corticosteroids, smoking, wound hematoma, and preexisting infection such as chorioamnionitis and  pelvic inflammatory disease . [ 43 ]  Such wound infections mainly take the form of either  incisional abscess  or wound  cellulitis . Typically, both confer  erythema , but only an incisional abscess confers purulent drainage. The recommended treatment of an incisional abscess after hysterectomy is by  incision and drainage , and then coverage by a thin layer of  gauze  followed by sterile  dressing . The dressing should be changed and the wound irrigated with normal saline at least twice each day. In addition, it is recommended to administer an antibiotic active against staphylococci and streptococci, preferably  vancomycin  when there is a risk of  MRSA . [ 43 ]  The wound can be allowed to close by  secondary intention . Alternatively, if the infection is cleared and healthy granulation tissue is evident at the base of the wound, the edges of the incision may be reapproximated, such as by using  butterfly stitches ,  staples  or  sutures . [ 43 ]  Sexual intercourse remains possible after hysterectomy. Reconstructive surgery remains an option for women who have experienced benign and malignant conditions. [ 44 ]   : 1020–1348


Hysterectomy may cause an increased risk of the relatively rare  renal cell carcinoma . The increased risk is particularly pronounced for young women; the risk was lower after vaginally performed hysterectomies. [ 45 ]  Hormonal effects or injury of the ureter were considered as possible explanations. [ 46 ] [ 47 ]  In some cases the renal cell carcinoma may be a manifestation of an undiagnosed  hereditary leiomyomatosis and renal cell cancer  syndrome.


Removal of the uterus without removing the ovaries can produce a situation that on rare occasions can result in  ectopic pregnancy  due to an undetected fertilization that had yet to descend into the uterus before surgery. Two cases have been identified and profiled in an issue of the  Blackwell Journal of Obstetrics and Gynecology ; over 20 other cases have been discussed in additional medical literature. [ 48 ]  On very rare occasions, sexual intercourse after hysterectomy may cause a transvaginal evisceration of the small bowel. [ 49 ]  The  vaginal cuff  is the uppermost region of the vagina that has been sutured closed. A rare complication, it can dehisce and allow the evisceration of the small bowel into the vagina. [ 50 ]


Depending on the indication there are alternatives to hysterectomy:


Levonorgestrel intrauterine devices  are highly effective at controlling  dysfunctional uterine bleeding  (DUB) or  menorrhagia  and should be considered before any surgery. [ 51 ]


Menorrhagia (heavy or abnormal menstrual bleeding) may also be treated with the less invasive  endometrial ablation  which is an outpatient procedure in which the lining of the uterus is destroyed with heat, mechanically or by radio frequency ablation. [ 52 ]  Endometrial ablation greatly reduces or eliminates monthly bleeding in ninety percent of patients with DUB. It is not effective for patients with very thick uterine lining or uterine fibroids. [ 53 ]


Levonorgestrel intrauterine devices  are highly effective in limiting menstrual blood flow and improving other symptoms. Side effects are typically very moderate because the  levonorgestrel  (a  progestin ) is released in low concentration locally. There is now substantial evidence that Levongestrel-IUDs provide good symptomatic relief for women with fibroids. [ 54 ]


Uterine fibroids may be removed and the uterus reconstructed in a procedure called " myomectomy ". A myomectomy may be performed through an open incision, laparoscopically, or through the vagina (hysteroscopy). [ 55 ]


Uterine artery embolization  (UAE) is a minimally invasive procedure for treatment of  uterine fibroids . Under local anesthesia a catheter is introduced into the femoral artery at the groin and advanced under radiographic control into the uterine artery. A mass of microspheres or  polyvinyl alcohol  (PVA) material (an  embolus ) is injected into the uterine arteries in order to block the flow of blood through those vessels. [ 56 ]  The restriction in blood supply usually results in significant reduction of fibroids and improvement of heavy bleeding tendency. The 2012 Cochrane review comparing hysterectomy and UAE did not find any major advantage for either procedure. While UAE is associated with shorter hospital stay and a more rapid return to normal daily activities, it was also associated with a higher risk for minor complications later on. There were no differences between UAE and hysterectomy with regards to major complications. [ 57 ]


Uterine fibroids can be removed with a non-invasive procedure called  Magnetic Resonance guided Focused Ultrasound  (MRgFUS).


Prolapse may also be corrected surgically without removal of the uterus. [ 58 ]  There are several strategies that can be utilized to help strengthen pelvic floor muscles and prevent the worsening of prolapse. These include, but are not limited to, use of " kegel exercises ", vaginal pessary, constipation relief, weight management, and care when lifting heavy objects. [ 59 ]


Hysterectomy, in the literal sense of the word, means merely removal of the uterus. However other organs such as ovaries, fallopian tubes, and the cervix are very frequently removed as part of the surgery. [ 60 ]


Subtotal (supracervical) hysterectomy was originally proposed with the expectation that it may improve sexual functioning after hysterectomy, it has been postulated that removing the cervix causes excessive neurologic and anatomic disruption, thus leading to vaginal shortening,  vaginal vault prolapse , and vaginal cuff granulations. [ 62 ]  These theoretical advantages were not confirmed in practice, but other advantages over total hysterectomy emerged. The principal disadvantage is that risk of cervical cancer is not eliminated and women may continue cyclical bleeding (although substantially less than before the surgery).
These issues were addressed in a systematic review of total versus supracervical hysterectomy for  benign gynecological conditions , which reported the following findings: [ 63 ]


In the short-term, randomized trials have shown that cervical preservation or removal does not affect the rate of subsequent pelvic organ prolapse. [ 65 ]


Supracervical hysterectomy does not eliminate the possibility of having  cervical cancer  since the cervix itself is left intact and may be contraindicated in women with increased risk of this cancer; regular  pap smears  to check for  cervical dysplasia  or  cancer  are still needed. [ 66 ] [ 67 ]


Hysterectomy can be performed in different ways. The oldest known technique is vaginal hysterectomy. The first planned hysterectomy was performed by  Konrad Johann Martin Langenbeck  - Surgeon General of the Hannovarian army, although there are records of vaginal hysterectomy for prolapse going back as far as 50BC. [ 68 ]


The first abdominal hysterectomy recorded was by Ephraim McDowell. He performed the procedure in 1809 for a mother of five for a large ovarian mass on her kitchen table. [ 69 ]


In modern medicine today, laparoscopic vaginal (with additional instruments passing through ports in small abdominal incisions, close or in the navel) and total laparoscopic techniques have been developed.


Most hysterectomies in the United States are done via  laparotomy  (abdominal incision, not to be confused with  laparoscopy ). A  transverse (Pfannenstiel) incision  is made through the abdominal wall, usually above the  pubic bone , as close to the upper hair line of the individual's lower  pelvis  as possible, similar to the incision made for a  caesarean section . This technique allows  physicians  the greatest access to the reproductive structures and is normally done for removal of the entire reproductive complex. [ 70 ]  The recovery time for an open hysterectomy is 4–6 weeks and sometimes longer due to the need to cut through the  abdominal wall . Historically, the biggest problem with this technique was infections, but infection rates are well-controlled and not a major concern in modern medical practice. An open hysterectomy provides the most effective way to explore the abdominal cavity and perform complicated surgeries. Before the refinement of the vaginal and laparoscopic vaginal techniques, it was also the only possibility to achieve subtotal hysterectomy; meanwhile, the vaginal route is the preferable technique in most circumstances. [ 71 ] [ 72 ]


Vaginal hysterectomy is performed entirely through the vaginal canal and has clear advantages over abdominal surgery such as fewer complications, shorter hospital stays and shorter healing time. [ 73 ] [ 74 ]  Abdominal hysterectomy, the most common method, is used in cases such as after caesarean delivery, when the indication is cancer, when complications are expected, or surgical exploration is required.


With the development of laparoscopic techniques in the 1970s and 1980s, the "laparoscopic-assisted vaginal hysterectomy" (LAVH) has gained great popularity among  gynecologists  because compared with the abdominal procedure it is less invasive and the post-operative recovery is much faster. It also allows better exploration and slightly more complicated surgeries than the vaginal procedure. LAVH begins with  laparoscopy  and is completed such that the final removal of the uterus (with or without removing the ovaries) is via the vaginal canal. Thus, LAVH is also a total hysterectomy; the cervix is removed with the uterus. [ 75 ]  If the cervix is removed along with the uterus, the upper portion of the vagina is sutured together and called the  vaginal cuff . [ 76 ]


The "laparoscopic-assisted supracervical hysterectomy" (LASH) was later developed to remove the uterus without removing the cervix using a  morcellator  which cuts the uterus into small pieces that can be removed from the abdominal cavity via the laparoscopic ports. [ 77 ]


Total laparoscopic hysterectomy (TLH) was developed in the early 90s by Prabhat K. Ahluwalia in Upstate New York. [ 78 ]  TLH is performed solely through the laparoscopes in the abdomen, starting at the top of the uterus, typically with a uterine manipulator. The entire uterus is disconnected from its attachments using long thin instruments through the "ports". Then all tissue to be removed is passed through the small abdominal incisions.


Supracervical (subtotal) laparoscopic hysterectomy (LSH) is performed similar to the total laparoscopic surgery but the uterus is amputated between the cervix and fundus. [ 79 ]


Dual-port laparoscopy is a form of laparoscopic surgery using two 5 mm midline incisions: the uterus is detached through the two ports and removed through the vagina. [ 80 ] [ 81 ]


"Robotic hysterectomy" is a variant of laparoscopic surgery using special remotely controlled instruments that allow the surgeon finer control as well as three-dimensional magnified vision. [ 82 ]


Patient characteristics such as the reason for needing a hysterectomy, uterine size, descent of the uterus, presence of diseased tissues surrounding the uterus, previous surgery in the pelvic region, obesity, history of pregnancy, the possibility of  endometriosis , or the need for an  oophorectomy , will influence a surgeon's surgical approach when performing a hysterectomy. [ 83 ] [ needs update ]


Vaginal hysterectomy is recommended over other variants where possible for women with benign diseases. [ 71 ] [ 72 ] [ 83 ]  Vaginal hysterectomy was shown to be superior to LAVH and some types of laparoscopic surgery causing fewer short- and long-term complications, more favorable effect on sexual experience with shorter recovery times and fewer costs. [ 84 ] [ 85 ] [ 86 ]


Laparoscopic surgery offers certain advantages when vaginal surgery is not possible but also has the disadvantage of significantly longer time required for the surgery. [ 83 ] [ 73 ]


In one 2004 study conducted in the UK comparing abdominal (laparotomic) and laparoscopic techniques, laparoscopic surgery was found to cause longer operation time and a higher rate of major complications while offering much quicker healing. [ 87 ]  In another study conducted in 2014, laparoscopy was found to be "a safe alternative to laparotomy" in patients receiving total hysterectomy for endometrial cancer. Researchers concluded the procedure "offers markedly improved perioperative outcomes with a lower reoperation rate and fewer postoperative complications when the standard of care shifts from open surgery to laparoscopy in a university hospital". [ 88 ]


The abdominal technique is very often applied in difficult circumstances or when complications are expected. Given these circumstances the complication rate and time required for surgery compares very favorably with other techniques, however time required for healing is much longer. [ 83 ]


Hysterectomy by abdominal laparotomy is correlated with much higher incidence of intestinal adhesions than other techniques. [ 42 ]


Time required for completion of surgery in the eVAL trial is reported as follows: [ 87 ]


Morcellation  has been widely used especially in laparoscopic techniques and sometimes for the vaginal technique, but now appears to be associated with a considerable risk of spreading benign or malignant tumors. [ 89 ] [ 90 ]  In April 2014, the FDA issued a memo alerting medical practitioners to the risks of power morcellation. [ 91 ]


Robotic assisted surgery is presently used in several countries for hysterectomies. Additional research is required to determine the benefits and risks involved, compared to conventional laparoscopic surgery. [ 92 ]


A 2014 Cochrane review found that robotic assisted surgery may have a similar complication rate when compared to conventional laparoscopic surgery. In addition, there is evidence to suggest that although the surgery make take longer, robotic assisted surgery may result in shorter hospital stays. [ 92 ]  More research is necessary to determine if robotic assisted hysterectomies are beneficial for people with cancer. [ 92 ]


Previously reported marginal advantages of robotic assisted surgery could not be confirmed; only differences in hospital stay and cost remain statistically significant. [ 93 ] [ 94 ] [ 95 ]  In addition, concerns over widespread misleading marketing claims have been raised. [ 96 ]


In  Canada , the number of hysterectomies between 2008 and 2009 was almost 47,000. The national rate for the same timeline was 338 per 100,000 population, down from 484 per 100,000 in 1997. The reasons for hysterectomies differed depending on whether the woman was living in an urban or rural location. Urban women opted for hysterectomies due to  uterine fibroids  and rural women had hysterectomies mostly for  menstrual disorders . [ 101 ]


Hysterectomy is the second most common major surgery among women in the United States (the first is cesarean section). In the 1980s and 1990s, this statistic was the source of concern among some consumer rights groups and puzzlement among the medical community, [ 102 ]  and brought about informed choice advocacy groups like Hysterectomy Educational Resources and Services (HERS) Foundation, founded by  Nora W. Coffey  in 1982.


According to the  National Center for Health Statistics , of the 617,000 hysterectomies performed in 2004, 73% also involved the surgical removal of the ovaries. There are currently an estimated 22 million women in the United States who have undergone this procedure. Nearly 68 percent were performed for benign conditions such as endometriosis, irregular bleeding and uterine fibroids. [ 1 ]  Such rates being highest in the industrialized world has led to the controversy that hysterectomies are being largely performed for unwarranted reasons. [ 103 ]  More recent data suggests that the number of hysterectomies performed has declined in every state in the United States. From 2010 to 2013, there were 12 percent fewer hysterectomies performed, and the types of hysterectomies were more minimally invasive in nature, reflected by a 17 percent increase in laparoscopic procedures. [ 104 ]


In the UK, 1 in 5 women is likely to have a hysterectomy by the age of 60, and ovaries are removed in about 20% of hysterectomies. [ 105 ]


The number of hysterectomies in  Germany  has been constant for many years. In 2006, 149,456 hysterectomies were performed. Additionally, of these, 126,743 (84.8%) successfully benefitted the patient without incident. Women between the ages of 40 and 49 accounted for 50 percent of hysterectomies, and those between the ages of 50 and 59 accounted for 20 percent. [ 106 ]  In 2007, the number of hysterectomies decreased to 138,164. [ 64 ]  In recent years, the technique of laparoscopic or laparoscopically assisted hysterectomies has been raised into the foreground. [ 107 ] [ 108 ]


In  Denmark , the number of hysterectomies from the 1980s to the 1990s decreased by 38 percent. In 1988, there were 173 such surgeries per 100,000 women, and by 1998 this number had been reduced to 107. The proportion of abdominal supracervical hysterectomies in the same time period grew from 7.5 to 41 percent. A total of 67,096 women underwent hysterectomy during these years. [ 109 ]


Irreversible electroporation  or  IRE  is a soft tissue  ablation  technique using short but strong  electrical fields  to create permanent and hence lethal nanopores in the  cell membrane , to disrupt cellular  homeostasis . The resulting cell death results from induced  apoptosis  or  necrosis  induced by either membrane disruption or secondary breakdown of the membrane due to transmembrane transfer of electrolytes and  adenosine triphosphate . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  The main use of IRE lies in tumor ablation in regions where precision and conservation of the  extracellular matrix , blood flow and nerves are of importance. The first generation of IRE for clinical use, in the form of the NanoKnife System, became commercially available for research purposes in 2009, solely for the surgical ablation of soft tissue tumors. [ 5 ]  Cancerous tissue ablation via IRE appears to show significant cancer specific immunological responses which are currently being evaluated alone and in combination with  cancer immunotherapy . [ 6 ] [ 7 ] [ 8 ] [ 9 ]


First observations of IRE effects go back to 1754. Nollet reported the first systematic observations of the appearance of red spots on animal and human skin that was exposed to electric sparks. [ 10 ]  However, its use for modern medicine began in 1982 with the seminal work of Neumann and colleagues. [ 11 ]  Pulsed electric fields were used to temporarily permeabilize cell membranes to deliver foreign DNA into cells. In the following decade, the combination of high-voltage pulsed electric fields with the chemotherapeutic drug bleomycin and with DNA yielded novel clinical applications:  electrochemotherapy  and  gene electrotransfer , respectively. [ 12 ] [ 13 ] [ 14 ] [ 15 ] [ 16 ]  The use of irreversible electroporation for therapeutic applications was first suggested by Davalos, Mir, and Rubinsky. [ 17 ]


Utilizing ultra short pulsed but very strong electrical fields, micropores and nanopores are induced in the  phospholipid bilayers  which form the outer cell membranes. [ citation needed ]  Two kinds of damage can occur:


It should be stated that even though the ablation method is generally accepted to be apoptosis, some findings seem to contradict a pure apoptotic cell death, making the exact process by which IRE causes cell death unclear. [ 18 ] [ 4 ]  In any case, all studies agree that the cell death is an induced one with the cells dying over a varying time period of hours to days and does not rely on local extreme heating and melting of tissue via high energy deposition like most ablation technologies  (see  radiofrequency ablation ,  microwave ablation ,  High-intensity focused ultrasound ). [ citation needed ]


When an electrical field of more than 0.5 V/nm [ 19 ]  is applied to the resting trans-membrane potential, it is proposed that water enters the cell during this dielectric breakdown. Hydrophilic pores are formed. [ 20 ] [ 21 ]  A molecular dynamics simulation by Tarek [ 22 ]  illustrates this proposed pore formation in two steps: [ 23 ]


It is proposed that as the applied electrical field increases, the greater is the perturbation of the phospholipid head groups, which in turn increases the number of water filled pores. [ 24 ]  This entire process can occur within a few nanoseconds. [ 22 ]  Average sizes of nanopores are likely cell-type specific. In swine livers, they average around 340-360 nm, as found using  SEM . [ 23 ]


A secondary described mode of cell death was described to be from a breakdown of the membrane due to transmembrane transfer of electrolytes and adenosine triphosphate. [ 3 ]  Other effects like heat [ 25 ]  or electrolysis [ 26 ] [ 27 ]  were also shown to play a role in the currently clinically applied IRE pulse protocols.


A number of electrodes, in the form of long needles, are placed around the target volume. The point of penetration for the electrodes is chosen according to anatomical conditions. Imaging is essential to the placement and can be achieved by ultrasound, magnetic resonance imaging or tomography. The needles are then connected to the IRE-generator, which then proceeds to sequentially build up a potential difference between two electrodes. The geometry of the IRE-treatment field is calculated in real time and can be influenced by the user. Depending on the treatment-field and number of electrodes used, the ablation takes between 1 and 10 minutes. In general muscle relaxants are administered, since even under general anesthetics, strong muscle contractions are induced by excitation of the motor end-plate. [ citation needed ]


Typical parameters (1st generation IRE system): [ citation needed ]


The shortly pulsed, strong electrical fields are induced through thin, sterile, disposable electrodes. The potential differences are calculated and applied by a computer system between these electrodes in accordance to a previously planned treatment field. [ 39 ]