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Hamed OH, Gusani NJ, Kimchi ET, Kavic SM. Minimally invasive surgery in gastrointestinal cancer: benefits, challenges, and solutions for underutilization. JSLS 2016; 18:JSLS.2014.00134. [PMID: 25489209 PMCID: PMC4254473 DOI: 10.4293/jsls.2014.00134] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Background and Objectives: After the widespread application of minimally invasive surgery for benign diseases and given its proven safety and efficacy, minimally invasive surgery for gastrointestinal cancer has gained substantial attention in the past several years. Despite the large number of publications on the topic and level I evidence to support its use in colon cancer, minimally invasive surgery for most gastrointestinal malignancies is still underused. Methods: We explore some of the challenges that face the fusion of minimally invasive surgery technology in the management of gastrointestinal malignancies and propose solutions that may help increase the utilization in the future. These solutions are based on extensive literature review, observation of current trends and practices in this field, and discussion made with experts in the field. Results: We propose 4 different solutions to increase the use of minimally invasive surgery in the treatment of gastrointestinal malignancies: collaboration between surgical oncologists/hepatopancreatobiliary surgeons and minimally invasive surgeons at the same institution; a single surgeon performing 2 fellowships in surgical oncology/hepatopancreatobiliary surgery and minimally invasive surgery; establishing centers of excellence in minimally invasive gastrointestinal cancer management; and finally, using robotic technology to help with complex laparoscopic skills. Conclusions: Multiple studies have confirmed the utility of minimally invasive surgery techniques in dealing with patients with gastrointestinal malignancies. However, training continues to be the most important challenge that faces the use of minimally invasive surgery in the management of gastrointestinal malignancy; implementation of our proposed solutions may help increase the rate of adoption in the future.
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Affiliation(s)
- Osama H Hamed
- Department of Surgery, King Hussein Cancer Center, Amman, Jordan
| | - Niraj J Gusani
- Department of Surgery, Penn State Cancer Center, Hershey, PA, USA
| | - Eric T Kimchi
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Stephen M Kavic
- Department of Surgery, University of Maryland, Baltimore, MD, USA
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Lingohr P, Dohmen J, Matthaei H, Schwandt T, Hong GS, Konieczny N, Bölke E, Wehner S, Kalff JC. Development of a standardized laparoscopic caecum resection model to simulate laparoscopic appendectomy in rats. Eur J Med Res 2014; 19:33. [PMID: 24934381 PMCID: PMC4094547 DOI: 10.1186/2047-783x-19-33] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Accepted: 05/20/2014] [Indexed: 01/08/2023] Open
Abstract
Background Laparoscopic appendectomy (LA) has become one of the most common surgical procedures to date. To improve and standardize this technique further, cost-effective and reliable animal models are needed. Methods In a pilot study, 30 Wistar rats underwent laparoscopic caecum resection (as rats do not have an appendix vermiformis), to optimize the instrumental and surgical parameters. A subsequent test study was performed in another 30 rats to compare three different techniques for caecum resection and bowel closure. Results Bipolar coagulation led to an insufficiency of caecal stump closure in all operated rats (Group 1, n = 10). Endoloop ligation followed by bipolar coagulation and resection (Group 2, n = 10) or resection with a LigaSure™ device (Group 3, n = 10) resulted in sufficient caecal stump closure. Conclusions We developed a LA model enabling us to compare three different caecum resection techniques in rats. In conclusion, only endoloop closure followed by bipolar coagulation proved to be a secure and cost-effective surgical approach.
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Affiliation(s)
- Philipp Lingohr
- Department of General, Visceral, Thoracic and Vascular Surgery, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
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Huang SG, Li YP, Zhang Q, Redmond HP, Wang JH, Wang J. Laparotomy and laparoscopy diversely affect macrophage-associated antimicrobial activity in a murine model. BMC Immunol 2013; 14:27. [PMID: 23786397 PMCID: PMC3711975 DOI: 10.1186/1471-2172-14-27] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2013] [Accepted: 06/18/2013] [Indexed: 02/08/2023] Open
Abstract
Background Surgical intervention-related trauma contributes largely to the development of postoperative immunosuppression, with reduced resistance to secondary bacterial infection. This study compared the impact of laparotomy versus laparoscopy on macrophage-associated bactericidal ability and examined whether laparotomy renders the host more susceptible to microbial infection. Results BALB/c mice were randomized into control, laparotomy, and laparoscopy groups. Laparotomy, but not laparoscopy, significantly downregulated CR3 expression on macrophages, diminished macrophage-induced uptake and phagocytosis of E. coli and S. aureus, and impaired macrophage-mediated intracellular bacterial killing. Consistent with this, mice that underwent laparotomy displayed substantially higher bacterial counts in the blood and visceral organs as well as a significantly enhanced mortality rate following bacterial infection, whereas mice subjected to laparoscopy did not show any defects in their bacterial clearance. Conclusion Laparotomy has an adverse effect on host innate immunity against microbial infection by impairing macrophage-mediated phagocytosis and killing of the invaded bacteria. By contrast, laparoscopy appears to preserve macrophage-associated bactericidal ability, thus alleviating the development of postoperative immunosuppression.
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Affiliation(s)
- Shun Gen Huang
- Department of Pediatric Surgery, Affiliated Children's Hospital, Soochow University, Suzhou, China
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Pucher P, Sodergren MH, Alkhusheh M, Clark J, Jethwa P, Teare J, Yang GZ, Darzi A. The effects of natural orifice translumenal endoscopic surgery (NOTES) on cardiorespiratory physiology: a systematic review. Surg Innov 2012; 20:183-9. [PMID: 22991384 DOI: 10.1177/1553350612460767] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Despite the increasing awareness of natural orifice translumenal endoscopic surgery (NOTES), there remain obstacles to its wider implementation. We aim to examine the current evidence for the effects of variable uncontrolled insufflation pressures using either air or carbon dioxide in NOTES, as well the effects of NOTES procedures themselves, on physiological parameters. METHOD We undertook a systematic review of all publications relating to the effects of NOTES on physiology, in particular compared with laparoscopy. RESULTS Eleven reports were identified comprising comparative trials involving a total of 237 pigs. With one exception, no difference was found between the effect of NOTES and laparoscopic surgery on cardiopulmonary parameters. No difference was found also for the effect on inflammatory mediators such as interleukin-6. Two studies also assessed the effects choice of insufflation gas, with no change in inflammatory markers. Two further studies assessing the effects of variable pneumoperitoneal pressures found negative cardiorespiratory effects with higher pressures. DISCUSSION Existing evidence is limited to small-sample animal trials but appears to show noninferiority for NOTES compared with laparoscopy. The development of a pressure regulation device for NOTES must be considered.
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Nair CK, Kothari KC. Role of diagnostic laparoscopy in assessing operability in borderline resectable gastrointestinal cancers. J Minim Access Surg 2012; 8:45-9. [PMID: 22623825 PMCID: PMC3353612 DOI: 10.4103/0972-9941.95533] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2010] [Accepted: 03/23/2011] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND: Diagnostic laparoscopy helps in diagnosing and staging Gastrointestinal (GI) cancers. Routine laparoscopy before laparotomy, especially in cancers that have equivocal operability, helps to avoid unnecessary laparotomies. Present study evaluates utility of laparoscopy in diagnosing and staging GI cancers. MATERIALS AND METHODS: Diagnostic laparoscopy was done in 41 patients with gastrointestinal (GI) cancers who were thought to have equivocal operability. Patients with suspected or known non-metastatic GI cancers, in whom resectability was found doubtful by clinical assessment and pre-operative imaging, were included. Patients with non-GI cancers (lymphoma, gynaecologic cancers, genitourinary cancers, retroperitoneal sarcoma, sarcoma and abdominal metastasis of non-GI cancers) and metastatic cancers which were beyond the scope of curative surgery were excluded from the study. RESULTS: After diagnostic laparoscopy (DL) five patients had benign diagnosis. Out of 36 patients with malignant diagnosis, after DL, 22 patients (61.1%) were inoperable, 11 patients (30.6%) were operable, and three (8.3%) patients were of equivocal operability. Sensitivity, specificity, positive predictive value, and negative predictive value of laparoscopy in detecting operability were 100%, 91.7%, 81.8%, and 100%, respectively. CONCLUSIONS: Laparoscopy helped in a significant number of patients with advanced GI cancers to avoid laparotomy. The morbidity of DL was acceptable.
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Affiliation(s)
- Chandramohan K Nair
- Department of Surgical Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
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6
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Moehrlen U, Lechner A, Bäumel M, Dostert K, Röhrl J, Meuli M, Männel DN, Hamacher J. Immune cell populations and cytokine production in spleen and mesenteric lymph nodes after laparoscopic surgery versus conventional laparotomy in mice. Pediatr Surg Int 2012; 28:507-13. [PMID: 22426493 DOI: 10.1007/s00383-012-3070-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/05/2012] [Indexed: 10/28/2022]
Abstract
PURPOSE There is evidence that open as well as minimally invasive abdominal surgery impair post-operative innate and acquired immune function. To compare the impact of these approaches as well as the one of different peritoneal gas exposures on immune function, we investigated cellular as well as cytokine-based immune parameters in mesenteric lymph nodes and the spleen postoperatively. METHODS Mice (n = 26) were randomly assigned to the 4 study groups: (1) sham controls undergoing anesthesia alone, (2) laparotomy, and (3) air, or (4) carbon dioxide pneumoperitoneum. Mice were sacrificed 48 h after the intervention, and their spleens and mesenteric lymph nodes were harvested. Cytokine production (TNF-α, IL-6, IL-10, and IFN-γ), splenic T cell subpopulations (cytotoxic T cells, T helper cells, and regulatory T cells) were analyzed. RESULTS TNF-α production of splenocytes 16 h after ex vivo lipopolysaccharides (LPS) stimulation was significantly increased in the laparotomy group compared to all other groups. In contrast, TNF-α production of lymph node cells and IL-6 production of splenocytes after ex vivo LPS stimulation did not differ significantly between the groups. The numbers of regulatory T cells (Treg) in the spleen differed between groups. A significant reduction in Treg cell frequency was detected in the CO(2) insufflation group compared to the laparotomy and the air insufflation group. CONCLUSION Our findings demonstrate a distinct difference in immune effector functions and cellular composition of the spleen with regard to splenic TNF-α production and increased numbers of Treg cells in the spleen. These findings are in line with a higher peritoneal inflammatory status consequent to peritoneal air rather than CO(2) exposure. Treg turned out to be key modulators of postoperative dysfunction of acquired immunity.
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Affiliation(s)
- Ueli Moehrlen
- Department of Pediatric Surgery, University Children's Hospital Zurich, Steinwiesstr. 75, 8032, Zurich, Switzerland.
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Moran E, Hanes M, Huebner M, Gostout CJ, Bingener J. Pulmonary and peritoneal inflammatory findings in transgastric NOTES compared with laparoscopy: pooled analysis from randomized porcine survival studies. Gastrointest Endosc 2011; 74:1103-7. [PMID: 21890136 DOI: 10.1016/j.gie.2011.06.031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2011] [Accepted: 06/23/2011] [Indexed: 12/11/2022]
Abstract
BACKGROUND Laparoscopy, which is a minimally invasive surgery, is associated with decreased peritoneal adhesions and inflammatory response compared with laparotomy. OBJECTIVE To evaluate whether natural orifice transluminal endoscopic surgery (NOTES) leads to an attenuated peritoneal response compared with laparoscopy. DESIGN Pooled histologic analysis from 2 randomized porcine trials. SETTING Laboratory. INTERVENTION Histologic analysis of swine undergoing diagnostic laparoscopy, diagnostic NOTES peritoneoscopy, NOTES with transgastric mesh placement, or diagnostic endoscopy (no gastrotomy) followed by laparoscopic mesh placement. MAIN OUTCOME MEASUREMENTS The presence and grade of inflammation in necropsy specimens of lung, liver, and spleen as reviewed by a blinded veterinary pathologist. RESULTS Four NOTES mesh animals exhibited mesh infections at necropsy. Tissue from 48 swine were available for analysis. Pulmonary inflammation, liver fibrosis, and spleen capsulitis were the primary findings. No difference was seen in the incidence of each finding among groups. The severity of the pulmonary inflammation in the laparoscopy group was significantly higher than in the NOTES groups. The NOTES mesh group exhibited significantly more severe liver fibrosis and spleen capsulitis. There was no difference between clinical behavior, serum white blood cell count, or peritoneal white blood cell count among groups in either study. Intra-abdominal pressures during NOTES were lower than during laparoscopy. LIMITATIONS Pooled analysis of 2 separate studies. CONCLUSION More severe pulmonary inflammation was found in animals undergoing longer laparoscopic procedures with higher intra-abdominal pressures. Intraperitoneal inflammation was most significant with transgastric mesh placement, likely caused by infections.
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Affiliation(s)
- Erica Moran
- Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA
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Ayers AS, Lee SW. Physiology, Immunologic and Metabolic Responses to Laparoscopic Surgery. SEMINARS IN COLON AND RECTAL SURGERY 2010. [DOI: 10.1053/j.scrs.2010.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Lee SW, Whelan RL. Immunologic and oncologic implications of laparoscopic surgery: what is the latest? Clin Colon Rectal Surg 2010; 19:5-12. [PMID: 20011447 DOI: 10.1055/s-2006-939525] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Laparoscopic surgery has been associated with many short-term benefits such as a shorter time to recovery, return of bowel function, less pain, and a decrease in wound infection rate. Several animal and human experiments have demonstrated an immunologic and oncologic benefit of minimally invasive surgery. Whether these results will translate into similar results in human settings is unclear. Although the first published prospective randomized clinical trial suggests better long-term outcomes for patients undergoing laparoscopic surgery, results from other ongoing randomized, controlled clinical trials are needed to verify this controversial result.
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Affiliation(s)
- Sang W Lee
- Department of Surgery, New York Presbyterian Hospital, Weill Medical College of Cornell University, New York, NY 10021, USA.
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Goldfarb M, Brower S, Schwaitzberg SD. Minimally invasive surgery and cancer: controversies part 1. Surg Endosc 2010; 24:304-34. [PMID: 19572178 PMCID: PMC2814196 DOI: 10.1007/s00464-009-0583-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2009] [Accepted: 05/14/2009] [Indexed: 12/17/2022]
Abstract
Perhaps there is no more important issue in the care of surgical patients than the appropriate use of minimally invasive surgery (MIS) for patients with cancer. Important advances in surgical technique have an impact on early perioperative morbidity, length of hospital stay, pain management, and quality of life issues, as clearly proved with MIS. However, for oncology patients, historically, the most important clinical questions have been answered in the context of prospective randomized trials. Important considerations for MIS and cancer have been addressed, such as what are the important immunologic consequences of MIS versus open surgery and what is the role of laparoscopy in the staging of gastrointestinal cancers? This review article discusses many of the key controversies in the minimally invasive treatment of cancer using the pro-con debate format.
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Affiliation(s)
| | - Steven Brower
- Memorial Health University Medical Center, Savanna, GA USA
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Donigan M, Norcross LS, Aversa J, Colon J, Smith J, Madero-Visbal R, Li S, McCollum N, Ferrara A, Gallagher JT, Baker CH. Novel murine model for colon cancer: non-operative trans-anal rectal injection. J Surg Res 2008; 154:299-303. [PMID: 19101690 DOI: 10.1016/j.jss.2008.05.028] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2008] [Revised: 05/16/2008] [Accepted: 05/21/2008] [Indexed: 02/06/2023]
Abstract
BACKGROUND This study was conducted to develop a modified murine model of colon cancer that is non-operative. Currently, the most accurate orthotopic murine model of colon cancer requires an invasive procedure involving cecal injection of colon cancer cells and therefore limits the ability to perform immunological studies subsequent to cecal resections. MATERIALS AND METHODS Murine colon cancer (CT26) cells were injected submucosally into the distal, posterior rectum of BALB/c mice. Care was taken not to pass transmurally into the pelvic cavity. Different magnifications (10x versus 100x) were used for injection, and primary tumor growth and metastatic disease were studied. RESULTS In the initial study, 3/7 mice injected using 10x magnifications had notable, large tumor originating from the rectal wall, and histology revealed that all excised tumors were poorly differentiated adenocarcinoma. In the second study, 8/10 mice injected using 100x magnifications had notable tumor originating from the rectal well, and 4/8 mice had abnormal lung tissue with pathological evidence of hemorrhagic pulmonary edema. The use of 10x magnification resulted in 43% tumor take. In sharp contrast, 80% tumor take was observed with 100x magnification. The overall success of tumor take was 65% using the trans-anal rectal injection model. CONCLUSIONS Our modified orthotopic murine model of colon cancer offers an alternative non-operative murine model for colon cancer and is less invasive than the traditional orthotopic model (i.e., cecal injection). This model may allow for more accurate investigations of inflammation and immune responses to surgical intervention without the influence of previous abdominal surgery.
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Affiliation(s)
- Melissa Donigan
- Cancer Research Institute of M. D. Anderson Cancer Center Orlando, Orlando, Florida 32806, USA
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Abstract
PURPOSE OF REVIEW The aim of this article is to provide an overview of the incidence, pathophysiology, risk factors and possible methods of reducing the risk of port site metastases following uro-oncological procedures. RECENT FINDINGS To our knowledge, 28 cases of port site metastasis have been reported in the urologic literature. There has been an increased interest in the use of intraperitoneal instillation of various tumoricidals in order to reduce the risk of port site seeding. SUMMARY The risk of port site metastases remains low, provided that surgeons rigorously adhere to the principles of oncological surgery.
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Whelan RL. What Does It All Mean? SEMINARS IN COLON AND RECTAL SURGERY 2007. [DOI: 10.1053/j.scrs.2007.10.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Feingold DL. Plasma Protein Alterations Associated with Surgery. SEMINARS IN COLON AND RECTAL SURGERY 2007. [DOI: 10.1053/j.scrs.2007.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Allendorf J. Oncologic Impact of Surgery in the Early Postoperative Period. SEMINARS IN COLON AND RECTAL SURGERY 2007. [DOI: 10.1053/j.scrs.2007.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Yoo J, Lee S. Immunologic Ramifications of Minimally Invasive Surgery. SEMINARS IN COLON AND RECTAL SURGERY 2007. [DOI: 10.1053/j.scrs.2007.10.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Sylla P. Microarray Studies of Immune Function After Surgery. SEMINARS IN COLON AND RECTAL SURGERY 2007. [DOI: 10.1053/j.scrs.2007.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Corrigan M, Cahill RA, Redmond HP. The immunomodulatory effects of laparoscopic surgery. Surg Laparosc Endosc Percutan Tech 2007; 17:256-61. [PMID: 17710044 DOI: 10.1097/sle.0b013e318059b9c3] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Laparoscopic alternatives to conventional surgical procedures confer many advantages to patients including reduced postoperative pain, shortened convalescence and, perhaps, improved disease-related outcomes. The diminished degree of immune dysfunction apparent with these techniques may underpin these beneficial aspects. However, minimal access is accompanied by various ancillary anesthetic and mechanical associations (including the induction of a carbon dioxide pneumoperitoneum), which must be considered in addition to reduced tissue trauma when attempting to correlate cause with effect. Furthermore, the opportunity to establish causation between the immunomodulatory aspects of laparoscopy and subsequent clinical outcome by prospective, randomized study is difficult because of the rapid incorporation of minimal access techniques into clinical practice. Therefore, experimental in vitro and in vivo studies must be used to complement the limitations of clinical studies in this area. Although the initial investigations into the immunological effects of laparoscopy are encouraging, many of the intricacies associated with this approach still await elaboration.
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Affiliation(s)
- Mark Corrigan
- Department of Academic Surgery, Cork University Hospital, Wilton, Cork, Ireland
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Carter JJ, Feingold DL, Oh A, Kirman I, Wildbrett P, Stapleton G, Asi Z, Fowler R, Bhagat G, Huang EH, Fine RL, Whelan RL. Perioperative immunomodulation with Flt3 kinase ligand or a whole tumor cell vaccine is associated with a reduction in lung metastasis formation after laparotomy in mice. Surg Innov 2006; 13:41-7. [PMID: 16708154 DOI: 10.1177/155335060601300107] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
INTRODUCTION Laparotomy has been associated with temporary postoperative immunosuppression and accelerated tumor growth in experimental models. In a previous murine study, a whole cell vaccine plus the adjuvant monophosphoryl-lipid A was shown to be effective in decreasing the number of lung metastases that develop after laparotomy. This study was conducted to assess the impact of the adjuvant fetal liver tyrosine kinase 3 (Flt3) ligand on perioperative tumor growth when used alone or with a tumor cell vaccine. METHODS An intravenous tumor cell injection lung metastases model was used. Sixty female A/J mice were divided into six equal groups designated (1) anesthesia control (AC), (2) AC with Flt3 ligand (ACFlt3), (3) sham laparotomy (OP), (4) OP with Flt3 ligand (OPFlt3), (5) OP with vaccine (OPVac), and (6) OP with Flt3 ligand and vaccine (OPFlt3Vac). Groups 2, 4, and 6 received daily intraperitoneal injections of Flt3 ligand (10 microg/dose with carrier) for 5 days before and 5 days after surgery. Groups 1 and 3 received similar injections of saline on the same schedule. Groups 5 and 6 were vaccinated with irradiated whole Ta3Ha tumor cells intraperitoneally three times before and twice after surgery. Immediately after surgery, all mice were injected with 10(5) Ta3Ha tumor cells via a tail vein. After 14 days, the mice were sacrificed and their lungs and tracheas were excised en bloc. Specimens were stained and counterstained with India ink and Fekete solution, and surface metastases were counted by a blinded observer. Differences between study groups were determined by analysis of variance. The peritumoral inflammatory cell infiltrate of some Flt3 and control specimens was also assessed. RESULTS Regarding laparotomy, Flt3 ligand (mean, 1.22 metastases), whole cell vaccine (1.12 metastases), and the combination of these two agents (0.1 metastases) were each effective in significantly decreasing the number of surface lung metastases compared with surgery alone (9.88 metastases, P < .05 for all comparisons). There were no differences between the various treatment groups in regards to number of metastases. Only the combination of Flt3 and the vaccine significantly lowered the incidence of tumors (number of mice with > or =1 tumors). Histologic analysis revealed that the Flt3-treated mice demonstrated increased numbers of antigen-presenting cells surrounding the tumors compared with controls. CONCLUSIONS Perioperative treatment with either Flt3 ligand or a whole cell tumor vaccine significantly reduced the number of lung metastases after laparotomy. The combination of the Flt3 ligand and the vaccine also decreased the incidence of metastases and was the most effective treatment. Further studies regarding perioperative immune modulation in the setting of cancer appear warranted.
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Affiliation(s)
- Joseph J Carter
- Laparoscopic Physiology Laboratory, Department of Surgery, College of Physician and Surgeons, Columbia University, New York, NY 10016, USA.
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Moehrlen U, Ziegler U, Boneberg E, Reichmann E, Gitzelmann CA, Meuli M, Hamacher J. Impact of carbon dioxide versus air pneumoperitoneum on peritoneal cell migration and cell fate. Surg Endosc 2006; 20:1607-13. [PMID: 16823647 DOI: 10.1007/s00464-005-0775-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2005] [Accepted: 03/02/2006] [Indexed: 10/24/2022]
Abstract
BACKGROUND Postoperative systemic immune function is suppressed after open abdominal surgery, as compared with that after minimally invasive abdominal surgery. As a first line of defense, peritoneal macrophages (PMo) and polymorphonuclear neutrophil granulocytes (PMNs) are of primary importance in protecting the body from microorganisms. Previous studies have shown changes in these cell populations over time after open versus laparoscopic surgery. This study aimed to investigate the dynamics of cell recruitment and clearance of peritoneal cells. METHODS Female NMRI mice (33 +/- 2 g) were randomly assigned to carbon dioxide (CO2) or air insufflation. Intravasal cells with phagocytic capabilities were selectively stained by intravenous injection of the fluorescent dye PKH26 24 h before surgery. Gas was insufflated into the peritoneal cavity through a catheter, and the pneumoperitoneum was maintained for 30 min. Peritoneal lavage was performed 1, 3, 8, or 24 h after surgery. Apoptotic cells were assessed by flow cytometry using a general caspase substrate. RESULTS The total peritoneal cell count did not differ between groups. The PKH26-positive PMo level was significantly increased after CO2, as compared with air, at 1 h and 24 h. The ratio of apoptotic PMo did not differ between the groups. In the peritoneal lavage, polymorphonuclear leukocytes (PMNs) were tripled in the air group, as compared with the CO2 group, whereas the ratio of apoptotic PMNs was significantly decreased. There was a higher fraction of PKH26-positive PMNs after air exposure, as compared with that after CO2. CONCLUSIONS Air exposure triggered a higher transmigration rate of PMNs from the blood compartment into the peritoneal cavity and decreased PMN apoptosis, as compared with CO2. The lower proportion of PKH26-positive peritoneal macrophages in the air group might have been attributable to a higher inflammatory stimulation than in the CO2 group, leading to increased emigration of PMo to draining lymph nodes. All the findings underscore a complex cell-specific regulation of cell recruitment and clearance in the peritoneal compartment.
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Affiliation(s)
- U Moehrlen
- Department of Pediatric Surgery, University Children's Hospital Zurich, Switzerland, Steinwiesstrasse 75, CH-8032, Zurich, Switzerland
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Sylla P, Nihalani A, Whelan RL. Microarray analysis of the differential effects of open and laparoscopic surgery on murine splenic T-cells. Surgery 2006; 139:92-103. [PMID: 16364722 DOI: 10.1016/j.surg.2005.06.041] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2004] [Revised: 03/17/2005] [Accepted: 06/10/2005] [Indexed: 11/20/2022]
Abstract
BACKGROUND Surgical trauma depresses cell-mediated immunity of a duration and magnitude proportional to the degree of injury. However, the cellular mechanism underlying this effect is poorly understood. Microarrays were used to survey gene expression in murine splenic T-cells after pneumoperitoneum and laparotomy. METHODS C3H/HeJ mice were assigned randomly to undergo anesthesia alone, sham laparotomy, or CO(2) pneumoperitoneum and sacrificed 12 or 24 hours later. RNA was isolated from purified splenic T-cells and hybridized to Affymetrix oligonucleotide microarrays. RESULTS Relative to anesthesia, 116 genes after pneumoperitoneum and 398 genes after laparotomy showed a > or =2-fold change in expression at 12 hours. One hundred thirty-two genes after pneumoperitoneum and 157 genes after laparotomy met those criteria at 24 hours. Comparing surgical modalities, 177 genes were increased and 15 decreased > or =2-fold after laparotomy relative to pneumoperitoneum at 12 hours, compared with 44 and 5 genes respectively at 24 hours. Expression changes for 8 genes were validated by quantitative real-time polymerase chain reaction. CONCLUSIONS Laparotomy and pneumoperitoneum alter splenic T-cell gene expression, with the most extensive changes occurring 12 hours after laparotomy. This study is one of the first comprehensive genomic studies of the molecular effects of surgical manipulation on immune function. The genes identified are potential targets for modulating the immune response to surgery.
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Affiliation(s)
- Patricia Sylla
- Department of Surgery 7GS-313, College of Physicians and Surgeons of Columbia University, Milstein Hospital Building, 622 West 168th Street, New York, NY 10032, USA.
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Jacobi CA, Hartmann J, Ordemann J. Immunologie, minimal invasive Chirurgie und Karzinom. Visc Med 2005. [DOI: 10.1159/000083359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Abstract
Surgical trauma causes significant alterations in host immune function. Compared with open surgery, laparoscopic surgery is associated with reduced postoperative pain and more rapid return to normal activity. Experimental data have also shown more aggressive tumor establishment and growth rates following open surgery and laparoscopic surgery. Surgery-related immunosuppression may be partly responsible for the differences in cancer growth and outcome noted. It is clear that the choice of abdominal surgical approach has immunologic consequences. Further studies are needed to better the time course and extent of surgery-related alterations in the immune system and their clinical importance. A better understanding of the impact of surgery on the immune system may provide opportunities for pharmacologic manipulation of postoperative immune function to improve clinical results.
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Affiliation(s)
- Patricia Sylla
- Department of Surgery, College of Physicians and Surgeons of Columbia University, 630 West 168th Street, New York, NY 10032, USA
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25
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Burns JM, Matthews BD, Pollinger HS, Mostafa G, Joels CS, Austin CE, Kercher KW, Norton HJ, Heniford BT. Effect of carbon dioxide pneumoperitoneum and wound closure technique on port site tumor implantation in a rat model. Surg Endosc 2005; 19:441-7. [PMID: 15645327 DOI: 10.1007/s00464-004-8937-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2004] [Accepted: 08/25/2004] [Indexed: 11/26/2022]
Abstract
BACKGROUND The purpose of this study was to evaluate the effects of carbon dioxide (CO2) pneumoperitoneum and wound closure technique on port site tumor implantation. METHODS A standard quantity of rat mammary adenocarcinoma (SMT2A)was allowed to grow in a flank incision in Wistar-Furth rats (n = 90) for 14 days. Thereafter, 1-cm incisions were made in each animal in three quadrants. There were six control animals. The experimental animals were divided into a 60-min CO2 pneumoperitoneum group (n = 42) and a no pneumoperitoneum (n = 42) group. The flank tumor was lacerated transabdominally in the experimental groups. The three wound sites were randomized to closure of (a) skin; (b) skin and fascia; and (c) skin, fascia, and peritoneum. The abdominal wounds were harvested en bloc on postoperative day 7. RESULTS Histologic comparison of the port sites in the pneumoperitoneum and no-pneumoperitoneum groups did not demonstrate a statistically significant difference in tumor implantation for any of the closure methods. Evaluation of the closure techniques showed no statistical difference between the pneumoperitoneum group and the no-pneumoperitoneum group in the incidence of port site tumor implantation. Within the no-pneumoperitoneum group, there was a significant increase (p = 0.03) in tumor implantation with skin closure alone vs all three layers. Additionally, when we compared all groups by closure technique, the rate of tumor implantation was found to be significantly higher (p = 0.01) for skin closure alone vs closure of all three layers. CONCLUSIONS This study suggests that closure technique may influence the rate of port site tumor implantation. The use of a CO2 pneumoperitoneum did not alter the incidence of port site tumor implantation at 7 days postoperatively.
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Affiliation(s)
- J M Burns
- Department of General Surgery, James G. Cannon Research Center, Carolinas Medical Center, Charlotte, NC, USA
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Abstract
The use of laparoscopic approaches to surgical disease continues to advance quickly. Laparoscopy applied to oncologic surgery continues to be debated. We review the experience of laparoscopy as it relates to surgery for tumors. Specifically, we discuss the physiologic changes and tumor response to laparoscopy, as well as the current concepts explaining port site recurrence.
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Affiliation(s)
- James R Ouellette
- Division of Surgical Oncology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA
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27
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Neuhaus SJ, Watson DI. Pneumoperitoneum and peritoneal surface changes: a review. Surg Endosc 2004; 18:1316-1322. [PMID: 15136922 DOI: 10.1007/s00464-003-8238-2] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2003] [Accepted: 01/07/2004] [Indexed: 10/26/2022]
Abstract
BACKGROUND Recent evidence suggests that the use of carbon dioxide to create a pneumoperitoneum during laparoscopy can lead to adverse structural, metabolic, and immune derangements within the peritoneal cavity, and that these can be dependent on the specific insufflation gas used. These changes include structural alterations in the mesothelial lining, pH disturbances, and alterations in peritoneal macrophage responsiveness. This contrasts with an apparent systemic benefit associated with laparoscopic, as compared with open, surgery. METHODS Recently published clinical and experimental studies related to the effect of pneumoperitoneum on the peritoneal surface are reviewed, and their relevance is discussed. RESULTS Structural changes in the peritoneal mesothelial surface layer such as widening of the intercellular junctions can be demonstrated with electron microscopy. Acidification of the peritoneum in response to carbon dioxide insufflation occurs not only at the peritoneal surface, but also in the underlying connective tissue, resulting in disturbances in the electrical surface charge and the release of various immune mediators such as endotoxin. Pneumoperitoneum also affects the local peritoneal immune environment resulting in alterations in cytokine production and phagocytic function, as well as diminished antitumor cell cytotoxicity. CONCLUSIONS Ultrastructural, metabolic, and immune alterations are observed at the peritoneal surface in response to a pneumoperitoneum. Experimental evidence suggests that these changes are carbon dioxide-specific effects. The consequences of these alterations to the local peritoneal environment are not well understood, but they may facilitate tumor implantation within the peritoneal cavity and adversely affect the ability to clear intraperitoneal infections. Further investigation into this area is warranted.
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Affiliation(s)
- S J Neuhaus
- Flinders University Department of Surgery, Flinders Medical Centre, 5042, Bedford Park, South Australia, Australia
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Novitsky YW, Litwin DEM, Callery MP. The net immunologic advantage of laparoscopic surgery. Surg Endosc 2004; 18:1411-9. [PMID: 15791361 DOI: 10.1007/s00464-003-8275-x] [Citation(s) in RCA: 147] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2004] [Accepted: 06/03/2004] [Indexed: 01/10/2023]
Abstract
The trauma of surgery evokes a variety of physiologic and immunologic alterations that should contribute to host defense. However, an exaggerated response to injury may result in immunosuppression and lead to significant postoperative morbidity and mortality. Laparoscopic surgery may result in less induced surgical trauma than conventional open surgery. Decreased postoperative pain and speedy functional recovery of laparoscopic patients may be attributable to the reduced inflammatory response and minimal immunosuppression. Inflammation, an early protective homeostatic immune response to injury, is characterized by the production of proinflammatory cytokines and by activation of cellular and humoral immune mechanisms. Postoperative levels of the inflammatory cytokines have been consistently lower after laparoscopic procedures, indicating a smaller degree of surgical insult and acute inflammatory reaction. Surgical stress derails the functions of both polymorphonuclear and mononuclear cells, which may lead to an increased risk of postoperative infection. Comparative studies of cellular immunity after laparoscopic and conventional surgery demonstrate immunologic advantage conferred by laparoscopy. Exaggerated activation of peritoneal immunity may lead to a relative local immunosuppression, resulting in ineffective intraperitoneal bacterial clearance and serious postoperative infections. Functions of the peritoneal macrophages are better preserved when laparotomy is avoided. Decreased perioperative stress may be particularly important for oncologic patients. Laparoscopic approaches may result in diminished perioperative tumor dissemination and better cancer outcomes. Although laparoscopy is "minimally invasive," systemic immune responses still are undeniably activated. However, laparoscopic surgery appears to induce a smaller injury, resulting in proportionally decreased immunologic changes. In addition to improved cosmesis and faster functional recovery, a patient undergoing laparoscopic surgery may benefit most from a net immunologic advantage.
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Affiliation(s)
- Y W Novitsky
- Department of Surgery, University of Massachusetts Medical School, Worcester, MA, USA
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Abstract
BACKGROUND Concerns about port site metastases have limited the application of minimally invasive surgery for intra-abdominal malignancies. The purpose of this review article was to summarize the current literature regarding port site metastases. METHODS A Medline search identified >100 articles in English published during the last 15 years regarding the history, incidence, etiology, and prevention of port site metastases. These articles were reviewed and are summarized. RESULTS The incidence of port site metastases, initially thought to be as high as 21%, is now thought to be closer to the incidence of wound metastases after open surgery. Multiple etiologic factors have been studied including direct wound contamination, surgical technique, effects of carbon dioxide pneumoperitoneum, and changes in host immune response. Various preventive measures have been proposed. CONCLUSIONS Port site metastases are a well-documented and devastating complication after laparoscopic resection of intra-abdominal malignancies. Although the etiology is not yet understood, a number of factors are contributory. All efforts should be made to prevent port site metastases.
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Affiliation(s)
- Myriam J Curet
- Department of Surgery H3680, Stanford Hospitals and Clinics, 300 Pasteur Dr, Stanford, CA 94305, USA.
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Wu WX, Sun YM, Hua YB, Shen LZ. Laparoscopic versus conventional open resection of rectal carcinoma: A clinical comparative study. World J Gastroenterol 2004; 10:1167-70. [PMID: 15069719 PMCID: PMC4656354 DOI: 10.3748/wjg.v10.i8.1167] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To evaluate the feasibility of laparoscopic resection of rectal carcinoma and to compare the short-term outcome of laparoscopic procedure with conventional open surgery for rectal cancer.
METHODS: Thirty-eight patients with rectal cancer were included in a prospective non-randomized study. The patients were assigned to laparoscopic (n = 18) or open (n = 18) colorectal resection. Case selection, surgical technique, and clinical and pathological results were reviewed.
RESULTS: The operative time was longer in laparoscopic resection group (LAP) than in open resection group (189 ± 18 min vs 146 ± 22 min, P < 0.05). Intraoperative blood loss and postoperative complications were less in LAP resection group than in open resection group. An earlier return of bowel motility was observed after laparoscopic surgery. The overall postoperative morbidity was 5.6% in the LAP resection group and 27.8% in open resection group (P < 0.05). No anastomotic leakage was found in both groups. The pathologic examination showed that the length of the resected specimen, the mean number of harvested lymph nodes in laparoscopic resection group were comparable to those in open resection group.
CONCLUSION: Laparoscopic total mesorectal excision (TME) for rectal cancer is a feasible but technically demanding procedure. The present study demonstrates the safety of the procedure, while oncologic results are comparable to the open surgery, with a favorable short-term outcome.
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Affiliation(s)
- Wen-Xi Wu
- Department of Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanijng 210029, Jiangsu Province, China.
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31
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Jacobi C, Ordemann J. Immunologische Veränderungen während minimal invasiver Chirurgie. Visc Med 2004. [DOI: 10.1159/000083349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Carter JJ, Feingold DL, Kirman I, Oh A, Wildbrett P, Asi Z, Fowler R, Huang E, Whelan RL. Laparoscopic-assisted cecectomy is associated with decreased formation of postoperative pulmonary metastases compared with open cecectomy in a murine model. Surgery 2003; 134:432-6. [PMID: 14555930 DOI: 10.1067/s0039-6060(03)00136-3] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND It was shown in a murine model that sham laparotomy is associated with a higher incidence of postoperative lung metastases when compared with results seen after carbon dioxide pneumoperitoneum. Using the same tumor model, the present study was undertaken to determine if the addition of bowel resection to the operative procedure would impact the results. METHODS Sixty mice underwent anesthesia alone (anesthesia control [AC]), laparoscopic-assisted cecectomy (LC), or open cecectomy (OC). After surgery, all animals received tail vein injections of 105 TA3-Ha tumor cells. On postoperative day 14, the lungs and trachea were excised en bloc and processed, and surface lung metastases were counted and recorded by a blinded observer. RESULTS The mean number of surface lung metastases in the AC, LC, and OC groups was 30.9, 76.3, and 134.5, respectively. Significantly more metastases were documented after OC (P<.001) and LC (P<.05) than after anesthesia alone. Mice in the LC group had significantly fewer lung metastases (43% less) than mice in the OC group (P<.01). CONCLUSIONS OC was associated with significantly more lung metastases than either LC or AC. Surgery-related immune suppression or trophic tumor cell stimulation occurring after surgery may contribute to this phenomenon.
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Affiliation(s)
- Joseph J Carter
- Department of Surgery, College of Physician and Surgeons, Columbia University, New York, NY, USA
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Lee SW, Feingold DL, Carter JJ, Zhai C, Stapleton G, Gleason N, Whelan RL. Peritoneal macrophage and blood monocyte functions after open and laparoscopic-assisted cecectomy in rats. Surg Endosc 2003; 17:1996-2002. [PMID: 14569448 DOI: 10.1007/s00464-003-8154-5] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2003] [Accepted: 06/25/2003] [Indexed: 12/11/2022]
Abstract
BACKGROUND It has been well established that open abdominal surgery results in systemic immunosuppression postoperatively; in contrast, laparoscopic surgery is associated with significantly better preserved systemic immune function. However, when intraperitoneal (local) immune function is considered, laparoscopic procedures done under a CO2 pneumoperitoneum (pneumo) have been shown to result in greater immunosuppression compared to that of open surgery. Few studies have simultaneously assessed systemic and local immune function. The purpose of this study was to assess peripheral blood mononuclear cell (PBMC) and peritoneal macrophage tumor necrosis factor-alpha (TNF-alpha) levels, H2O2 production, and MHC class II antigen expression after open and laparoscopically assisted cecectomy in a rat model. METHODS A total of 75 Sprague Dawley rats were used for three separate experiments. For each study, rats were randomly divided into three groups: anesthesia alone (AC), laparoscopic-assisted cecectomy (LC), and open cecectomy via full laparotomy (OP). A CO2 pneumo was used for laparoscopic operations. On postoperative day 1 the animals were sacrificed, macrophages were harvested via intraperitoneal lavage, and PBMCs were isolated from whole blood obtained by cardiac puncture. In experiment 1, macrophages and PBMC from each animal were stimulated with lipopolysaccharide, after which TNF-alpha levels of the supernatant were determined. In experiment 2, after stimulation with PMA, H2O2 release was assessed by measuring fluorescence. In experiment 3, via flow cytometry, the number of cells with surface MHC class II proteins were determined. Data from the three groups in each experiment were compared using analysis of variance Tukey-Kramer tests. RESULTS Macrophages and PBMC from rats in the OP group released significantly more TNF-alpha than cells from rats in the LC ( p < 0.05) or AC ( p < 0.05) groups. Macrophages from rats in the OP group released significantly less H2O2 than cells from the AC ( p < 0.01) and LC ( p < 0.05) groups. There was no difference between the AC and LC results. No significant differences in PBMC H2O2 release were noted among any of the groups. OP group macrophages expressed significantly less MHC class II antigen than did AC group macrophages ( p < 0.05). No differences were noted among the LC results and either the OP or AC group's outcomes. No differences were noted in PBMC MHC class II expression among any of the groups. CONCLUSIONS In all instances, the LC group's macrophage results were similar to the AC group's results. OC group macrophages produced significantly more TNF-alpha and less H2O2 than both the AC and LC groups. MHC class II protein expression was less for the OC group than for the AC group. OC group PBMCs produced more TNF-alpha. No differences in PBMC H2O2 release or MHC class II expression were noted. Laparoscopic methods better preserves the baseline values of the parameters studied.
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Affiliation(s)
- S W Lee
- Division of Colon and Rectal Surgery, New York Presbyterian Hospital, Cornell-Weill University, New York, NY 10021, USA
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Abstract
PURPOSE Laparoscopic surgery is rapidly gaining widespread acceptance among urologists, including extensive application in malignant conditions. However, untoward occurrences of port site metastases have not eluded to urological applications. This up-to-date review on port site metastases in urology delineates possible contributing factors and describes techniques to prevent it. MATERIALS AND METHODS We comprehensively reviewed published experimental and clinical studies with special emphasis on the incidence, pathophysiology and prevention of port site metastases. RESULTS Nine cases of port site metastases after urological laparoscopy have been described in clinical and experimental studies. Etiological factors include natural malignant disease behavior, host immune status, local wound factors, laparoscopy related factors such as aerosolization of tumor cells (the use of gas, type of gas, insufflation and desufflation, and pneumoperitoneum) and sufficient technical experience of the surgeons and operating team (adequate laparoscopic equipment, skill, minimal handling of the tumor, surgical manipulation and wound contamination during instruments change, organ morcellation and specimen removal). CONCLUSIONS Port site metastases is a multifactorial phenomenon with an as yet undetermined incidence. The problem is influenced to some extent by surgeon and operating team experience and, therefore, it could be partially prevented. The suggested preventive steps are avoiding laparoscopic surgery when there are ascites, trocar fixation to prevent dislodgment, avoiding gas leakage along and around the trocar, sufficient technical readiness of the operating team (adequate laparoscopic equipment and technique, minimal handling and avoiding tumor boundary violation of the tumor), using a bag for specimen removal, placing drainage when needed before desufflation, povidone-iodine irrigation of instruments, trocars and port site wounds, and suturing 10 mm. and larger trocar wounds.
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Affiliation(s)
- Alexander Tsivian
- Department of Urologic Surgery, Edith Wolfson Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Holon, Israel
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Abstract
Laparoscopic bowel surgery has demonstrated patient care benefits of decreased duration of hospital stay, smaller incisions, lower risk of cardiopulmonary complications, and reduced risk of small-bowel obstruction. Resection of complicated diverticular disease and inflammatory bowel disease can be technically challenging and may be associated with higher conversion rates. The applicability of these techniques to colon cancer is supported by a growing body of evidence that demonstrates similar survival and recurrence rates obtained by open resection and the exaggeration of the risk of port site recurrences. Laparoscopic colorectal surgery has also challenged much of the standard postoperative care plans used for colectomy. Optimal postoperative care of the laparoscopic colectomy patient requires an appreciation of the faster recovery enjoyed by these patients and the fact that ambulation and dietary advancement need to be accelerated. Coordination between the surgical team and the postoperative care team is essential to obtain all the benefits associated with this new approach to the management of colorectal disease.
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Affiliation(s)
- Anthony J Senagore
- Department of Colorectal Surgery, the Cleveland Clinic Foundation, OH, USA
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Abstract
BACKGROUND Laparoscopic surgery is believed to lessen surgical trauma and so cause less disturbance of immune function. This may contribute to the rapid recovery noted after many laparoscopic operations. Preservation of both systemic and intraperitoneal immunity is particularly important in surgery for sepsis or cancer and so an understanding of the impact of laparoscopy on immune function is relevant. METHODS Literature on immunological changes following laparoscopy and open surgery was identified from Medline, along with cross-referencing from the reference lists of major articles on the subject. RESULTS AND DISCUSSION Despite a few contradictory reports, systemic immunity appears to be better preserved after laparoscopic surgery than after open surgery. However, the local intraperitoneal immune system behaves in a particular way when exposed to carbon dioxide pneumoperitoneum; suppression of intraperitoneal cell-mediated immunity has been demonstrated in a number of studies. This feature may be clinically important and should be acknowledged when considering laparoscopic surgery in patients with malignancy or sepsis.
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Affiliation(s)
- A Gupta
- University of Adelaide Department of Surgery, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia
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Lee SW, Gleason NR, Stapleton GS, Zhai C, Huang EH, Bessler M, Whelan RL. Increased platelet-derived growth factor (PDGF) release after laparotomy stimulates systemic tumor growth in mice. Surg Endosc 2001; 15:981-5. [PMID: 11443442 DOI: 10.1007/s004640080012] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2000] [Accepted: 12/07/2000] [Indexed: 10/26/2022]
Abstract
BACKGROUND Our laboratory has demonstrated that tumors grow larger and are more easily established following laparotomy than after carbon dioxide (CO2) pneumoperitoneum or anesthesia alone. We have also shown that tumor cells incubated with serum from laparotomized mice proliferated significantly faster in vitro than those incubated with plasma from mice that underwent laparoscopy or anesthesia alone. We hypothesized that differing levels of a plasma-soluble growth factor(s) postoperatively causes tumors to proliferate faster after laparotomy. This study's purpose was to isolate and characterize the plasma growth factor(s) responsible for the increased growth of systemic tumors after laparotomy. METHODS Female Balb/C mice (n = 100) were randomized to two groups: anesthesia control (AC) or midline sham laparotomy (4 cm) (Open). Plasma was collected on Postoperative day 4. For the tumor proliferation assay, C-26 colon cancer cells were incubated in media with either 10% AC or Open "raw" plasma (not passed through column), or AC or Open plasma that had been passed through the column. For elution of heparin-binding proteins, plasma from each group was passed through a heparin-sepharose column. Elution of bound proteins was accomplished with a 0.1-2 M NaCl gradient. Each fraction was examined for protein content. For the anti-platelet-derived growth factor (PDGF) neutralizing antibody study, C-26 cells were incubated with one of four plasma preparations: AC or Open plasma alone, or AC or Open plasma incubated with anti-PDGF antibody. For both studies, tumor proliferation was determined after 2 days with an MTS/PMS assay. Results from each group were compared and differences determined using analysis of variance (ANOVA) and Tukey-Kramer tests. RESULTS On heparin chromatography, a single elution peak consistent with PDGF was present in both AC and Open plasma and was 1.5 times greater in the Open plasma. The first tumor proliferation assay showed that tumor cells incubated with Open plasma proliferated 2.5 times faster than those with AC plasma (p < 0.0001). Passage of AC plasma through the column did not alter its mitogenic activity, but Open plasma thus treated demonstrated significantly decreased mitogenic activity. The second tumor proliferation assay showed that anti-PDGF antibody had no effect on the mitogenic activity of the AC plasma but decreased the mitogenic activity of the Open plasma to the AC plasma level. CONCLUSIONS Laparotomy is associated with higher levels of a heparin-binding plasma factor, consistent with PDGF. The enhanced mitogenic activity of the OP plasma was neutralized with anti-PDGF antibody. Increased plasma levels of PDGF after laparotomy may be responsible for accelerated tumor growth following laparotomy in mice.
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Affiliation(s)
- S W Lee
- Department of Surgery, Columbia University College of Physicians & Surgeons, 161 Fort Washington Ave, New York, NY 10032, USA
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Affiliation(s)
- O Zmora
- Department of Colorectal Surgery, Cleveland Clinic Florida, Fort Lauderdale, Florida, USA
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Vithiananthan S, Cooper Z, Betten K, Stapleton GS, Carter J, Huang EH, Whelan RL. Hybrid laparoscopic flexure takedown and open procedure for rectal resection is associated with significantly shorter length of stay than equivalent open resection. Dis Colon Rectum 2001; 44:927-35. [PMID: 11496070 DOI: 10.1007/bf02235478] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE Laparoscopic-assisted, sphincter-saving resection (largest incision < 7 cm) of the middle and distal rectum is technically very difficult and, with regard to cancers, has not been demonstrated to be oncologically safe. The hypothesis of this retrospective study is that a hybrid operation that combines laparoscopic and open methods would be associated with short-term outcome benefits compared with open surgery results for patients undergoing sphincter-saving proctectomy. METHODS A total of 31 hybrid and 25 fully open rectal resection patients were compared in this retrospective review. All patients had splenic flexure takedown and rectal anastomosis. The hybrid approach consisted of laparoscopic splenic flexure takedown (with or without partial rectal mobilization and devascularization) followed by completion of the procedure via infraumbilical midline laparotomy. The indication was neoplasm in 87 percent of hybrid patients and in 68 percent of open patients. The majority of tumors were located between 4 and 10 cm from the dentate line. RESULTS Fifty-eight percent of hybrid and 68 percent of open patients had low anterior or coloanal resections, and 48 percent of hybrid and 64 percent of open patients underwent temporary diversion via ileostomy. The mean hybrid midline incision length was 11 cm compared with 24 cm for open patients (P < 0.0001). The neoplastic specimens were similar with regard to margins and lymph node harvest. Similar complication rates were noted in both groups. Nonsignificant benefits for hybrid patients (0.9-1.2 days) were seen with regard to length of time until toleration of liquid or solid diet and first flatus. Hybrid patients experienced their first bowel movements 4.1 days vs. 5.7 days for the open group (P = 0.03). Mean length of stay was significantly shorter for hybrid patients (6.1. days) than for open patients (11.1 days; P = 0.0006). CONCLUSION This preliminary retrospective study suggests that a combined hybrid laparoscopic and open approach to sphincter-saving proctectomy permits a similar resection as open methods and may be associated with a length-of-stay benefit and more rapid return of bowel function. Prospective studies will be needed before any firm conclusions can be drawn.
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Affiliation(s)
- S Vithiananthan
- Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, NY 10032
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Gutt CN, Riemer V, Kim ZG, Erceg J, Lorenz M. Impact of laparoscopic surgery on experimental hepatic metastases. Br J Surg 2001; 88:371-5. [PMID: 11260101 DOI: 10.1046/j.1365-2168.2001.01700.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
BACKGROUND Metastatic disease to the liver is one of the major factors determining outcome after colonic resection with curative intention. The influence of laparoscopic surgery on metastatic disease in the liver is still largely unknown. METHODS An intrasplenic tumour cell inoculation was performed in 30 WAG-Rij rats. After 7 days the rats were randomized into three operative groups: laparotomy (n = 10), laparoscopy with 7 mmHg carbon dioxide pneumoperitoneum (n = 10) and gasless laparoscopy (n = 10). A small bowel segmental resection was carried out in all rats. Some 21 days later the rats were evaluated for number and diameter of tumour nodules and cancer index score at eight different abdominal sites. RESULTS Hepatic tumour growth scored with the cancer index was significantly reduced in the gasless laparoscopy group compared with that in the carbon dioxide laparoscopy group (P = 0.04) and the laparotomy group (P = 0.02). Tumour growth at the port site and total tumour load were significantly reduced in the gasless group compared with the laparotomy group (P < or = 0.04). CONCLUSION Laparoscopy with carbon dioxide insufflation seems to stimulate the growth of dormant tumour cells into overt liver metastases. Gasless laparoscopy on the other hand may have a protective effect against metastatic disease in the liver. The promoting and inhibiting effects of laparoscopic procedures on growth of liver metastases need further evaluation.
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Affiliation(s)
- C N Gutt
- Department of General and Vascular Surgery, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
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Abstract
The fate of laparoscopic methods for the treatment of cancer remains uncertain. Published middle-range oncologic results from nonrandomized studies demonstrate that laparoscopic methods are associated with an outcome comparable with results after open resection. The world awaits the 3- and 5-year oncologic results of the ongoing randomized and prospective trials. There is a possibility that laparoscopic methods may be associated with a survival benefit. Port tumors remain a concern. However, results at this writing suggest that these recurrences take place at a frequency similar to that of incisional recurrences following open cancer resection. Port tumors currently are viewed as local recurrences. Traumatization of the tumor at the time of resection is thought to be the most important surgery-related risk factor. The demonstration of a survival benefit in a randomized trial would likely have a tremendous impact on the surgical world. Avoidance of laparotomy-related immunosuppression and tumor stimulation, both of which have been well demonstrated in animal studies, theoretically, might account for differences in cancer outcome. The early postoperative period may be a critical time during which the fate of many cancer patients is determined. It is possible that this may be an ideal time frame for antitumor immunotherapy because the tumor burden is at its lowest, and because immunotherapy, unlike conventional chemotherapy, is unlikely to have a negative impact on wound and anastomotic healing. Perioperative nonspecific upregulation of immune function via pharmacologic means may improve long-term oncologic results. Similarly, preoperative tumor vaccines might provide patients with a specific means of combating any remaining tumor cells after curative resection. The results of several recently completed murine studies support both of these ideas. Finally, early postoperative administration of monoclonal antitumor antibodies might provide patients with specific means of combating any remaining tumor cells after curative resection. The introduction of advanced minimally invasive techniques nearly a decade ago has led to new methods of approaching malignant tumors that have the potential to have an impact on the oncologic outcome of cancer patients. This decade-long journey also has led to new insights regarding the impact of surgery on the patient. It also has alerted us concerning the importance of the immediate postoperative period in the patient's ongoing struggle against the tumor. These insights hopefully will lead to better surgical methods and new perioperative adjuvant therapies that will increase the rate of survival and reduce the recurrence rates for cancer patients.
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Affiliation(s)
- R L Whelan
- Department of Surgery, Columbia University College of Physicians and Surgeons, 161 Fort Washington Avenue, Suite 819, New York, NY 10032, USA
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Lopes AG, Rodrigues CJ, Lopes LH, Vilca-Melendez H, Rodrigues AJ. Differences in tumour growth, tumour cell proliferation and immune function after laparoscopy and laparotomy in an animal model. HPB (Oxford) 2001; 3:213-7. [PMID: 18333017 PMCID: PMC2020628 DOI: 10.1080/136518201753242235] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Clinical and experimental studies have shown that laparoscopy preserves the immune response and can give better clinical results than laparotomy. However, the use of laparoscopy for the treatment of cancer patients is still controversial due to the risk of port-site and haematogenous metastases and increased tumour growth. The purpose of this experimental study was to assess tumour growth and the mechanism of differential tumour behaviour after laparoscopy and laparotomy. METHODS Seventy-five young, male Wistar rats were randomly assigned to one of two experiments. Experiment 1: 45 animals were inoculated subcutaneously with Walker carcinosarcoma 256 cells and were subdivided into three groups of 15 rats. Control group la was submitted to anaesthesia only, group 1b received carbon dioxide (CO(2)) pneumoperitoneum,while group 1c received a laparotomy. Animals were sacrificed on postoperative day (POD) 7; tumours were excised and weighed to evaluate tumour growth. Nucleolar organiser regions identified by silver staining (AgNORs) were analysed to evaluate cell proliferation. Experiment 2: 30 rats were submitted to the same procedures as before, with ten animals in each group (2a, 2b, 2c), and a delayed-type hypersensitivity response (DTH) was used to evaluate the immune function. RESULTS The average tumour mass was 1.76 g in group 1a, 2.81 g in group 1b and 4.21 g in group 1c (p < 0.05). The AgNOR expression results were similar in the three groups. The immune function was better preserved in the control group (2a: average inflammatory area on POD1 = 106 mm(2) and on POD2 = 128.18 mm(2)), than in the pneumoperitoneum group (2b: average inflammatory area on POD1 = 79.75 mm(2) and on POD2 = 126.93 mm(2)); the worst results were in the laparotomy group (2c: average inflammatory area on POD1 = 33.33 mm(2) and on POD2 = 61.32 mm(2)).There were significant differences between groups 2a and 2c and between 2b and 2c. CONCLUSION Laparotomy stimulates a greater tumour growth than CO(2) pneumoperitoneum, but there is no difference in tumour cell proliferation. The cellular immune function is better preserved in animals submitted to CO pneumoperitoneum than in the laparotomized animals. These results suggest a relationship between a weaker immune response and a greater tumour growth.
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Affiliation(s)
- AG Lopes
- Department of Surgery, State University of LondrinaLondrinaBrazil
| | - CJ Rodrigues
- Department of Surgery, University of Sao PauloSao Paulo SPBrazil
| | - LH Lopes
- Department of Surgery, State University of LondrinaLondrinaBrazil
| | | | - AJ Rodrigues
- Department of Surgery, University of Sao PauloSao Paulo SPBrazil
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Kaouk JH, Gill IS, Meraney AM, Desai MM, Carvalhal EF, Fergany AF, Sung GT. Retroperitoneal minilaparoscopic nephrectomy in the rat model. Urology 2000; 56:1058-62. [PMID: 11113768 DOI: 10.1016/s0090-4295(00)00781-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
OBJECTIVES Development of small animal models for laparoscopic surgery is important for basic pathophysiologic and oncologic studies, instrument development, and surgical training. Although transperitoneal laparoscopy has been described in the rat, the technical feasibility of the retroperitoneoscopic approach for major renal surgery has not been reported previously. Herein, we describe the development of a rat model for retroperitoneal minilaparoscopic nephrectomy. METHODS Sixteen male Sprague-Dawley rats underwent a three-port bilateral retroperitoneoscopic nephrectomy using 2 and 3-mm instruments and optics exclusively. After developing the technique in 10 animals, the study was conducted in 6 animals. Following retroperitoneal balloon dilation and CO(2) pneumoretroperitoneum (mean 4.5 mm Hg), nephrectomy was accomplished by intracorporeal en bloc ligation of the renal pedicle. To prevent peritoneal entry, the anterior surface of the kidney was mobilized subcapsularly. Volume of the created retroperitoneal space and peritoneal integrity were confirmed by a contrast x-ray study. Intraperitoneal pressure was monitored constantly during the procedure. RESULTS Mean surgical time was 74.5 minutes (range 60 to 95) and estimated blood loss was less than 1 mL. Mean volume of the retroperitoneal space was 8.4 mL after initial balloon dilation, and 11.5 mL after nephrectomy. Mean weight of the excised kidneys was 1. 4 g. Inadvertent peritoneotomy occurred during 3 of 12 study nephrectomies. Complications included renal artery hemorrhage leading to death in 1 animal and renal vein injury in 1 animal. CONCLUSIONS Laparoscopic retroperitoneal nephrectomy in the rat model is technically feasible. This novel small animal model can be used for further studies of the retroperitoneal laparoscopic approach.
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Affiliation(s)
- J H Kaouk
- Section of Laparoscopic and Minimally Invasive Urology, Department of Urology and The Minimally Invasive Center, Cleveland Clinic Foundation, Cleveland, Ohio, USA
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Abstract
The unique challenges of a laparoscopic approach to colorectal surgery have delayed its widespread adoption into clinical practice. Advances in instrumentation, modifications of technique, and an unequivocal demonstration of its safety undoubtedly will increase its popularity in the future.
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Affiliation(s)
- A M Metcalf
- Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, USA
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Canis M, Botchorishvili R, Wattiez A, Pouly JL, Mage G, Manhes H, Bruhat MA. Cancer and laparoscopy, experimental studies: a review. Eur J Obstet Gynecol Reprod Biol 2000; 91:1-9. [PMID: 10817870 DOI: 10.1016/s0301-2115(99)00251-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVE To review the experimental studies on laparoscopy and cancer and to propose guidelines for the clinical management of gynecologic cancer. METHODS The literature in MEDLINE was searched from January 1992 to December 1998 using the terms 'cancer', 'laparoscopy' and 'experimental or animal study'. Cross-referencing identified additional publications. Abstracts and letters to the editor were excluded. All the relevant papers were reviewed. RESULTS Depending on the model used, controversial results have been reported on the incidence of trocar site metastasis when comparing CO(2) laparoscopy and laparotomy. In contrast, the following conclusions can be proposed: (i) tumour growth after laparotomy is greater than after endoscopy; (ii) tumour dissemination is worse after CO(2) laparoscopy than after laparotomy; (iii) some of the disadvantages of CO(2) laparoscopy may be treated using local or intravenous treatments or avoided using other endoscopic exposure methods, such as gasless laparoscopy. CONCLUSIONS The laparoscopic treatment of gynecologic cancer has potential advantages and disadvantages, and may only be performed in prospective clinical trials. The risk of dissemination appears high when a large number of malignant cells are present. Adnexal tumours with external vegetations, and bulky lymph nodes should be considered as contra-indications to CO(2) laparoscopy.
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Affiliation(s)
- M Canis
- Department of Obstetrics, Gynecology and Reproductive Medicine, Polyclinique, 13 Bd Charles de Gaulle, 63033, Clermont Ferrand, France
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Abstract
BACKGROUND A number of controversies exist in the laparoscopic treatment of colorectal cancer, and thus the technique has so far failed to gain widespread acceptance throughout the United Kingdom. This review aims to discuss these issues in the context of ongoing published trials, assessing both purported advantages and disadvantages. METHODS The United States National Library of Medicine Medline database, and the Bath Information Data Service (BIDS) were searched using keywords related to laparoscopic colorectal cancer surgery. Recent surgical journals were also reviewed for relevant publications. Attempts have been made to quote only the most recent work from institutions with multiple publications using the same group of patients, in order to present the most coherent picture. The data are presented as randomized controlled trials, nonrandomized controlled studies, and series comprising more than 10 patients. CONCLUSIONS This review confirms that laparoscopic colorectal cancer surgery is technically feasible. In addition patients lose less blood, have less immunosuppression, and have shorter postoperative ileus, in-patient stay, and require less analgesia. However, concerns still remain as to the development of port-site metastases, the longer operating times, and the overall cost of the equipment. In view of these concerns, the place of laparoscopically assisted colorectal cancer surgery is likely to remain controversial for some years yet. Randomized, controlled trials are as yet too few to provide definitive answers to all these issues.
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Abstract
This article discusses multimodal treatment of noncomplicated colon and rectal cancer, considerations for specific types of colon cancer, considerations that may modify the extent and technique of surgery, the role of adjuvant chemotherapy for colon adenocarcinoma and rectal cancer, and surgical treatment of complicated colorectal cancer.
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Affiliation(s)
- I C Lavery
- Department of Colon and Rectal Surgery, Cleveland Clinic Foundation, Ohio, USA
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Abstract
In this review we present a broad survey of fundamental scientific and medically applied studies on keyhole limpet hemocyanin (KLH). Commencing with the biochemistry of KLH, information on the biosynthesis and biological role of this copper-containing respiratory protein in the marine gastropod Megathura crenulata is provided. The established methods for the purification of the two isoforms of KLH (KLH1 and KLH2) are then covered, followed by detailed accounts of the molecular mass determination, functional unit (FU) structure, carbohydrate content, immunological analysis and recent aspects of the molecular genetics of KLH. The transmission electron microscope (TEM) has contributed significantly to the understanding of KLH structure, primarily from negatively stained images. We give a brief account of TEM studies on the native KLH oligomers, the experimental manipulation of the oligomeric states, together with immunolabelling data and studies on subunit reassociation. The field of cellular immunology has provided much relevant biomedical information on KLH and has led to the expansion of use of KLH in experimental immunology and clinically as an immunotherapeutic agent; this area is presented in some detail. The major clinical use of KLH is specifically for the treatment of bladder carcinoma, with efficacy probably due to a cross-reacting carbohydrate epitope. KLH also has considerable possibilities for the treatment of other carcinomas, in particular the epithelially derived adenocarciomas, when used as a carrier for carcinoma ganglioside and mucin-like epitopes. The widespread use of KLH as a hapten carrier and generalised vaccine component represent other major on-going aspects of KLH research, together with its use for the diagnosis of Schistosomiasis, drug assay and the treatment of drug addiction. Immune competence testing, assessment of stress and the understanding of inflammatory conditions are other areas where KLH is also making a useful contribution to medical research.
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Affiliation(s)
- J R Harris
- Institute of Zoology, University of Mainz, Germany.
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