Subscribe to RSS
DOI: 10.1055/s-0035-1545684
Surgical Methods for the Treatment of Uterine Fibroids – Risk of Uterine Sarcoma and Problems of Morcellation: Position Paper of the DGGG
Exstirpierende Verfahren zur Behandlung von Uterusmyomen – Uterussarkomrisiko und Problematik der Morcellation: Positionspapier der DGGGPublication History
received 06 January 2015
revised 09 January 2015
accepted 09 January 2015
Publication Date:
16 March 2015 (online)
Abstract
The appropriate surgical technique to treat patients with uterine fibroids is still a matter of debate as is the potential risk of incorrect treatment if histological examination detects a uterine sarcoma instead of uterine fibroids. The published epidemiology for uterine sarcoma is set against the incidence of accidental findings during surgery for uterine fibroids. International comments on this topic are discussed and are incorporated into the assessment by the German Society for Gynecology and Obstetrics (DGGG). The ICD-O-3 version of 2003 was used for the anatomical and topographical coding of uterine sarcomas, and the “Operations- und Prozedurenschlüssel” (OPS) 2014, the German standard for process codes and interventions, was used to determine surgical extirpation methods. Categorical qualifiers were defined to analyze the data provided by the Robert Koch Institute (RKI), the German Federal Bureau of Statistics (DESTATIS; Hospital and Causes of Death Statistics), the population-based Cancer Register of Bavaria. A systematic search was done of the MEDLINE database and the Cochrane collaboration, covering the period from 1966 until November 2014. The incidence of uterine sarcoma and uterine fibroids in uterine surgery was compared to the literature and with the different registries. The incidence of uterine sarcoma in 2010, standardized for age, was 1.53 for Bavaria, or 1.30 for every 100 000 women, respectively, averaged for the years 2002–2011, and 1.30 for every 100 000 women in Germany. The mean incidence collated from various surveys was 2.02 for every 100 000 women (0.35–7.02; standard deviation 2.01). The numbers of inpatient surgical procedures such as myoma enucleation, morcellation, hysterectomy or cervical stump removal to treat the indication “uterine myoma” have steadily declined in Germany across all age groups (an absolute decrease of 17 % in 2012 compared to 2007). There has been a shift in the preferred method of surgical access from an abdominal/vaginal approach to endoscopic or endoscopically assisted procedures to treat uterine fibroids, with the use of morcellation increasing by almost 11 000 coded procedures in 2012. Based on international statements (AAGL, ACOG, ESGE, FDA, SGO) on the risk of uterine sarcoma as an coincidental finding during uterine fibroid surgery and the associated risk of a deterioration of prognosis (in the case of morcellation procedures), this overview presents the opinion of the DGGG in the form of four Statements, five Recommendation and four Demands.
Zusammenfassung
In der Behandlung der Patientin mit Uterus myomatosus gibt es Diskussionen über die Art der Operationstechnik und das damit verbundene Risiko der eventuellen falschen Behandlung, wenn sich in der histologischen Aufarbeitung keine Uterusmyome, sondern ein Uterussarkom herausstellt. Die publizierte Epidemiologie von Uterussarkomen wird hier ins Verhältnis zu Zufallsbefunden bei Operationen zur Behandlung von Uterusmyomen gesetzt. Die internationalen Stellungnahmen zu diesem Thema werden diskutiert, um eine Bewertung seitens der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe (DGGG) abzugeben. Zur anatomischen und topografischen Codierung der Uterussarkome wurde der ICD-O-3 in der Ausgabe von 2003 und für die Operations- und Prozedurenschlüssel der exstirpierenden Verfahren der OPS 2014 benutzt. Um die übermittelten Daten des Robert Koch-Instituts (RKI), des Statistischen Bundesamts (DESTATIS; Abteilung Krankenhausstatistik und Todesursachenstatistik), des bevölkerungsbezogenen Krebsregisters Bayern auswerten zu können, wurden eindeutige Abfragekriterien definiert. Zusätzlich wurde eine systematische Literaturrecherche in MEDLINE von 1966 bis November 2014 und bei der Cochrane Collaboration durchgeführt. Die Inzidenz von Uterussarkomen und Uterusmyomen bei Operationen der Gebärmutter wurden in den verschiedenen Registern und in der Literatur verglichen. Die altersstandardisierte Inzidenz im Jahr 2010 für Uterussarkome war für Bayern 1,53, respektive 1,30 auf 100 000 Frauen gemittelt über die Jahre 2002–2011, in Deutschland bei 1,30 auf 100 000 Frauen. Die mittlere Inzidenz aus verschiedenen Erhebungen beträgt 2,02 auf 100 000 Frauen (0,35–7,02; Standardabweichung 2,01). Stationär durchgeführte Operationen wie Myomenukleation, Morcellation, Hysterektomie oder Zervixstumpfresektion sind bei der Indikation Uterusmyom in Deutschland gleichbleibend über alle Altersgruppen hinweg zurückgegangen (absoluter Rückgang von 17 % im Jahr 2012 zum Jahr 2007). Es zeigt sich eine Verschiebung des operativen Zugangswegs von abdominal/vaginal zu endoskopisch bzw. endoskopisch assistierten zur Behandlung von Uterusmyomen mit einer ansteigenden Benutzung der Morcellation von fast 11 000 codierten Prozeduren im Jahr 2012. Nach den Veröffentlichungen von internationalen Stellungnahmen (AAGL, ACOG, ESGE, FDA, SGO) zum Risiko Uterussarkom als Zufallsbefund im Rahmen einer Myomoperation und dem damit verbundenen Risiko einer Prognoseverschlechterung (im Falle einer Morcellation) wird in dieser Übersichtsarbeit die DGGG-Stellungnahme in Form von 4 Statements, 5 Empfehlungen und 4 Forderungen dargestellt.
Key words
uterine sarcoma - morcellation - uterine fibroid - epidemiology - myomectomy - hysterectomySchlüsselwörter
Uterussarkom - Morcellation - Uterusmyom - Epidemiologie - Myomektomie - Hysterektomie-
References
- 1 U.S. Food and Drug Administration. Laparoscopic uterine power morcellation in hysterectomy and myomectomy: FDA safety communication. Online: http://www.fda.gov/medicaldevices/safety/alertsandnotices/ucm393576.htm last access: 15.07.2014
- 2 Society of Gynecologic Oncology. SGO position statement: morcellation. Online: https://www.sgo.org/newsroom/position-statements-2/morcellation/ last access:15.07.2014
- 3 Society of Gynecologic Oncology. Statement of the SGO to the FDAʼs Obstetrics and Gynecology Medical Devices Advisory Committee concerning safety of laparoscopic power morcellation. Online: https://www.sgo.org/wp-content/uploads/2014/04/SGO-Testimony-to-FDA-on-Power-Morcellation-FINAL.pdf last access: 15.07.2014
- 4 U.S. Food and Drug Administration. Updated laparoscopic uterine power morcellation in hysterectomy and myomectomy: FDA safety communication. Online: http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm424443.htm last access: 24.11.2014
- 5 AAGL Advancing Minimally Invasive Gynecology Worldwide. AAGL practice report: Morcellation during uterine tissue extraction. J Minim Invasive Gynecol 2014; 21: 517-530
- 6 American College of Obstetricians and Gynecologists. Power morcellation and occult malignancy in gynecologic surgery. Online: http://www.acog.org/Resources-And-Publications/Task-Force-and-Work-Group-Reports/Power-Morcellation-and-Occult-Malignancy-in-Gynecologic-Surgery last access: 15.07.2014
- 7 Bin Han Ong M. FDA Advisors Debate Ban, Black Box and Status quo of Power Morcellators. The Cancer Letter 2014; 40: 5-7
- 8 AAGL Advancing Minimally Invasive Gynecology Worldwide. AAGL statement to the FDA on power morcellation. Online: http://www.aagl.org/aaglnews/aagl-statement-to-the-fda-on-power-morcellation/ last access: 15.07.2014
- 9 Ethicon Inc.. Wichtige Kundeninformation zu Ethicon Morcellations Geräten. 2014. Online: http://www.bfarm.de/SharedDocs/Kundeninfos/DE/14/2014/2451-14_Kundeninfo_de.pdf?__blob=publicationFile&v=1 last access: 06.08.2014
- 10 Ethicon Inc.. Rückruf für das Tissue Morcellation System, Ethicon. Online: http://www.ethicon.com/sites/default/files/managed-documents/Ethicon%2520Morcellation%2520Devices%2520Customer%2520Letter%2520Final.pdf last access: 06.08.2014
- 11 Beckmann MW, Denschlag D, Gaß P et al. 195. Stellungnahme der DGGG – Durchführung des Medizinproduktegesetzes – Gynäkologische Morcellatoren. Online: http://www.dggg.de/leitlinienstellungnahmen/aktuelle-stellungnahmen/?eID=dam_frontend_push& docID=2607; last access: 17.10.2014
- 12 Deutsches Institut für Medizinische Dokumentation und Information. International classification of diseases for oncology. 3rd ed. Online: http://www.dimdi.de/static/de/klassi/icdo3/index.htm last access: 28.06.2014
- 13 Deutsches Institut für Medizinische Dokumentation und Information. German procedure classification (OPS) 2014. Online: http://www.dimdi.de/static/de/klassi/ops/index.htm last access: 28.06.2014
- 14 Statistisches Bundesamt. DRG-Statistik 2005 – 2012. Bonn: Eigenverlag des Statistischen Bundesamtes; 2014
- 15 DGGG. Uterine sarkoma, 2015. National German Guideline (S1). Long version. AWMF registry no. 015/074. 2014 (Manuscript submitted for publication).
- 16 Toro JR, Travis LB, Wu HJ et al. Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978–2001: an analysis of 26,758 cases. Int J Cancer 2006; 119: 2922-2930
- 17 Brooks SE, Zhan M, Cote T et al. Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989–1999. Gynecol Oncol 2004; 93: 204-208
- 18 Harlow BL, Weiss NS, Lofton S. The epidemiology of sarcomas of the uterus. J Natl Cancer Inst 1986; 76: 399-402
- 19 Nordal RR, Thoresen SO. Uterine sarcomas in Norway 1956–1992: incidence, survival and mortality. Eur J Cancer 1997; 33: 907-911
- 20 Mastrangelo G, Coindre JM, Ducimetière F et al. Incidence of soft tissue sarcoma and beyond: a population-based prospective study in 3 European regions. Cancer 2012; 118: 5339-5348
- 21 Robert Koch-Institut (RKI). Inzidenz von Sarkomen nach histologischem Typ (Deutschland). Berlin: Gesundheitsberichterstattung des Bundes; 2014
- 22 Bevölkerungsbezogenes Krebsregister Bayern. Inzidenz von Sarkomen nach histologischem Typ (Bayern). Erlangen: Bevölkerungsbezogenes Krebsregister Bayern Registerstelle; 2014
- 23 Denschlag D, Masoud I, Stanimir G et al. Prognostic factors and outcome in women with uterine sarcoma. Eur J Surg Oncol 2007; 33: 91-95
- 24 Norris HJ, Taylor HB. Mesenchymal tumors of the uterus. I. A clinical and pathological study of 53 endometrial stromal tumors. Cancer 1966; 19: 755-766
- 25 Kjerulff KH, Langenberg P, Seidman JD et al. Uterine leiomyomas. Racial differences in severity, symptoms and age at diagnosis. J Reprod Med 1996; 41: 483-490
- 26 Fang Z, Matsumoto S, Ae K et al. Postradiation soft tissue sarcoma: a multiinstitutional analysis of 14 cases in Japan. J Orthop Sci 2004; 9: 242-246
- 27 Yildirim Y, Inal MM, Sanci M et al. Development of uterine sarcoma after tamoxifen treatment for breast cancer: report of four cases. Int J Gynecol Cancer 2005; 15: 1239-1242
- 28 Lavie O, Barnett-Griness O, Narod SA et al. The risk of developing uterine sarcoma after tamoxifen use. Int J Gynecol Cancer 2008; 18: 352-356
- 29 Wysowski DK, Honig SF, Beitz J. Uterine sarcoma associated with tamoxifen use. N Engl J Med 2002; 346: 1832-1833
- 30 Wickerham DL, Fisher B, Wolmark N et al. Association of tamoxifen and uterine sarcoma. J Clin Oncol 2002; 20: 2758-2760
- 31 American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. ACOG committee opinion. No. 336: Tamoxifen and uterine cancer. Obstet Gynecol 2006; 107: 1475-1478
- 32 Toro JR, Nickerson ML, Wei MH et al. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 2003; 73: 95-106
- 33 Schwartz SM, Weiss NS, Daling JR et al. Exogenous sex hormone use, correlates of endogenous hormone levels, and the incidence of histologic types of sarcoma of the uterus. Cancer 1996; 77: 717-724
- 34 Trope CG, Abeler VM, Kristensen GB. Diagnosis and treatment of sarcoma of the uterus. A review. Acta Oncol 2012; 51: 694-705
- 35 Fletcher CDM et al. WHO Classification of Tumours of soft Tissue and Bone. Genf: World Health Organization (WHO); 2013
- 36 DʼAngelo E, Prat J. Uterine sarcomas: a review. Gynecol Oncol 2010; 116: 131-139
- 37 Prat J. FIGO staging for uterine sarcomas. Int J Gynaecol Obstet 2009; 104: 177-178
- 38 FIGO. Corrigendum to FIGO staging for uterine sarcomas. Int J Gynaecol Obstet 2009; 104: 179
- 39 Abeler VM, Røyne O, Thoresen S et al. Uterine sarcomas in Norway. A histopathological and prognostic survey of a total population from 1970 to 2000 including 419 patients. Histopathology 2009; 54: 355-364
- 40 Chew I, Oliva E. Endometrial stromal sarcomas: a review of potential prognostic factors. Adv Anat Pathol 2010; 17: 113-121
- 41 Gadducci A. Prognostic factors in uterine sarcoma. Best Pract Res Clin Obstet Gynaecol 2011; 25: 783-795
- 42 Rauh-Hain JA, del Carmen MG. Endometrial stromal sarcoma: a systematic review. Obstet Gynecol 2013; 122: 676-683
- 43 Park JY, Park SK, Kim DY et al. The impact of tumor morcellation during surgery on the prognosis of patients with apparently early uterine leiomyosarcoma. Gynecol Oncol 2011; 122: 255-259
- 44 Seidman MA, Oduyebo T, Muto MG et al. Peritoneal dissemination complicating morcellation of uterine mesenchymal neoplasms. PLoS One 2012; 7: e50058
- 45 Li AJ, Giuntoli 2nd RL, Drake R et al. Ovarian preservation in stage I low-grade endometrial stromal sarcomas. Obstet Gynecol 2005; 106: 1304-1308
- 46 Amant F, Coosemans A, Debiec-Rychter M et al. Clinical management of uterine sarcomas. Lancet Oncol 2009; 10: 1188-1198
- 47 Wallwiener D, Jonat W, Kreienberg R, Friese K, Diedrich K, Beckmann MW Hrsg. Atlas der gynäkologischen Operationen. 7. Aufl.. Stuttgart: Thieme; 2009
- 48 Bhave Chittawar P, Franik S, Pouwer AW et al. Minimally invasive surgical techniques versus open myomectomy for uterine fibroids. Cochrane Database Syst Rev 2014; (10) CD004638
- 49 DGGG. Indication and operative methods for hysterectomy, 2015. National German Guideline. Long version. AWMF registry no. 015/070. (Manuscript submitted for publication).
- 50 Nieboer TE, Johnson N, Lethaby A et al. Surgical approach to hysterectomy for benign gynaecological disease. Cochrane Database Syst Rev 2009; (3) CD003677
- 51 Sinha R, Hegde A, Mahajan C et al. Laparoscopic myomectomy: do size, number, and location of the myomas form limiting factors for laparoscopic myomectomy?. J Minim Invasive Gynecol 2008; 15: 292-300
- 52 Steiner RA, Wight E, Tadir Y et al. Electrical cutting device for laparoscopic removal of tissue from the abdominal cavity. Obstet Gynecol 1993; 81: 471-474
- 53 Brucker S, Solomayer E, Zubke W et al. A newly developed morcellator creates a new dimension in minimally invasive surgery. J Minim Invasive Gynecol 2007; 14: 233-239
- 54 Milad MP, Milad EA. Laparoscopic morcellator-related complications. J Minim Invasive Gynecol 2014; 21: 486-491
- 55 Brölmann H, Tanos V, Grimbizis G et al. Options on fibroid morcellation; a literature review. Gynecol Surg 2014; DOI: 10.1007/s10397-015-0878-4.
- 56 Leung F, Terzibachian JJ, Gay C et al. [Hysterectomies performed for presumed leiomyomas: should the fear of leiomyosarcoma make us apprehend non laparotomic surgical routes?]. Gynecol Obstet Fertil 2009; 37: 109-114
- 57 Einstein MH, Barakat RR, Chi DS et al. Management of uterine malignancy found incidentally after supracervical hysterectomy or uterine morcellation for presumed benign disease. Int J Gynecol Cancer 2008; 18: 1065-1070
- 58 Wright JD, Tergas AI, Burke WM et al. Uterine pathology in women undergoing minimally invasive hysterectomy using morcellation. JAMA 2014; 312: 1253-1255
- 59 Major FJ, Blessing JA, Silverberg SG et al. Prognostic factors in early-stage uterine sarcoma. A Gynecologic Oncology Group study. Cancer 1993; 71 (4 Suppl.) 1702-1709
- 60 Pritts EA. Obstetrics and Gynecology Devices Panel of the FDA Medical Devices Advisory Committee, July 10, 2014.
- 61 Leibsohn S, dʼAblaing G, Mishell jr. DR et al. Leiomyosarcoma in a series of hysterectomies performed for presumed uterine leiomyomas. Am J Obstet Gynecol 1990; 162: 968-974 discussion 974–976
- 62 Parker WH, Fu YS, Berek JS. Uterine sarcoma in patients operated on for presumed leiomyoma and rapidly growing leiomyoma. Obstet Gynecol 1994; 83: 414-418
- 63 Kamikabeya TS, Etchebehere RM, Nomelini RS et al. Gynecological malignant neoplasias diagnosed after hysterectomy performed for leiomyoma in a university hospital. Eur J Gynaecol Oncol 2010; 31: 651-653
- 64 Cantú de León D, González H, Pérez Montiel D et al. Uterine sarcomas: review of 26 years at The Instituto Nacional de Cancerologia of Mexico. Int J Surg 2013; 11: 518-523
- 65 Leung F, Terzibachian JJ, Aouar Z et al. [Uterine sarcomas: clinical and histopathological aspects. Report on 15 cases]. Gynecol Obstet Fertil 2008; 36: 628-635
- 66 Leung F, Terzibachian JJ. Re: “The impact of tumor morcellation during surgery on the prognosis of patients with apparently early uterine leiomyosarcoma”. Gynecol Oncol 2012; 124: 172-173 author reply 173
- 67 Kido A, Togashi K, Koyama T et al. Diffusely enlarged uterus: evaluation with MR imaging. Radiographics 2003; 23: 1423-1439
- 68 Ramm O, Gleason JL, Segal S et al. Utility of preoperative endometrial assessment in asymptomatic women undergoing hysterectomy for pelvic floor dysfunction. Int Urogynecol J 2012; 23: 913-917
- 69 Tulandi T, Ferenczy A. Biopsy of uterine leiomyomata and frozen sections before laparoscopic morcellation. J Minim Invasive Gynecol 2014; 21: 963-966
- 70 Tamura R, Kashima K, Asatani M et al. Preoperative ultrasound-guided needle biopsy of 63 uterine tumors having high signal intensity upon T2-weighted magnetic resonance imaging. Int J Gynecol Cancer 2014; 24: 1042-1047
- 71 Bansal N, Herzog TJ, Burke W et al. The utility of preoperative endometrial sampling for the detection of uterine sarcomas. Gynecol Oncol 2008; 110: 43-48
- 72 Rha SE, Byun JY, Jung SE et al. CT and MRI of uterine sarcomas and their mimickers. AJR Am J Roentgenol 2003; 181: 1369-1374
- 73 Koyama T, Togashi K, Konishi I et al. MR imaging of endometrial stromal sarcoma: correlation with pathologic findings. AJR Am J Roentgenol 1999; 173: 767-772
- 74 Tirumani SH, Ojili V, Shanbhogue AK et al. Current concepts in the imaging of uterine sarcoma. Abdom Imaging 2013; 38: 397-411
- 75 Hagemann IS, Hagemann AR, LiVolsi VA et al. Risk of occult malignancy in morcellated hysterectomy: a case series. Int J Gynecol Pathol 2011; 30: 476-483
- 76 Montella F, Riboni F, Cosma S et al. A safe method of vaginal longitudinal morcellation of bulky uterus with endometrial cancer in a bag at laparoscopy. Surg Endosc 2014; 28: 1949-1953
- 77 Favero G, Anton C, Silva e Silva A et al. Vaginal morcellation: a new strategy for large gynecological malignant tumor extraction: a pilot study. Gynecol Oncol 2012; 126: 443-447
- 78 Harter P, El-Khalfaoui K, Heitz F et al. Operative and conservative treatment of uterine sarcomas. Geburtsh Frauenheilk 2014; 74: 267-270
- 79 Bonvalot S, Rivoire M, Castaing M et al. Primary retroperitoneal sarcomas: a multivariate analysis of surgical factors associated with local control. J Clin Oncol 2009; 27: 31-37
- 80 Oduyebo T, Rauh-Hain AJ, Meserve EE et al. The value of re-exploration in patients with inadvertently morcellated uterine sarcoma. Gynecol Oncol 2014; 132: 360-365
- 81 Perri T, Korach J, Sadetzki S et al. Uterine leiomyosarcoma: does the primary surgical procedure matter?. Int J Gynecol Cancer 2009; 19: 257-260
- 82 Morice P, Rodriguez A, Rey A et al. Prognostic value of initial surgical procedure for patients with uterine sarcoma: analysis of 123 patients. Eur J Gynaecol Oncol 2003; 24: 237-240
- 83 Kamp JE, David M, Scheurig-Muenkler C et al. [Clinical outcome of magnetic-resonance-guided focused ultrasound surgery (MRgFUS) in the treatment of symptomatic uterine fibroids]. Rofo 2013; 185: 136-143
- 84 van der Kooij SM, Ankum WM, Hehenkamp WJ. Review of nonsurgical/minimally invasive treatments for uterine fibroids. Curr Opin Obstet Gynecol 2012; 24: 368-375
- 85 Gupta JK, Sinha A, Lumsden MA et al. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev 2012; (5) CD005073
- 86 Uccella S, Cromi A, Bogani G et al. Transvaginal specimen extraction at laparoscopy without concomitant hysterectomy: our experience and systematic review of the literature. J Minim Invasive Gynecol 2013; 20: 583-590
- 87 Brucker SY, Hahn M, Kraemer D et al. Laparoscopic radiofrequency volumetric thermal ablation of fibroids versus laparoscopic myomectomy. Int J Gynaecol Obstet 2014; 125: 261-265
- 88 DʼAngelo A, Amso NN, Wood A. Uterine leiomyosarcoma discovered after uterine artery embolisation. J Obstet Gynaecol 2003; 23: 686-687
- 89 Common AA, Mocarski EJ, Kolin A et al. Therapeutic failure of uterine fibroid embolization caused by underlying leiomyosarcoma. J Vasc Interv Radiol 2001; 12: 1449-1452
- 90 American College of Obstetricians and Gynecologists. Informed Consent. 2012. Online: http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Ethics/Informed-Consent last access: 01.08.2014
- 91 Paul PG, Koshy AK. Multiple peritoneal parasitic myomas after laparoscopic myomectomy and morcellation. Fertil Steril 2006; 85: 492-493
- 92 ESGE Directors and Executive Board. Statement on morcellation. Online: http://www.esge.org/article/218 last access: 15.07.2014
- 93 Reiter RC, Wagner PL, Gambone JC. Routine hysterectomy for large asymptomatic uterine leiomyomata: a reappraisal. Obstet Gynecol 1992; 79: 481-484
- 94 Takamizawa S, Minakami H, Usui R et al. Risk of complications and uterine malignancies in women undergoing hysterectomy for presumed benign leiomyomas. Gynecol Obstet Invest 1999; 48: 193-196