轉化醫(yī)學與中國微創(chuàng)外科的發(fā)展

李 俊 郭 偉 張 軍 張忠濤

(首都醫(yī)科大學附屬北京友誼醫(yī)院普外科腫瘤侵襲和轉移機制研究北京市重點實驗室國家消化系統(tǒng)疾病臨床研究中心，北京100050)

1 Concept and development of translational medicine

The translational medicine(TM)was first introduced in 1992.Since then the definition of TM has been continuously improved.The core objective of TM is to translate basic scientific findings into therapeutic interventions for patients and to increase understanding of important disease processes，which should be regarded as a two-way road:Bench to Bedside and Bedside to Bench(B to B).

To prevent basic and clinical medicine being disjointed and fragmented，in the past 20 years，TM has received worldwide concern and attention.In the United States，the National Institutes of Health(NIH)launched the TM Award in 2006 and now invests about 500 million per year.The introduction of extramural collaborations in 2006 has resulted in partnerships between 74 institu-tions，27 of which are Clinical and Translational Science Award sites［1］.The European Strategic Forum on Research Infrastructures(ESFRI)was launched in April 2002.The field of biomedical and life sciences is one of the ESFRI-fields with very high societal impact，of which the European Advanced Translational Research Infra-Structure in Medicine(EATRIS)is one of the prioritized research infrastructures.EATRIS aims for faster and more efficient translation of basic research into innovative products，by providing academic and industry access to the state-of-the-art expertise and highly capital-intensive facilities residing in Europe's top translational research centers and hospitals.In 2012，EATRIS entered its construction phase.A legal framework was devised for EATRIS，and an agreement made by the participating countries. The firstpilotprojects have been started in 2013［2］.

In China，Central South University established a“Xiangya TM Center”in 2009.During the first six months of 2010，at least seven institutes or centers for TM were established in China，amongst which the Union Center for TM can be considered a further milestone toward the development of TM in China as pronounced by Professor Zhu Chen，minister of Ministry of Health of China［3］.In 2011，the Chinese government，in the “Twelfth Five Year Development Plan”report，put forward that the investment of TM would reach 20 billion Chinese yuan.This has greatly accelerated the development of TM in China.Throughout the history of the development of medicine，TM has promoted the transformation of basic medicine to clinical medicine and the development of medicine.Similarly，the development of minimally invasive surgery has benefited from the B to B mode of TM.

2 History of the development of minimally invasive surgery(MIS)

MIS which is also called minimal access surgery(MAS)is redefining the field of surgery.This term is used to describe a number of surgeries as well as diagnostic procedures.MIS includes both laparoscopy(surgery through small holes)and endoscopy(diagnostic and therapeutic procedures performed through the body's organs and vessels).With MIS，the surgeon makes a few small holes，usually less than 1/2 an inch in diameter.Following this，specifically designed instruments are inserted through these small opening with sophisticated video equipment being used to perform the operation.The benefits of MIS include less pain，quicker return to normal activities and less tissue damage than with traditional surgeries［4］.The development of MIS， from clinical needs to repeated animal experiments and then to clinical applications，follows the B to B mode.

On 23rd September 1901，at the 73rd meeting of the Society of German Natural Scientists and Physicians in Hamburg，the surgeon and gastroenterologist Georg Kelling from Dresden performed a laparoscopy on a dog，following his lecture on“The inspection of the gullet and the stomach with flexible instruments”.He called this procedure coelioscopy.Kelling's ingenious idea to connect his oral insufflation device with the Fiedler trocar and the Nitze cystocope，led to the coelioscopy in 1901 and marked the birth of laparoscopy.Until today，Georg Kelling has not experienced the appreciation he is entitled to.He is the forgotten pioneer of a method that today plays an important role in diagnostics and therapeutics［5］.

With the accumulative experiences of animal experiments，Hans C Jacobeus performed the first human laparoscopies and thoracoscopies in 1909.Although limited to the diagnosis，it marked the milestone of the laparoscope being stepped up from basic experiments to clinical applications.In 1918，the importance of pneumoperitoneum was recognized after Goetze's works of his inflating needle.In 1938，Janos Veress developed a needle with a safety tip for the practice of therapeutic pneumothorax in tuberculosis.In 1953，Hopkins led the invention of the cylindrical lenses system，which provided images with a greater clarity，brightness and color.The real advances in instrumentation and techniques of laparoscopic surgery were made by Kurt Semm in the 1960s to the 1980s whistdeveloping an automatic insufflator with a pressure monitor and many devices for laparoscopy.In 1980，Camran Nezhat carried out the first vedio-laparoscopic operation.Familiar with Semm's work，Erich Mühe took interest in surgery of the gallbladder and designed a new laparoscope，called the“Galloscope”.The tube diameter was larger and had a system for indirect vision and valves that prevented the loss of gas.On September 12th，1985，Mühe performed the first laparoscopic cholecystectomy(LC)in the world.Throughout this time，laparoscopic visualization was restricted exclusively to the surgeon.The greatest advance in this field was the development and coupling of the mini video-camera in 1987，which allowed assistants to observe surgeries and help more efficiently.Thus，in 1987，Philippe Mouret performed the first video-LC.In subsequent years，Dubois published the first series of laparoscopic cholecystectomies and performed a numerous laparoscopic procedures，developing new techniques such as vagotomy in the treatment of ulcers in 1989.

Since the 1990s，the MIS has gone through three stages.In the early 1990s，MIS focused on the benign lesions excision and abdominal organ repair，such as LC.In the late 1990s，MIS focused on the laparoscopic resection of gastrointestinal malignancies.In the early 2000s，MIS entered the era of laparoscopic resection of digestive system cancers，such as liver and pancreas［6］.In recent years，MIS is evolving from the porous laparoscopic operation to the single port laparoscopic operation and naturalorifice transluminalendoscopic surgery(NOTES)without scarring on the skin.The Da Vinci robotic surgery system，as the representative of robotic surgical systems in laparoscopic surgery，has shown a series of advantages in the past few years.Hand-assisted laparoscopic surgery(HALS)is a hybrid laparoscopic technique，incorporating elements of both the laparoscopic and the traditional open techniques.The most important advantage of HALS is that the surgeon regains tactile feedback.Surgeons can palpate the tumor or organs，and the surgeons'hand can be used for blunt dissection，retraction，control of bleeding，and specimen removal［7］.

3 TM and the development of MIS in China

Following many animal experiments，the doctors from Hong Kong and Taiwan carried out the first LC in 1990.Laparoscopic surgery in the mainland of China began in 1991，when Dr.Xun Zuwu from the Second Hospital of Qujing City in Yunnan Province successfully performed the first LC.From then on，the implementation of laparoscopic techniques have increased rapidly all over China.The first series of laparoscopic colorectal resection was reported by authors of Shanghai Ruijin Hospital in 1993.Laparoscopic subtotal gastrectomy was first reported by Shanghai Changhai Hospital in 1995.Laparoscopic pancreaticoduodenectomy was first reported by Shanghai Ruijin Hospital in 2004 showing that Chinese surgeons had the ability to undertake most complex surgical procedures except for liver transplantation［8］.

Meanwhile，the basic and experimental researches which were carried out with clinical application of laparoscopic provide a theoretical basis.By comparative study of parameters of traditional and laparoscopy surgery，such as serum immunoglobulins，lymphocyte subsets，cytokines，complement，glucose，insulin and plasma amino acid spectra showed that the impact of laparoscopic surgery on neuroendocrine，metabolism，humoral and cellular immunity，inflammation，etc.is less than traditional surgery.Preliminary results of a multicenter randomized controlled trial have shown that there is no significant difference in the patient's 5-year survival，recurrence rate and implantation rate，etc.between laparoscopic surgery and traditional surgery.The results confirms the safety of laparoscopic surgery and promotes the development of minimally invasive surgery.Today，minimally invasive techniques have been used almost in all fields of general surgery including colorectal，gastric，hepatic，pancreatic，thyroid and mammary surgeries.

In order to accelerate the development of MIS，laparoscopic training of young doctors is imminent，many domestic medical centers established many laparoscopic simulation training bases.Laparoscopic skill can be measured objectively in a simulator，and performance improves progressively with practice.These skills also can be incorporated into the training and evaluation of young doctors in laparoscopic surgery.This laparoscopic training is very convenient and efficient.Meanwhile，surgeons can do lots of laparoscopic experiments on animals before the implementation of the new surgical procedure.It is a model of TM applications.

So far，the Laparoscopic and Endoscopic Surgery Group of Chinese Medical Association has developed in-dependently or jointly endoscopic operations or laparoscopic operations guidelines of the gallbladder，biliary tract，colorectal cancer，gastric cancer，metabolic diseases，etc.In 2010，the Ministry of Health issued“Diagnosis and Treatment Guidelines of Gastric Cancer，”and“Diagnosis and Treatment Guidelines of Colorectal Cancer”.The two guidelines indicated the importance of laparoscopy surgery.In 2012，the Ministry of Health held a diagnostic and therapeutic endoscopic management and technology exchange conference which standardized training and access system for MIS.This has greatly accelerated the development of MIS［9］.

4 Development of NOTES and laparoscopic techniques

With the development of laparoscopic techniques，the next step of improvement laparoscopic surgery was to move toward the use of fewer trocars or even the use of natural orifices as access points that could conceal the scar of the incision.Moreover，recent evidence showed that the reduction in ports results in reduced operative morbidity［10］.Defined as the acronym NOTES for“Natural Orifice Translumenal Endoscopic Surgery”，the first description of NOTES in animals was made by the Kalloo group in 2004，communicating their successes on a porcine model to which a peritoneoscopy and liver biopsy by the transgastric route had been made［11］.Postoperative peritonitis and gastrointestinal complications of leakage did not occur，and it confirmed the feasibility of NOTES.

In the following year，several groups described various techniques in animal models that awakened interest in the feasibility and reproducibility of NOTES.Kaloo's group［12］reports its satisfactory results performing tubal ligation and transgastric gastrojejunostomies and Thompson's group［13］does the same with their abdominal exploration transgastric experiences and the resection of gynecological organs.In connection with the transgastric cholecystectomy，also in 2005，the groups of Swanstrom and Park［14-15］successfully performed cholecystectomies and transgastric cholecystogastrostomies with flexible endoscopes.In 2006，Reddy and Rao reported the first human appendectomy by the transgastric route:this intervention aroused wide interest in the clinical application of NOTES［16］.On April 2 nd 2007，at the University Hospital of Strasbourg，Professor Jacques Marescaux successfully performed the first no scar surgery.This first human incisionless operation was carried out using a flexible endoscope for transvaginal cholecystectomy in a 30-year-old woman with symptomatic gallstones.In 2007，after almost 10 years of research，NOTES has evolved from concept to clinical practice［17］.

The laparoendoscopic single site surgery(LESS)using the umbilicus as an access site pioneered by the gynecologists in the 1960s and 1970s，goes back to the operative resectoscope developed by Buess in the 1980s.Nevertheless，the technology of that time did not provide the background for the development of the approach.The first report concerning LESS was by Raman et al.who performed a single umbilical incision nephrectomy in four pigs(eight renal units).The initial two LESS clinical urological cases(a simple nephrectomy and an ureterolithotomy)were reported by Rane as an abstract at the World Congress of Endourology in 2007.Since these first reports，a great amount of clinical experience with LESS has being accumulated with most ablative and reconstructive procedures in general surgery feasible through use of the LESS approach.Careful patient selection，experienced surgeons，and improved instrumentation led to further clinical investigation into LESS.

In 2008，Beijing Friendship Hospital reported the first complete transumbilical single port LC using the novel trichannel port.Based upon this technique，laparoscopic appendectomy，laparoscopic hepatic cyst fenestration，resection of the ileocecal junction and resection of hepatobiliary cystadenoma in the left lateral lobe by single incision with conventional laparoscopic instruments were performed firstly in China［8，18-19］.On August 1，2009，the Chinese NOTES Study Group(C-NOTES)was established in Shanghai，which is a landmark for Chinese MIS and a new start-point for NOTES in China.In August 2010，Laparoscopic and Endoscopic Surgery Group of Chinese Medical Association issued the“Experts Consensus of LESS”and“Experts Consensus of Laparoscopic and Endoscopic Combined Techniques in Gastrointestinal Surgery”.This is not only the first publication about the surgical technique guidance，but also the first fruits of C-NOTES.

TM is a branch of medicine developed in recent years，whose aim is to apply basic medical research results quickly into clinical applications.The development of MIS always follows the principle of the clinic to clinic，which is the B to B mode.The most important issue at this time is how we improve the conversion rate of basic medicine to clinical medicine.

［1］ The National Institutes of Health(NIH)Clinical Center［EB/OL］.［2014-01-02］.http://www.cc.nih.gov/ccc/btb/#slide_text.2013.

［2］ Van Dongen G A，Ussi A E，de Man F H，et al.EATRIS，a European initiative to boost translational biomedical research［J］.Am J Nucl Med Mol Imaging，2013，3(2):166-174.

［3］ Wang X D，Wang E，F(xiàn)rancesco M M.Translational medicine is developing in China:a new venue for collaboration［J］.J Transl Med，2011，9:3.

［4］ The University of Chicago Medicine［EB/OL］.［2014-01-02］.http://www.uchospitals.edu/specialties/minisurgery/mis.html.2013.

［5］ Schollmeyer T，Soyinka A S，Schollmeyer M，et al.Georg Kelling(1866-1945):the root of modern day minimal invasive surgery.A forgotten legend? ［J］.Arch Gynecol Obstet，2007，276(5):505-509.

［6］ 鄭民華.腹腔鏡技術的現(xiàn)狀與展望［J］.中國實用外科雜志，2010，30(3):164-166.

［7］ Orenstein S B，Elliott H L，Reines L A，et al.Advantages of the hand-assisted versus the open approach to elective colectomies［J］.Surg Endosc，2011，25(5):1364-1368.

［8］ Guo W，Zhang Z T.Laparoscopic surgery in the mainland of China［J］.Chin Med J:Engl，2009，122(19):2226-2228.

［9］ 鄭民華.中國腹腔鏡外科的現(xiàn)狀與進展［J］.中華腔鏡外科雜志:電子版，2010，3(1):1-6.

［10］ Pini G，Porpiglia F，Micali S，et al.Minilaparoscopy，needlescopy and microlaparoscopy:decreasing invasiveness，maintaining the standard laparoscopic approach［J］.Arch Esp Urol，2012，65(3):366-383.

［11］ Kalloo A N，Singh V K，Jagannath S B，et al.Flexible transgastric peritoneoscopy:a novel approach to diagnostic and therapeutic interventions in the peritoneal cavity［J］.Gastrointest Endosc，2004，60(1):114-117.

［12］ Kantsevoy S V，Jagannath S B，Niiyama H，et al.Endoscopic gastrojejunostomy with survival in a porcine model［J］.Gastrointest Endosc，2005，62(2):287-292.

［13］ Wagh M S，Merrifield B F，Thompson C C.Endoscopic transgastric abdominal exploration and organ resection:initial experience in a porcine model［J］.Clin Gastroenterol Hepatol，2005，3(9):892-896.

［14］ Swanstrom L L，Kozarek R，Pasricha P J，et al.Development of a new access device for transgastric surgery［J］.J Gastrointest Surg，2005，9(8):1129-1136.

［15］ Park P O，Bergstr?m M，Ikeda K，et al.Experimental studies of transgastric gallbladder surgery:cholecystectomy and cholecystogastric anastomosis(videos)［J］.Gastrointest Endosc，2005，61(4):601-606.

［16］ Reddy D N，Rao G V.Transgastric approach to the peritoneal cavity:are we on the right track? ［J］.Gastrointest Endosc，2005，61(4):601-606.

［17］ 周曉娜，張忠濤.經臍單孔腹腔鏡外科技術應用現(xiàn)狀和展望［J］.中國實用外科雜志，2009，29(1):42-43.

［18］ Guo W，Zhang Z T，Han W，et al.The application status and prospects of transumbilical laparoendoscopic single site surgery［J］.Chin Med J:Engl，2008，121(23):2463-2464.

［19］ Cai J，Zhang Z T，Sun J，et al.Transumbilical single-incision laparoscopic resection of ileocecal junction for benign disease:first report of two cases［J］.Surg Innov，2011，18(2):189-192.