GASTRIC MALT. CONCEPT AND ETIOLOGY. CLASIFICATION. CLINICAL ASPECTS. ENDOSCOPICAL AND HISTOLOGICAL. TREATMENTS VARIANT

40. GASTRIC MALT. CONCEPT AND ETIOLOGY. CLASIFICATION. CLINICAL ASPECTS. ENDOSCOPICAL AND HISTOLOGICAL. TREATMENTS VARIANTS.

41. Overview

42. Image :StomachYour stomach is a muscular sac about the size of a small melon that expands when you eat or drink to hold as much as a gallon of food or liquid. ...

43. Causes  The stomach is a muscular sac located in the upper middle of your abdomen, just below your ribs. The stomach walls are lined with three layers of powerful muscles that mix food with enzymes and acids produced by glands in the stomach's inner lining. Under normal conditions, your stomach produces 2 to 3 quarts of gastric juices every day. One of these, hydrochloric acid, is so corrosive it can dissolve iron nails. Your stomach's delicate tissues are protected from this powerful acid by a thick, jelly-like mucus that coats the stomach lining(SIALOMUCYN). Once the food in your stomach is thoroughly broken down and mixed, muscular contractions push it toward the pyloric valve, which leads into the upper portion of your small intestine (duodenum). The valve opens just enough to release a scant eighth of an ounce of food at a time. It may take three to four hours for your stomach to empty after you eat, depending on your diet. Foods high in fat increase the amount of time it takes for your stomach to empty.

44. Overview

46. INTRODUCCIONFactores de virulencia: CagA y VacA

47. Overview

48. Although adenocarcinomas account for about 95 percent of all stomach cancers, other forms of the disease can sometimes occur, including:Lymphomas. These are cancers of immune system tissue in the stomach wall. Some lymphomas are aggressive whereas others grow much more slowly. The latter, known medically as mucosa-associated lymphoid tissue (MALT) lymphomas, usually stem from H. pylori infection and are often curable when found in the early stages(Endoscopy, EUS, and eventually complementary Oncotherapy.

50. H. pylori infection frequently occurs in childhood and can last throughout life if not treated It's the primary cause of stomach ulcers, accounting for at least 80 percent of all cases. It may also be the main cause of stomach cancer. According to the World Health Organization, close to half the annual new cases of stomach cancer can be attributed to H. pylori infection. Having ulcers doesn't necessarily put you at higher risk of stomach cancer, but having H. pylori infection does. That's because long-term infection causes inflammation that can lead to precancerous changes in the stomach lining. One of these changes is atrophic gastritis, a condition in which the acid-producing glands are slowly destroyed. It's likely that low acid levels prevent cancer-causing toxins from being properly broken down or flushed out of your stomach. Countries such as China and Colombia, where a majority of children are infected with H. pylori, have a correspondingly high rate of stomach cancer.

51. Risk factors Having H. pylori infection makes you more likely to develop stomach cancer than someone who doesn't have the infection. Even so, most people with H. pylori don't get stomach cancer, and researchers believe that genetic factors make some people more susceptible to the disease. Having both H. pylori and a form of a gene that causes low stomach acid greatly increases your risk of stomach cancer and MALT.

52. DIRECT PCR FROM UREASE TEST AND Helicobacter pylori GENOTYPE 

53. EVOLUTION  H. pylori INFECTION

54. H. pylori Infection

55.  Virulence Factors : CagA and VacA

56. Genotipe vacA Prevalence

58. OBJETIVE Determine Direct PCR from Samples of Urease Test Pathogenetic Rol of Helicobacter pylori

59. METHODOLOGY and RESULTS

60. METHODOLOGYBiopsy SAMPLES

61. METHODOLOGYDNA Extraction

62. METHODOLOGYAmplification by PCR 16S RNAr

63. RESULTSAmplification through PCR (gen cagA)

64. METHODOLOGY PCR Amplification : cagA and vacA

65. RESULTSAmplification gen vacA (Signal Sequence)

66. RESULTSAmplification gen vacA Middle Region

67. Genotipes detected at ACHS

68. Genotipes detected at San Borja

69. PCR technic allow us to determine characteristics from many H Pylori subtypes. It is possible to use urease samples for PCR Study.. Eventually to determine antibiotic resistant subtypes to claritromicyn, without culture and antibiogram. CONCLUSIONS

70. FONDEF FOUNDATION CHILE 2005-8.

71.  Dr. Fernando Kawaguchi (1,2,3) DR Carlos Brice�o(1) Dr Patricio Ortiz(1) Dr Fernando Riquelme(1) Dr Rodrigo Loaiza(1) Dr Gonzalo Zuloaga(1) Dr Germ�n Abrigo(1) Dr Vicente Vera(1) Dra Apolinaria Garc�a(2) Dr Carlos Gonzalez(2) COLABORADORES Dr. Mauricio Gonz�lez (4) Prof. Rolando Montoya (2) Mag Juan Luis Castillo(2) Mag Marcelo Castillo(1) Dra CG Ya�ez(3) Dr German Errazuriz(5) Dr Alberto Rossle(1) Dr Oscar Venegas(1) Dr. Jaime Madariaga Boero (1) Dra. Alejandra Mart�nez, MsSc(2) Prof. Jorge Roa Sandoval, PhD (1) EU Edith Vega(3) EU Lorena Ruiz(1) ALUMNOS AYUDANTES Ignacio Alfaro P�rez Srta Tamara Perez Nelson Perez Lynch Mracela Lefer Sr Cristi�n Vasquez

72. CLINICAL ASPECTS And MINIMAL THERAPY: Gastric lYMPHOMA MALT is diagnosed more frequently as EARLY AS 30-50 years old, with a predominance of the men on the women of 1,7/1. At the moment of its diagnosis it is a tumor of low degree in a 70-85% of the cases. It seats preferently in ulcers: 41%, being able to be multifocal in a 33% (11). Gastric lymphoma MALT is one neoplasia that produces little clinical manifestations in its initial stages, being able even to be non symptoms. Usually it causes a dispepsia ulcer simil or functional. The advanced tumors very rarely produce a clinical picture similar to gastric carcinoma, with loss of weight, anorexy, bleeding and mass

73. Diagnosis Strategy: Dr Rodrigo Loaiza, Dr Vicente Vera The diagnosis of lymphoma MALT is based on the gastroscopy, with biopsies. Barium radiology is a method clearly inferior to the endoscopy. Endoscopically we will be able to be so single with a mucosa of eroded aspect, with a solution of continuity in the endoscopy, with the presence of ulcer, with fold frequently thickened and with irregular or polipoids masses. The mucosa can have an infiltrative aspect of isolated, diffuse or multicentric form. The finding of thickened fold and multiple ulcers, sometimes confluent, that even can exceed pilorous and to affect the duodenum is suggestive of linphomatous injury.

74. IN Submucosal compromise, Pathologist needs more samples which are taken under EUS , with biopsy in biopsy. We have already all this technics under Protocolus (ISO 9000), between endoscopist, pathologist, nurse and assistant. The tumorlike cells are generally lymphocytes B of small-medium size with somewhat abundant cytoplasm and nucleus of irregular form, resembling itself the centrocites, reason why denominates centrocitoid lymphocytes to them. Less frequently they can be monocitoids, or in form of small lymphocytes. In a same injury it can have a clear one predominant cellular type, or coexist several of them (3). Although the graduation of Wotherspoon (6), facilitates the histologyc diagnosis, this diagnosis based single on the morphology can be difficult, specially as opposed to certain cases of follicular gastritis. It is considered as the morphologic characteristic more characteristic of limphoma MALT to the presence of linfoepitelial, consisting of injury the invasion of cripta by aggregates of centrocitoids lymphocytes.

75. Other histologycal findings are with moderate atipia cellular of the tumorlike lymphocytes and the presence of lymphocytes with bodies of Dutcher, although its absence does not discard the diagnosis. Sometimes we need immunohistopathology, and Flow cytometry. Although false positives can occur and negatives, the monoclonality supports the diagnosis of limphoma. The inmunohistologics studies show positivity in CD20, CD21, CD35 and IgM and negatividad to CD5, CD10 and CD23 (8). The monoclonality of lymphocytes B studies by Southern Blot or techniques of PCR is not equivalent to malignance, being able to have monoclonality without lymphoma or to persist this one during a time after the disappearance of the tumor. The meaning of the monoclonality must be interpreted in the context of the morphologic injuries (10). The division in lymphoma of low and high degree becomes according to the proportion of blastics cells in the injury (9). The classification of the tumor in stop or under degree is important, since the high degree entails more aggressive a clinical picture and a worse prognosis.

76. El diagn�stico histol�gico del grado puede ser dif�cil en determinados pacientes, ya que ambos grados pueden coexistir en una misma lesi�n o en diferentes lesiones multifocales, habi�ndose descrito la transformaci�n evolutiva de bajo a alto grado en los linfomas MALT (2). Se considera que la presencia de islotes de m�s de 20 c�lulas transformadas, o una proporci�n superior al 15-20% de c�lulas de alto grado tiene significaci�n cl�nica (8). En determinados linfomas de alto grado no se aprecia ning�n signo de lesi�n de bajo grado, por lo que estos tumores pueden considerarse de alto grado "de novo". No obstante, este dato carece de significaci�n pron�stica al no haberse registrado diferencias cl�nicas con los linfomas que progresan de bajo a alto grado (3). Adem�s del grado histol�gico es muy importante la clasificaci�n de los linfomas MALT seg�n su estadio tumoral. La clasificaci�n m�s empleada es la Ann Arbor (12), modificada por Musshoff (13), que resumimos en la Tabla II, y que abarca desde el estadio E I: tumor limitado a las paredes del est�mago al E IV: afectaci�n diseminada a otros �rganos.

77. Logically an advanced tumorlike stage entails a worse prognosis. In the case of lymphoma of low degree, at the moment of the diagnosis a 80% are in stage and I1, are to say that the tumor limits the mucosa and gastric submucosa, without affecting deeper structures(EUS STUDY). In general, and unlike others lymphomas extra-nodals, gastric MALT tends to remain located in the wall of the stomach during long time, years, even allowing endoscopical treatment (+) H. Pylori treatment during 3 months and new control until two years. (3). Occasionally MALT can propagate through the stomach and have progression a distance, including the invasion of intestine, bone marrow and spleen.

79. At the moment the echo-endoscopy is very useful to even carry out a correct estadification of the tumor (14), that will be completed with the habitual techniques of image like TAC, and with the medullar punction.(Dr Fernando Kawaguchi, during last the 10 years) In our opinion the diagnostic strategy of gastric MALT needs: 1. - Confirmation of the infection by Helicobacter Pylori by means of fast test of urease and histologic study. 2. - Exhaustive Maping of the gastric mucosa and even of the duodenum, with biopsies at multiple levels to discard multifocal injuries. (HOSPITAL TRABAJADOR CONCEPCION PROTOCOL DURING LAST 10 years) 3. - Histologycal study, that can include macrobiopsies in the vegetating injuries, to confirm MALT and its degree. The anatomopathological study must be completed with inmunohistological and flowcytometry study and PCR to confirm the monoclonality of the lymphocytes.

80. treatment Nowadays we have several therapeutic possibilities to gastric MALT, which include: 1. - Erradicate treatment of the infection by Helicobacter Pylori; 2. - Surgical treatment; (Dr Oscar Lynch) 3. - Nonsurgical oncol�gical complementary treatment. (According to Protocol Dr Alberto Rossle, Dr Mario Fernandez, Dr Caesar Diaz) These modalities of treatment can be complemented to each other. In the case of low degree significant differences in the survival have not been after erradicate treatment, surgery, chemotherapy and surgery more chemotherapy or radiotheraphy (Depend on deeper compromise- EUS)(11). Treatment by means of the eradication of the Helicobacter Pylori: We have already commented that the practical totality of MALT are Helicobacter Pylori (+). In the tumors of low degree the immunological stimulus was demonstrated that the eradication of the bacterium was followed of the regression of neoplasia (15), when interrupting that maintained its growth. This tumorlike remission seems permanent, having itself confirmed in the 5 cases presented/displayed (2000-2005), passed 5 years of erradicaci�n(3 of 5 patients In last bibliographical revisions of 203 published cases, objective a total remission of the tumor in 80%, partisan in a 10% and nonregression in 10%.

81. It has been observed that most of the failures after the eradication of the Helicobacter Pylori corresponds to linfomas of high degree or low degree with stage superior to and I1, is to say with the tumor escaping submucosa(sm3). At the time to obtain the result after the eradication it is very important to consider that the tumorlike regression can require an important period of time. In a multicentric series of 49 patients, the passed average time from the eradication to the complete histol�gica remission was of 5 months, but in a 30% of patients a very superior time was needed (11), having itself published complete remissions that took up to 12 and 18 months (8).(6 months in our experience). For that reason, before considering like definitive a lack of tumorlike remission, endoscopy and echo-endoscopy of control must take place.

82. If the neoplasic injury stay stable not need more agresive treatment, without it increases the risk for the patient (3). At sight of these results, the treatment of election for lymphoma of low degree and tumorlike stage and I1, that we remembered supposes 80% of all MALT, would be the eradication of the Helicobacter Pylori.(During at least 3 months according to our experrience, according to sensitivity and antibiotic resistance. Corroborating this study with the later genotipificaci�n). In neoplasias locally from high degree, and although have obtained some cases of tumorlike remission, is advised that the erradicador treatment has character of complement to the rest of the therapeutic possibilities. The patients whose tumor sent with the eradication must be followed in specialized Centers, since they are going to need a strict evolutionary control. Although the type and the frequency of the controls post-eradication are in discussion, an advisable guideline could be the following one: endoscopical control to 3, 6 and 12 months after the eradication, Every 6 months during the second annual years. Given the recent erradication treatment, still there is no agreement on the duration . A period which includes up to 15 years, with multiple biopsies for morphologic study and of monoclonality, as well as technical of urease and histologyc examination has set out to discard a recidiva of the infection by Helicobacter

83. BIBLIOGRAPHY -1.- Isaacson P., Wright D.H. Malignant lymphoma of mucosa-associated lymphoid tissue. A distinctive type of B-cell lymphoma. Cancer. 1.983; 52: 1410-1416 2.- Gisbert J.P., Boixeda D., Martin de Argila C. Infecci�n por Helicobacter Pylori y c�ncer g�strico. En: Infecci�n por Helicobacter Pylori. �D�nde est� el l�mite?. Boixeda D., Gisbert J.P., Martin de Argila C. ed. Prous Science. Barcelona. Espa�a. 1.996: 179-197 3.- Zucca E. B-cell lymphoma of MALT type: a review with special emphasis on diagnostic and management problems of low-grade gastric tumours. Br. J. Haematol. 1.998; 100: 3-14 4.- Stolte M., Eidt S., Bayerdorffer E., Fischer R. Helicobacter Pylori associated gastric lymphoma. En: Helicobacter Pylori, basic mechanisms to clinical use. De Hunt R.H., Tytgat G.N. ed. Kluwer Academic Publishers. Lancaster U.K. 1.994: 498-503 5.- Borda F., Martinez-Pe�uela J.M., Echarri A., Valenti C. y cols. Linfoma G�strico primario e infecci�n por Helicobacter Pylori: �Puede haber una relaci�n epidemiol�gica de causalidad?. Anales. 1.998; 21 supl.2: 55-59 6.- Wotherspoon A.C., Doglioni C., Diss T.C., Pan L. y cols. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue after eradication of Helicobacter Pylori. Lancet. 1.993; 342: 575-577 7.- Du M., Diss T.C., Xu C., Peng H. y cols. Ongoing mutation in MALT lymphoma immunoglobulin gene suggests that antigen stimulation plays a role in the clonal expansion. Leukemia. 1.996; 10: 1190-1197 8.- Isaacson P.G. Primary gastric lymphoma. Haematologica (ed. Esp.). 1.998; 83 supl. 1: 509-513 9.- Espa�a M.P., Huelin J., De la Cruz J. Helicobacter Pylori y linfoma g�strico. En: Helicobacter Pylori, un paso m�s. Huelin J. ed. Prous Science. Barcelona. Espa�a. 1.997: 59-63 10.- Stolte M., Meining A. Helicobacter Pylori y linfoma MALT. Efecto del tratamiento. En: Infecci�n por Helicobacter Pylori en lesiones gastroduodenales. La segunda d�cada. Pajares J.M. ed. Prous Science. Barcelona. Espa�a. 1.998: 223-230

84. 11.- Pinotti G., Zucca E., Roggero E., Pascarella A. y cols. Clinical features, treatment outcome in a series of 93 patients with low-grade gastric MALT lymphoma. Leukemia and Lymphoma. 1.997; 26: 527-537 12.- Carbone P.P., Kaplan H. S., Musshoff K., Smithers D.W. y cols. Report of the comitee on Hodgkin�s disease staging procedures. Cancer Res. 1.971; 31: 1860-1861 13.- Musshoff K. Klinische Stadieneitenlung der nicht-Hodgkin lymphome. Strahlentherapie. 1.977; 153: 218-221 14.- Pavlick A.C., Gerdes H., Porlock C.S. Endoscopic ultrasound in the evaluation of gastric small lymphocitic mucosa-associated lymphoid tumours. J. Clin. Oncol. 1.997; 15: 1761-1766 15.- Stolte M., Eidt S. Healing MALT lymphomas by eradicating Helicobacter Pylori?. Lancet. 1.993; 342: 56816.- Hammel P., Haioun C., Chaumette M.T., Gaulard P. Y cols. Efficacy of single agent chemotherapy in low-grade B-cell mucosa-associated lymphoid tissue lymphoma with prominent gastric expression. J. Clin. Oncol. 1.995; 13: 2524-2529�� 14.- Pavlick A.C., Gerdes H., Porlock C.S. Endoscopic ultrasound in the evaluation of gastric small lymphocitic mucosa-associated lymphoid tumours. J. Clin. Oncol. 1.997; 15: 1761-1766 15.- Stolte M., Eidt S. Healing MALT lymphomas by eradicating Helicobacter Pylori?. Lancet. 1.993; 342: 568 16.- Hammel P., Haioun C., Chaumette M.T., Gaulard P. Y cols. Efficacy of single agent chemotherapy in low-grade B-cell mucosa-associated lymphoid tissue lymphoma with prominent gastric expression. J. Clin. Oncol. 1.995; 13: 2524-2529

85. Ann-Arbor Clasification lymphomas extra-nodals. Modification of Musshoff

86. Histological Graduation : infection by Helicobacter Pylori-MALT 1. Normal 2. Active Chronic Gastritis 3 . Active Chronic Gastritis with limphoid nodes 4 . Lymphoid Infiltrate in lamina propia 5. Lymphoid Infiltrate in lamina propia. Probably Lymphoma 6. MALT of Low Grade

87. Indicaciones y efectividad cl�nica. La EUS posee una serie de indicaciones establecidas en las que es superior a otras t�cnicas de imagen incluyendo la tomograf�a axial computarizada (TAC) y la arteriograf�a La EUS permite la identificaci�n y la estadificaci�n de tumores gastrointestinales, del es�fago, est�mago, recto y del p�ncreas y v�as biliares, tanto en el grado de infiltraci�n parietal ( etapificaci�n T) como en la detecci�n de adenopat�as (estadificaci�n N), con una certeza diagn�stica superior a la de otras t�cnicas de imagen. En el caso del linfoma MALT de bajo grado, la EUS permite predecir la respuesta al tratamiento erradicador. En un estudio del grupo de Bayerdoerffer , si el linfoma estaba localizado en la mucosa o submucosa (estad�o E-I1), la probabilidad de regresi�n completa fue del 100% a los 14 meses, mientras que ninguno de los pacientes con estad�o m�s avanzado mostraron regresi�n completa

88. Caracter�sticas a determinar en un Tsm por EUS. Recientemente, un estudio prospectivo y multic�ntrico ha definido los criterios ecoendosc�picos por los que deben remitirse a cirug�a aqu�llos Tsm que cumplan uno o m�s de los criterios expuestos en la tabla III. En este estudio se analizaron 122 Tsm en 120 pacientes y se remitieron a cirug�a aqu�llos pacientes cuyos TSM ten�an una de estas caracter�sticas. Se resecaron 46 TSM y dado que el valor predictivo positivo para malignidad fue del 68%, se recomienda la cirug�a si se cumple alguna de estas circunstancias. La EUS en el estudio de los TSM y compresiones extr�nsecas ha demostrado en estudios controlados, reducir el n�mero de pruebas diagn�sticas (algunas invasivas), proporciona una indicaci�n racional de cirug�a y la relaci�n coste-beneficio depende del coste de la EUS y el de las otras t�cnicas evitadas.

89. PUNCION-ASPIRACION BIOPSIA CON AGUJA FINA Los patrones ecogr�ficos orientativos descriptivos que intentaban diferenciar entre adenopat�as inflamatorias o metast�sicas han quedado obsoletos con la PA-EUS. Se han comparado estos criterios ecogr�ficos frente a los hallazgos finales citol�gicos, obteni�ndose una especificidad del 24% y del 93%, respectivamente. La PA-EUS proporciona adem�s de un diagn�stico por imagen, uno de certeza anatomopatol�gico. Por razones t�cnicas, existen diferencias de rendimiento de la PA-EUS dependiendo de la naturaleza de la lesi�n diana. As�, en un estudio multic�ntrico de Wiersema, la sensibilidad y la certeza diagn�stica fueron superiores en adenopat�as y masas extramurales frente a las lesiones murales

90. Tabla VI. Rendimiento diagn�stico dependiendo de la naturaleza de la lesi�n �

91. Implicancias terap�uticas en la etapificaci�n tumoral por PA-EUS.

92. MUCOSECTOMY. La resecci�n endosc�pica de tumores localizados en la capa mucosa o mucosectom�a, puede realizarse en es�fago, est�mago y recto-colon. En Jap�n esta t�cnica es un tratamiento establecido en la terapia radical del c�ncer g�strico en vez de la cirug�a, en adenocarcinomas bien diferenciados, no ulcerados, limitados a la mucosa(o sm1) y menores de 2 cms de di�metro(Seg�n �ltimos Protocolos de Consenso de Par�s) Los tumores localizados en la capa mucosa pueden ser subsidiarios de resecci�n endosc�pica con asa de diatermia, tras inyectar adrenalina 1/20 en su base. Pero, para realizar esta t�cnica la tumoraci�n debe estar confinada a la capa mucosa, o sm1. Es una t�cnica curativa del c�ncer totalmente endosc�pica, con pocas complicaciones. En el trabajo de Kida se analizan los resultados en una serie de 246 resecciones endosc�picas de tumores mucosos, con una tasa de resecci�n radical del 68.3% (168 de 246), de recurrencia tumoral del 2.8% (7 casos) y sin mortalidad debida al tumor.

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