Pancreas transplantation: 50 years of experience | Cirugía Española (English Edition)

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The advent of organ transplantations was a wake-up call that definitively propelled the development of important technical and immunological advances. The era was one of social controversy as well as incredible technological development, culminating in the Space Race and man landing on the Moon in 1969.Kidney transplantation had been developed before this wave of innovations, thanks to the vision and persistence of Hume, Kuss and, especially, Murray and Merrill who, at the Peter Bent Brigham Hospital in Boston, had successfully performed the first kidney transplantation between 2 twin brothers in 1954. These advances, made fundamentally in the US, were due to the willingness of a series of hospitals, whose objective was the clinical application of organ transplantation after many years of research programs. Liver (1963), lung (1963), heart (1967), pancreas (1967) and colon (1967) transplants and a group of pioneers including Starzl, Calne, Sunway, Barnard, Hardy, Lillehei, Kelly, Murray and Najarian blazed a trail that many surgeons throughout the world have later followed.<a class="elsevierStyleCrossRef" href="#bib0240">2</a>For a long time, pancreas transplantation was considered the Cinderella of solid organ transplants. As the objective was to cure diabetes though the normalization of carbohydrate metabolism, it took a while to comprehend that, in order to substitute only 2% of insulin-producing pancreas cells, it was necessary to transplant the entire pancreas, which involved technical and immunological problems. Furthermore, the availability of insulin for the control of diabetes meant that many doctors did not adequately contemplate the deterioration caused by the disease, even with apparently good metabolic control.The University of Minnesota in Minneapolis is a prestigious hospital with a long tradition of clinical research thanks to a group of physicians who, under the leadership of Professor Wangensteen, were able to develop the first experiences in cardiac surgery thanks to Varco and the Lillehei brothers. Richard Lillehei, who had consolidated an important research program in shock, postulated that a pancreas transplant could be the solution for those patients with diabetes and kidney failure who, until that time, were practically given up on by medicine. Lillehei and Kelly, 2 surgeons with independent laboratories and research fellows, joined forces and, together with the diabetologist Goetz, made the unheard of decision to simultaneously perform kidney and pancreas transplantations in a 28-year-old patient who had been diabetic since the age of 9 and who presented end-stage renal disease. This transplantation, led by Kelly and assisted by Lillehei and Merkel, was done at the Mayo Memorial Hospital in Minneapolis, by the prestigious Surgery Department headed by Wangensteen.<a class="elsevierStyleCrossRef" href="#bib0235">1</a>The pancreas transplant consisted of a segmental graft with the pancreas duct ligated. This patient remained insulin free for 6 days; however, after this period, insulin was required, probably related with the high doses of steroids necessary to try to avoid rejection. Likewise, the patient developed pancreatitis of the graft, possibly due to the duct ligation, and on February 14, 1967 Kelly and Lillehei removed the pancreas graft; the kidney was rejected shortly thereafter. The recipient died due to pulmonary embolism 13 days after the transplantectomy (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>This first case is an example of the morbidity that was associated with pancreas transplantation for many years: surgical complications, infections and rejection. In spite of this complicated first case, the Minnesota team demonstrated the technical possibilities of this transplantation. Prior to clinical application, Merkel had developed in the laboratory of Dr. Kelly a canine model of segmental pancreas transplantation, trying to reduce exocrine secretion by graft radiation.<a class="elsevierStyleCrossRefs" href="#bib0245">3,4</a> Meanwhile, in the laboratory of Dr. Lillehei, another 2 surgical fellows, Largiader from Zurich and Idezuki from Tokyo, worked on a canine pancreatic-duodenal transplant model, with drainage of the exocrine secretion by means of Roux-en-Y duodenojejunostomy.<a class="elsevierStyleCrossRefs" href="#bib0255">5,6</a> With this new surgical model, Lillehei led the second pancreas transplantation on the morning of New Year's day (1/1/1967). This transplant functioned for 4.5 months, with excellent follow-up of both organs. Acute rejection was controlled with high doses of prednisone, although in the end the rejection episodes affected the duodenum. After the first case, another 12 were carried out by the same team until 1973, using a complete pancreas-duodenum graft in most, with intestinal diversion of the exocrine secretion through a percutaneous duodenostomy. In this series of transplants, 9 were associated with kidney transplantation and 4 were isolated pancreas transplantation<a class="elsevierStyleCrossRefs" href="#bib0265">7,8</a> (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>The majority of the transplants functioned immediately, but the rejection—given the empirical immunosuppression of the time (azathioprine and corticosteroids)—and the surgical complications were reasons that influenced the loss of enthusiasm in this type of transplants. Lillehei performed the last of the transplantations of the series on January 11, 1973.<a class="elsevierStyleCrossRef" href="#bib0275">9</a> Najarian, new director of the department since July 1967, had participated in some of the transplant surgeries with Lillehei and, as a result of the complications entailed, decided to manage the program with the aim to perform a less aggressive approach for the treatment of diabetes and kidney failure in these patients. New members of the team like Simmons and Kjellstrand developed an important kidney transplant program in uremic diabetic patients, and Sutherland initiated clinical research in islet transplantation.<a class="elsevierStyleCrossRefs" href="#bib0280">10,11</a>After the first pancreas transplants at the University of Minnesota in 1968, other hospitals in South America carried out 4 transplantations (Río de Janeiro, 1 case; Sao Paulo, 2 cases; and Buenos Aires, 1 case), although only in 1 was insulin independence temporarily achieved.<a class="elsevierStyleCrossRefs" href="#bib0290">12,13</a> In 1969, another 2 institutions in the US had experiences with pancreas transplantations: at the University of Colorado, Merkel and Starzl performed one case of simultaneous kidney and pancreas transplantation,<a class="elsevierStyleCrossRef" href="#bib0300">14</a> and a second case at the University of California, at the Irvine Medical Center, under Connolly.<a class="elsevierStyleCrossRef" href="#bib0305">15</a> In Europe, the first pancreas transplantation was conducted at the Guy's Hospital in London by Bewick in 1972.<a class="elsevierStyleCrossRef" href="#bib0310">16</a>Until 1970, only 25 pancreas transplantations had been done at 6 institutions worldwide. Two-thirds of these experiences were conducted simultaneously with renal transplantations. Out of all these cases, only one case in the Lillehei series functioned for one year.In November 1971, Gliedman performed his first transplant at the Montefiore Hospital in New York, diverting the exocrine secretion through an anastomosis of the Wirsung duct with the native ureter. With this technique, this group carried out 11 transplantations in the 1970s, with one case that functioned for 22 months and another for 50 months.<a class="elsevierStyleCrossRef" href="#bib0315">17</a> In 1976, Bewick, once again at the Guy's Hospital in London, conducted a pancreatic transplantation technique leaving the duct open. Another similar case at the University of Minnesota done by Sutherland functioned with insulin independence for 18 months: at that time, it was the case with the longest graft survival.<a class="elsevierStyleCrossRefs" href="#bib0310">16,18</a>Until 1980, only 105 pancreas transplantations had been carried out across the world, half of which had been done in the US, with active programs in Minnesota and the Montefiore Hospital in New York. The other half had been performed in Europe, where the most active programs were at the Huddinge Hospital in Stockholm (Sweden), headed by Groth, and at the Eduard Herriot Hospital in Lyon (France), headed by Dubernard (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).<elsevierMultimedia ident="fig0015"></elsevierMultimedia>In 1978, Dubernad had developed a new technique, injecting a polymer in the pancreatic duct (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>A) to try to induce fibrosis and abolish the exocrine secretion and, therefore, the complications dependent on the exocrine pancreas. The success of this ingenious technique encouraged other surgeons to utilize different polymers in the pancreatic duct, such as prolamin, used by Land in Munich, polyisoprene, used by MacMaster in Cambridge, and silicone, used by Sutherland at the University of Minnesota.<a class="elsevierStyleCrossRefs" href="#bib0325">19–21</a>In the 1980s, at the University of Minnesota, Sutherland developed a major pancreas transplantation program with live donors using segmental grafts, whereas in transplants from cadaveric donors, the model used was a pancreas-duodenal graft with intestinal bypass.<a class="elsevierStyleCrossRefs" href="#bib0340">22–24</a>In 1983, Sollinger, a German surgeon who went to the University of Wisconsin to work with Beltzer, followed the experiences of Gliedman in New York and developed with good results a bladder diversion technique for exocrine secretions using anastomosis of the pancreas segment to the bladder. This technique was perfected by Corry and Ngheim at the University of Iowa, utilizing the bladder diversion of the entire pancreatic-duodenal graft by means of anastomosis of the duodenum with the bladder (Fig 3C).<a class="elsevierStyleCrossRefs" href="#bib0355">25–27</a>With this technique, in addition to a significant decrease in surgical complications, it was possible to measure urine amylase levels as a marker of rejection (Prieto).<a class="elsevierStyleCrossRef" href="#bib0370">28</a> Therefore, bladder diversion was the choice in many programs in the 1990s. Despite this, urinary complications (urethritis, hematuria, metabolic acidosis, urinary fistula, etc.) caused some hospitals to reconvert many patients to intestinal diversion.Simultaneously, at the University of Pittsburgh in 1984, Starzl had started a transplant program that returned to the original technique described by Lillehei using intestinal drainage. Likewise, the Stockholm group (Groth and Tyden) had already successfully developed intestinal diversion with a segmental graft (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>B).<a class="elsevierStyleCrossRefs" href="#bib0375">29–31</a>Encouraged by the improved results, at other medical centers in the US and Europe, pancreas transplantation programs were successfully initiated with variations of certain technical aspects related with the type of graft, the exocrine secretion diversion model and venous drainage of the graft.From the standpoint of immunosuppression, Calne was the first to apply cyclosporine to pancreas transplantations at Cambridge,<a class="elsevierStyleCrossRefs" href="#bib0390">32,33</a> and Sutherland introduced quadruple therapy, including induction therapy.<a class="elsevierStyleCrossRef" href="#bib0400">34</a> Starzl was the first to introduce tacrolimus in this transplant in 1989,<a class="elsevierStyleCrossRef" href="#bib0405">35</a> and in the mid-1990s mycophenolate mofetil was introduced by Sollinger.<a class="elsevierStyleCrossRef" href="#bib0410">36</a>From a technical standpoint, the diversion used in the decade of the 1990s was urinary, whereas in the decade of 2000 the diversion was intestinal (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>).<elsevierMultimedia ident="fig0020"></elsevierMultimedia>Since then, more than 50,000 diabetic patients have received transplants at more than 200 medical centers worldwide, with one-year patient survival rates of 95% and graft survival rates greater than 85%.<a class="elsevierStyleCrossRef" href="#bib0415">37</a> The improvement of the results has been progressive thanks to a better knowledge of the particularities of this transplant type in all its stages, from appropriate early indication to meticulous technique and, especially, the application of a more effective regimen of immunosuppressants. The results are registered with the International Pancreas Transplant Registry (IPTR), founded by Sutherland, who has been a University of Minnesota surgeon and alma mater in the world in this type of transplant for more than 30 years.<a class="elsevierStyleCrossRefs" href="#bib0420">38,39</a>In Spain, the first pancreas transplantation was performed on February 3, 1983 by Dr Gil Vernet and Dr Fernandez-Cruz at the Hospital Clínico y Provincial in Barcelona.<a class="elsevierStyleCrossRef" href="#bib0430">40</a> Dr. Gil Vernet had already performed the first successful kidney transplantation in our country and was very much aware of the trends in transplantation originating in other European countries and the US. Therefore, it was reasonable for this pioneer of renal transplantation in Spain, together with a young Fernández-Cruz (also a surgeon at the Hospital Clínico in Barcelona) to initiate this combined kidney and pancreas transplantation program. Professor Fernández-Cruz had done an internship at the University of San Diego in the US. He had also visited Dr. Sutherland in Minneapolis and started the program that has been a leader in our country ever since.The donor of this first transplant was a 17-year-old boy, who had died as a result of a car accident; the recipient was a 32-year-old patient with type I diabetes on renal dialysis for kidney failure. The technique used was a kidney transplant in the left iliac fossa, and a segmental pancreas transplantation with obliteration of the duct using prolamin in the right iliac fossa. The patient survived 11 years and died of myocardial infarction. The nephrology team was comprised of Dr. Caralps and Dr. Andreu.<a class="elsevierStyleCrossRef" href="#bib0435">41</a>After this experience, other centers in Spain, including Córdoba (Hospital Reina Sofía), Santander (Hospital Marqués de Valdecilla), Santiago de Compostela (Hospital Universitario), Málaga (Hospital Carlos Haya), Madrid (Hospital 12 de Octubre), Tenerife (University of the Canary Islands), etc., started pancreas transplantation programs. At present, there are 12 medical centers that have active programs that perform about 100 transplants per year.<a class="elsevierStyleCrossRefs" href="#bib0440">42,43</a>In 2005, a consensus meeting was organized by the National Transplant Organization in Spain. Following a debate among the parties involved (surgeons, nephrologists, endocrinologists, transplant coordinators), the criteria for indication, prioritization, organ distribution, hospital planning and accreditation mechanisms were established in order to optimize the treatment of diabetes in our country.<a class="elsevierStyleCrossRefs" href="#bib0450">44–46</a>After 50 years of history, we can say that pancreas transplantation has come a long way since its inception, thanks to the work of pioneering surgeons who have gone beyond conventional practice in the search for solutions to the complications of diabetes.The complexity of diabetic patients means that the benefits of these transplants are sometimes underestimated when compared with other procedures, such as cardiac transplantation or liver transplantation, in which graft function acquires vital connotations. However, today, pancreas transplantation has the same results in terms of patient survival, graft survival and quality of life as other solid organs (<a class="elsevierStyleCrossRefs" href="#fig0020">Figs. 4 and 5</a>).<elsevierMultimedia ident="fig0025"></elsevierMultimedia>As long as we do not have procedures for the prevention of diabetes, the solution for diabetic patients with risk of secondary complications will entail the replacement of functioning islet tissue by transplantation. Answers for this substitution are likely to involve cell transplantation in the future, but it is unquestionable that, after 50 years of progress, the fulfillment of these objectives involves vascularized pancreas transplantation. The clinical project initiated by Lillehei and continued by Sutherland and hundreds of enthusiasts came of age years ago, but it is time to pay homage to all those who dedicated part of their professional lives to try to improve the survival and quality of life of these patients (<a class="elsevierStyleCrossRef" href="#fig0030">Fig. 6</a>).<elsevierMultimedia ident="fig0030"></elsevierMultimedia>Conflict of interestsThe author has no conflict of interests to declare" "textoCompletoSecciones" => array:1 [ "secciones" => array:6 [ 0 => array:3 [ "identificador" => "xres868459" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec857388" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres868460" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec857387" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflict of interests" ] 5 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-02-09" "fechaAceptado" => "2017-02-21" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec857388" "palabras" => array:2 [ 0 => "Pancreas transplant" 1 => "Technical advances" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec857387" "palabras" => array:2 [ 0 => "Trasplante de páncreas" 1 => "Avances técnicos" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "In December 1966, the first pancreas transplant ever was performed at the University of Minnesota. R. Lillehei and W. Kelly, transplanted a kidney and a pancreas in a diabetic patient on dialysis, getting function of both organs. Since then, the technical and immunological advances in this transplant have resulted in graft and patient survival results as the rest of the abdominal solid organ transplants. The balance of these 50 years is that more than 50,000 diabetic patients have been transplanted in more than 200 centers around the world. In our country the first transplant was performed 34 years ago in Barcelona and now 12 centers perform about 100 transplants per year. Although advances in diabetes control have been very important, pancreas transplantation continues to be the only method that allows normalization of the carbohydrates metabolism to improve the quality of life and, above all, to increase the survival of these patients." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "En diciembre de 1966 se realizó en la Universidad de Minnesota el primer trasplante de páncreas de la historia. R. Lillehei y W. Kelly, trasplantaron un riñón y un páncreas a una paciente diabética en diálisis, consiguiendo función de ambos órganos. Desde entonces los avances técnicos e inmunológicos en este trasplante, han propiciado resultados en cuanto a supervivencia del injerto y del paciente superponibles al resto de los trasplantes de órganos sólidos abdominales. El balance de estos 50 años es que mas de 50.000 pacientes diabéticos han sido trasplantados en mas de 200 centros en todo el mundo. En nuestro país el primer trasplante se realizó hace 34 años en Barcelona y ahora 12 centros realizan alrededor de 100 trasplantes por año. Aunque los avances en el control de la diabetes han sido muy importantes, el trasplante de páncreas continúa siendo el único método que permite normalizar el metabolismo hidrocarbonado, mejorar la calidad de vida y sobre todo aumentar la supervivencia de estos pacientes." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Casanova D, en nombre de Grupo Español de Trasplante de Páncreas. Trasplante de páncreas: 50 años de experiencia. Cir Esp. 2017;95:254–260." ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 610 "Ancho" => 1425 "Tamanyo" => 141286 ] ] "descripcion" => array:1 [ "en" => "William Kelly with the first transplant recipient; Richard Lillehei." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 517 "Ancho" => 1555 "Tamanyo" => 148242 ] ] "descripcion" => array:1 [ "en" => "Transplantation models in the first 2 cases of R. Lillehei." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 612 "Ancho" => 1180 "Tamanyo" => 81677 ] ] "descripcion" => array:1 [ "en" => "Pancreas transplantation models: (A) injection with polymers; (B) intestinal diversion; (C) bladder diversion (from Sutherland)." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 732 "Ancho" => 1406 "Tamanyo" => 198605 ] ] "descripcion" => array:1 [ "en" => "Intestinal and bladder diversion models." ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 638 "Ancho" => 1750 "Tamanyo" => 134991 ] ] "descripcion" => array:1 [ "en" => "(A) David Sutherland; (B) Jean Michel Dubernard; (C) Hans Sollinge." ] ] 5 => array:7 [ "identificador" => "fig0030" "etiqueta" => "Fig. 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 754 "Ancho" => 1131 "Tamanyo" => 126569 ] ] "descripcion" => array:1 [ "en" => "At the 40th anniversary of the first pancreatic transplantation: D. 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Pancreas transplantation: 50 years of experience

Trasplante de páncreas: 50 años de experiencia

Daniel Casanova, on behalf of the Spanish Pancreas Transplant Group

Chairman Board Europeo de Trasplante, Servicio de Cirugía General y Digestiva Hospital Universitario Marqués de Valdecilla, Santander, Spain

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thanks to the vision and persistence of Hume&#44; Kuss and&#44; especially&#44; Murray and Merrill who&#44; at the Peter Bent Brigham Hospital in Boston&#44; had successfully performed the first kidney transplantation between 2 twin brothers in 1954&#46; These advances&#44; made fundamentally in the US&#44; were due to the willingness of a series of hospitals&#44; whose objective was the clinical application of organ transplantation after many years of research programs&#46; Liver &#40;1963&#41;&#44; lung &#40;1963&#41;&#44; heart &#40;1967&#41;&#44; pancreas &#40;1967&#41; and colon &#40;1967&#41; transplants and a group of pioneers including Starzl&#44; Calne&#44; Sunway&#44; Barnard&#44; Hardy&#44; Lillehei&#44; Kelly&#44; Murray and Najarian blazed a trail that many surgeons throughout the world have later followed&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">2</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">For a long time&#44; pancreas transplantation was considered the Cinderella of solid organ transplants&#46; As the objective was to cure diabetes though the normalization of carbohydrate metabolism&#44; it took a while to comprehend that&#44; in order to substitute only 2&#37; of insulin-producing pancreas cells&#44; it was necessary to transplant the entire pancreas&#44; which involved technical and immunological problems&#46; Furthermore&#44; the availability of insulin for the control of diabetes meant that many doctors did not adequately contemplate the deterioration caused by the disease&#44; even with apparently good metabolic control&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The University of Minnesota in Minneapolis is a prestigious hospital with a long tradition of clinical research thanks to a group of physicians who&#44; under the leadership of Professor Wangensteen&#44; were able to develop the first experiences in cardiac surgery thanks to Varco and the Lillehei brothers&#46; Richard Lillehei&#44; who had consolidated an important research program in shock&#44; postulated that a pancreas transplant could be the solution for those patients with diabetes and kidney failure who&#44; until that time&#44; were practically given up on by medicine&#46; Lillehei and Kelly&#44; 2 surgeons with independent laboratories and research fellows&#44; joined forces and&#44; together with the diabetologist Goetz&#44; made the unheard of decision to simultaneously perform kidney and pancreas transplantations in a 28-year-old patient who had been diabetic since the age of 9 and who presented end-stage renal disease&#46; This transplantation&#44; led by Kelly and assisted by Lillehei and Merkel&#44; was done at the Mayo Memorial Hospital in Minneapolis&#44; by the prestigious Surgery Department headed by Wangensteen&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">1</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The pancreas transplant consisted of a segmental graft with the pancreas duct ligated&#46; This patient remained insulin free for 6 days&#59; however&#44; after this period&#44; insulin was required&#44; probably related with the high doses of steroids necessary to try to avoid rejection&#46; Likewise&#44; the patient developed pancreatitis of the graft&#44; possibly due to the duct ligation&#44; and on February 14&#44; 1967 Kelly and Lillehei removed the pancreas graft&#59; the kidney was rejected shortly thereafter&#46; The recipient died due to pulmonary embolism 13 days after the transplantectomy &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">This first case is an example of the morbidity that was associated with pancreas transplantation for many years&#58; surgical complications&#44; infections and rejection&#46; In spite of this complicated first case&#44; the Minnesota team demonstrated the technical possibilities of this transplantation&#46; Prior to clinical application&#44; Merkel had developed in the laboratory of Dr&#46; Kelly a canine model of segmental pancreas transplantation&#44; trying to reduce exocrine secretion by graft radiation&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">3&#44;4</span></a> Meanwhile&#44; in the laboratory of Dr&#46; Lillehei&#44; another 2 surgical fellows&#44; Largiader from Zurich and Idezuki from Tokyo&#44; worked on a canine pancreatic-duodenal transplant model&#44; with drainage of the exocrine secretion by means of Roux-en-Y duodenojejunostomy&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">5&#44;6</span></a> With this new surgical model&#44; Lillehei led the second pancreas transplantation on the morning of New Year&#39;s day &#40;1&#47;1&#47;1967&#41;&#46; This transplant functioned for 4&#46;5 months&#44; with excellent follow-up of both organs&#46; Acute rejection was controlled with high doses of prednisone&#44; although in the end the rejection episodes affected the duodenum&#46; After the first case&#44; another 12 were carried out by the same team until 1973&#44; using a complete pancreas-duodenum graft in most&#44; with intestinal diversion of the exocrine secretion through a percutaneous duodenostomy&#46; In this series of transplants&#44; 9 were associated with kidney transplantation and 4 were isolated pancreas transplantation<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">7&#44;8</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">The majority of the transplants functioned immediately&#44; but the rejection&#8212;given the empirical immunosuppression of the time &#40;azathioprine and corticosteroids&#41;&#8212;and the surgical complications were reasons that influenced the loss of enthusiasm in this type of transplants&#46; Lillehei performed the last of the transplantations of the series on January 11&#44; 1973&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">9</span></a> Najarian&#44; new director of the department since July 1967&#44; had participated in some of the transplant surgeries with Lillehei and&#44; as a result of the complications entailed&#44; decided to manage the program with the aim to perform a less aggressive approach for the treatment of diabetes and kidney failure in these patients&#46; New members of the team like Simmons and Kjellstrand developed an important kidney transplant program in uremic diabetic patients&#44; and Sutherland initiated clinical research in islet transplantation&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">10&#44;11</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">After the first pancreas transplants at the University of Minnesota in 1968&#44; other hospitals in South America carried out 4 transplantations &#40;R&#237;o de Janeiro&#44; 1 case&#59; Sao Paulo&#44; 2 cases&#59; and Buenos Aires&#44; 1 case&#41;&#44; although only in 1 was insulin independence temporarily achieved&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">12&#44;13</span></a> In 1969&#44; another 2 institutions in the US had experiences with pancreas transplantations&#58; at the University of Colorado&#44; Merkel and Starzl performed one case of simultaneous kidney and pancreas transplantation&#44;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">14</span></a> and a second case at the University of California&#44; at the Irvine Medical Center&#44; under Connolly&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">15</span></a> In Europe&#44; the first pancreas transplantation was conducted at the Guy&#39;s Hospital in London by Bewick in 1972&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">16</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Until 1970&#44; only 25 pancreas transplantations had been done at 6 institutions worldwide&#46; Two-thirds of these experiences were conducted simultaneously with renal transplantations&#46; Out of all these cases&#44; only one case in the Lillehei series functioned for one year&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">In November 1971&#44; Gliedman performed his first transplant at the Montefiore Hospital in New York&#44; diverting the exocrine secretion through an anastomosis of the Wirsung duct with the native ureter&#46; With this technique&#44; this group carried out 11 transplantations in the 1970s&#44; with one case that functioned for 22 months and another for 50 months&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">17</span></a> In 1976&#44; Bewick&#44; once again at the Guy&#39;s Hospital in London&#44; conducted a pancreatic transplantation technique leaving the duct open&#46; Another similar case at the University of Minnesota done by Sutherland functioned with insulin independence for 18 months&#58; at that time&#44; it was the case with the longest graft survival&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">16&#44;18</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Until 1980&#44; only 105 pancreas transplantations had been carried out across the world&#44; half of which had been done in the US&#44; with active programs in Minnesota and the Montefiore Hospital in New York&#46; The other half had been performed in Europe&#44; where the most active programs were at the Huddinge Hospital in Stockholm &#40;Sweden&#41;&#44; headed by Groth&#44; and at the Eduard Herriot Hospital in Lyon &#40;France&#41;&#44; headed by Dubernard &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">In 1978&#44; Dubernad had developed a new technique&#44; injecting a polymer in the pancreatic duct &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>A&#41; to try to induce fibrosis and abolish the exocrine secretion and&#44; therefore&#44; the complications dependent on the exocrine pancreas&#46; The success of this ingenious technique encouraged other surgeons to utilize different polymers in the pancreatic duct&#44; such as prolamin&#44; used by Land in Munich&#44; polyisoprene&#44; used by MacMaster in Cambridge&#44; and silicone&#44; used by Sutherland at the University of Minnesota&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">19&#8211;21</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">In the 1980s&#44; at the University of Minnesota&#44; Sutherland developed a major pancreas transplantation program with live donors using segmental grafts&#44; whereas in transplants from cadaveric donors&#44; the model used was a pancreas-duodenal graft with intestinal bypass&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">22&#8211;24</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">In 1983&#44; Sollinger&#44; a German surgeon who went to the University of Wisconsin to work with Beltzer&#44; followed the experiences of Gliedman in New York and developed with good results a bladder diversion technique for exocrine secretions using anastomosis of the pancreas segment to the bladder&#46; This technique was perfected by Corry and Ngheim at the University of Iowa&#44; utilizing the bladder diversion of the entire pancreatic-duodenal graft by means of anastomosis of the duodenum with the bladder &#40;Fig 3C&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">25&#8211;27</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">With this technique&#44; in addition to a significant decrease in surgical complications&#44; it was possible to measure urine amylase levels as a marker of rejection &#40;Prieto&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">28</span></a> Therefore&#44; bladder diversion was the choice in many programs in the 1990s&#46; Despite this&#44; urinary complications &#40;urethritis&#44; hematuria&#44; metabolic acidosis&#44; urinary fistula&#44; etc&#46;&#41; caused some hospitals to reconvert many patients to intestinal diversion&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Simultaneously&#44; at the University of Pittsburgh in 1984&#44; Starzl had started a transplant program that returned to the original technique described by Lillehei using intestinal drainage&#46; Likewise&#44; the Stockholm group &#40;Groth and Tyden&#41; had already successfully developed intestinal diversion with a segmental graft &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>B&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">29&#8211;31</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Encouraged by the improved results&#44; at other medical centers in the US and Europe&#44; pancreas transplantation programs were successfully initiated with variations of certain technical aspects related with the type of graft&#44; the exocrine secretion diversion model and venous drainage of the graft&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">From the standpoint of immunosuppression&#44; Calne was the first to apply cyclosporine to pancreas transplantations at Cambridge&#44;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">32&#44;33</span></a> and Sutherland introduced quadruple therapy&#44; including induction therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">34</span></a> Starzl was the first to introduce tacrolimus in this transplant in 1989&#44;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">35</span></a> and in the mid-1990s mycophenolate mofetil was introduced by Sollinger&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">36</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">From a technical standpoint&#44; the diversion used in the decade of the 1990s was urinary&#44; whereas in the decade of 2000 the diversion was intestinal &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">Since then&#44; more than 50&#44;000 diabetic patients have received transplants at more than 200 medical centers worldwide&#44; with one-year patient survival rates of 95&#37; and graft survival rates greater than 85&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">37</span></a> The improvement of the results has been progressive thanks to a better knowledge of the particularities of this transplant type in all its stages&#44; from appropriate early indication to meticulous technique and&#44; especially&#44; the application of a more effective regimen of immunosuppressants&#46; The results are registered with the International Pancreas Transplant Registry &#40;IPTR&#41;&#44; founded by Sutherland&#44; who has been a University of Minnesota surgeon and <span class="elsevierStyleItalic">alma mater</span> in the world in this type of transplant for more than 30 years&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">38&#44;39</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">In Spain&#44; the first pancreas transplantation was performed on February 3&#44; 1983 by Dr Gil Vernet and Dr Fernandez-Cruz at the Hospital Cl&#237;nico y Provincial in Barcelona&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">40</span></a> Dr&#46; Gil Vernet had already performed the first successful kidney transplantation in our country and was very much aware of the trends in transplantation originating in other European countries and the US&#46; Therefore&#44; it was reasonable for this pioneer of renal transplantation in Spain&#44; together with a young Fern&#225;ndez-Cruz &#40;also a surgeon at the Hospital Cl&#237;nico in Barcelona&#41; to initiate this combined kidney and pancreas transplantation program&#46; Professor Fern&#225;ndez-Cruz had done an internship at the University of San Diego in the US&#46; He had also visited Dr&#46; Sutherland in Minneapolis and started the program that has been a leader in our country ever since&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The donor of this first transplant was a 17-year-old boy&#44; who had died as a result of a car accident&#59; the recipient was a 32-year-old patient with type I diabetes on renal dialysis for kidney failure&#46; The technique used was a kidney transplant in the left iliac fossa&#44; and a segmental pancreas transplantation with obliteration of the duct using prolamin in the right iliac fossa&#46; The patient survived 11 years and died of myocardial infarction&#46; The nephrology team was comprised of Dr&#46; Caralps and Dr&#46; Andreu&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">41</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">After this experience&#44; other centers in Spain&#44; including C&#243;rdoba &#40;Hospital Reina Sof&#237;a&#41;&#44; Santander &#40;Hospital Marqu&#233;s de Valdecilla&#41;&#44; Santiago de Compostela &#40;Hospital Universitario&#41;&#44; M&#225;laga &#40;Hospital Carlos Haya&#41;&#44; Madrid &#40;Hospital 12 de Octubre&#41;&#44; Tenerife &#40;University of the Canary Islands&#41;&#44; etc&#46;&#44; started pancreas transplantation programs&#46; At present&#44; there are 12 medical centers that have active programs that perform about 100 transplants per year&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">42&#44;43</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">In 2005&#44; a consensus meeting was organized by the National Transplant Organization in Spain&#46; Following a debate among the parties involved &#40;surgeons&#44; nephrologists&#44; endocrinologists&#44; transplant coordinators&#41;&#44; the criteria for indication&#44; prioritization&#44; organ distribution&#44; hospital planning and accreditation mechanisms were established in order to optimize the treatment of diabetes in our country&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">44&#8211;46</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">After 50 years of history&#44; we can say that pancreas transplantation has come a long way since its inception&#44; thanks to the work of pioneering surgeons who have gone beyond conventional practice in the search for solutions to the complications of diabetes&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The complexity of diabetic patients means that the benefits of these transplants are sometimes underestimated when compared with other procedures&#44; such as cardiac transplantation or liver transplantation&#44; in which graft function acquires vital connotations&#46; However&#44; today&#44; pancreas transplantation has the same results in terms of patient survival&#44; graft survival and quality of life as other solid organs &#40;<a class="elsevierStyleCrossRefs" href="#fig0020">Figs&#46; 4 and 5</a>&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0140" class="elsevierStylePara elsevierViewall">As long as we do not have procedures for the prevention of diabetes&#44; the solution for diabetic patients with risk of secondary complications will entail the replacement of functioning islet tissue by transplantation&#46; Answers for this substitution are likely to involve cell transplantation in the future&#44; but it is unquestionable that&#44; after 50 years of progress&#44; the fulfillment of these objectives involves vascularized pancreas transplantation&#46; The clinical project initiated by Lillehei and continued by Sutherland and hundreds of enthusiasts came of age years ago&#44; but it is time to pay homage to all those who dedicated part of their professional lives to try to improve the survival and quality of life of these patients &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 6</a>&#41;&#46;</p><elsevierMultimedia ident="fig0030"></elsevierMultimedia><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conflict of interests</span><p id="par0145" class="elsevierStylePara elsevierViewall">The author has no conflict of interests to declare</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">In December 1966&#44; the first pancreas transplant ever was performed at the University of Minnesota&#46; R&#46; Lillehei and W&#46; Kelly&#44; transplanted a kidney and a pancreas in a diabetic patient on dialysis&#44; getting function of both organs&#46; Since then&#44; the technical and immunological advances in this transplant have resulted in graft and patient survival results as the rest of the abdominal solid organ transplants&#46; The balance of these 50 years is that more than 50&#44;000 diabetic patients have been transplanted in more than 200 centers around the world&#46; In our country the first transplant was performed 34 years ago in Barcelona and now 12 centers perform about 100 transplants per year&#46; Although advances in diabetes control have been very important&#44; pancreas transplantation continues to be the only method that allows normalization of the carbohydrates metabolism to improve the quality of life and&#44; above all&#44; to increase the survival of these patients&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">En diciembre de 1966 se realiz&#243; en la Universidad de Minnesota el primer trasplante de p&#225;ncreas de la historia&#46; R&#46; Lillehei y W&#46; Kelly&#44; trasplantaron un ri&#241;&#243;n y un p&#225;ncreas a una paciente diab&#233;tica en di&#225;lisis&#44; consiguiendo funci&#243;n de ambos &#243;rganos&#46; Desde entonces los avances t&#233;cnicos e inmunol&#243;gicos en este trasplante&#44; han propiciado resultados en cuanto a supervivencia del injerto y del paciente superponibles al resto de los trasplantes de &#243;rganos s&#243;lidos abdominales&#46; El balance de estos 50 a&#241;os es que mas de 50&#46;000 pacientes diab&#233;ticos han sido trasplantados en mas de 200 centros en todo el mundo&#46; En nuestro pa&#237;s el primer trasplante se realiz&#243; hace 34 a&#241;os en Barcelona y ahora 12 centros realizan alrededor de 100 trasplantes por a&#241;o&#46; Aunque los avances en el control de la diabetes han sido muy importantes&#44; el trasplante de p&#225;ncreas contin&#250;a siendo el &#250;nico m&#233;todo que permite normalizar el metabolismo hidrocarbonado&#44; mejorar la calidad de vida y sobre todo aumentar la supervivencia de estos pacientes&#46;</p></span>"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Allotransplantation of the pancreas and duodenum along with the kidney in diabetic nephropathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "W&#46;D&#46; Kelly"
                            1 => "R&#46;C&#46; Lillehei"
                            2 => "F&#46;K&#46; Merkel"
                            3 => "Y&#46; Idezuki"
                            4 => "F&#46;C&#46; Goetz"
                          ]
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                    ]
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                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Surgery"
                        "fecha" => "1967"
                        "volumen" => "61"
                        "paginaInicial" => "827"
                        "paginaFinal" => "837"
                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/5338113"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
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                ]
              ]
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              "identificador" => "bib0240"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "ISBN&#58; O-9604606-7-5"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "History of transplantation&#58; Thirty-five recollections"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "UCLA Tissue Typing Laboratory"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:1 [
                      "Libro" => array:3 [
                        "fecha" => "1991"
                        "editorial" => "The Regents of the University of California"
                        "editorialLocalizacion" => "Los Angeles&#44; California"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0245"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Heterotopic dog pancreatic allografts"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "F&#46;K&#46; Merkel"
                            1 => "W&#46;D&#46; Kelly"
                            2 => "F&#46;C&#46; Goetz"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Surg Forum"
                        "fecha" => "1967"
                        "volumen" => "18"
                        "paginaInicial" => "381"
                        "paginaFinal" => "383"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
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              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Irradiated heterotopic segmental canine pancreatic allografts"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "F&#46;K&#46; Merkel"
                            1 => "W&#46;D&#46; Kelly"
                            2 => "F&#46;C&#46; Goetz"
                            3 => "J&#46; Maney"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Surgery"
                        "fecha" => "1968"
                        "volumen" => "63"
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                        "paginaFinal" => "297"
                      ]
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              ]
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            4 => array:3 [
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              "etiqueta" => "5"
              "referencia" => array:1 [
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Article information

ISSN: 21735077
Original language: English

DOI:10.1016/j.cireng.2017.02.002

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Year/Month	Html	Pdf	Total

2024 October	78	5	83
2024 September	187	7	194
2024 August	97	5	102
2024 July	100	15	115
2024 June	98	7	105
2024 May	85	24	109
2024 April	73	7	80
2024 March	103	9	112
2024 February	140	10	150
2024 January	169	3	172
2023 December	121	7	128
2023 November	157	6	163
2023 October	195	21	216
2023 September	98	8	106
2023 August	88	10	98
2023 July	134	6	140
2023 June	120	13	133
2023 May	182	8	190
2023 April	144	7	151
2023 March	105	16	121
2023 February	90	8	98
2023 January	145	25	170
2022 December	102	13	115
2022 November	121	13	134
2022 October	113	19	132
2022 September	117	23	140
2022 August	122	17	139
2022 July	100	16	116
2022 June	116	10	126
2022 May	128	33	161
2022 April	127	19	146
2022 March	170	15	185
2022 February	153	11	164
2022 January	206	14	220
2021 December	137	25	162
2021 November	120	52	172
2021 October	200	32	232
2021 September	169	17	186
2021 August	156	31	187
2021 July	102	27	129
2021 June	113	16	129
2021 May	126	13	139
2021 April	207	24	231
2021 March	144	16	160
2021 February	81	19	100
2021 January	107	14	121
2020 December	99	14	113
2020 November	128	15	143
2020 October	63	9	72
2020 September	92	22	114
2020 August	74	26	100
2020 July	86	12	98
2020 June	60	12	72
2020 May	97	19	116
2020 April	85	7	92
2020 March	87	6	93
2020 February	61	15	76
2020 January	68	7	75
2019 December	91	12	103
2019 November	64	18	82
2019 October	49	15	64
2019 September	75	19	94
2019 August	42	3	45
2019 July	58	33	91
2019 June	98	36	134
2019 May	227	86	313
2019 April	106	44	150
2019 March	25	7	32
2019 February	47	12	59
2019 January	40	5	45
2018 December	48	5	53
2018 November	50	7	57
2018 October	40	9	49
2018 September	52	6	58
2018 August	48	2	50
2018 July	22	3	25
2018 June	29	13	42
2018 May	38	1	39
2018 April	18	1	19
2018 March	5	0	5
2018 February	83	0	83
2018 January	35	1	36
2017 December	90	2	92
2017 November	26	1	27
2017 October	17	3	20
2017 September	13	1	14
2017 August	10	1	11
2017 July	0	3	3

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