Lymphatic mapping improves staging during laparoscopic colectomy for cancer.

BACKGROUND: Recently, lymphatic mapping (LM) of the sentinel lymph node (SN) has been coupled with ultrastaging methods to diagnose nodal micrometastases from colorectal cancer (CRC). We have developed a technique for LM at the time of laparoscopic colon resection (LCR). METHODS: Between August 1996 and February 2000, 11 patients with small early-stage CRC underwent laparoscopic LM and LCR. The primary tumor/polyp site was visualized through a colonoscope and either tattooed preoperatively with a carbon dye (India ink), or stained intraoperatively by peritumoral injection of isosulfan blue dye. Immediately after intraoperative injection of blue dye, efferent lymphatic channels were visualized through the laparoscope and followed to the SN. Each blue-stained SN was marked with a suture or clip. RESULTS: In all 11 cases, laparoscopic LM identified between one and three SN draining the primary tumor. LM added ~15-20 min to the operating time. The SN correctly reflected the nodal status of the entire specimen in all cases. In the one node-positive case, micrometastases were found only in an SN and only after cytokeratin immunohistochemistry (CK-IHC). In four cases, LM demonstrated unexpected primary lymphatic drainage that prompted an increase in the margins of resection. CONCLUSIONS: LM during laparoscopic colectomy for CRC may be useful to mark the primary tumor site and to demonstrate lymphatic drainage that can alter the margins of resection. Focused examination of SN identifies occult micrometastases that up-stage CRC.

Aberrant drainage and missed micrometastases: the value of lymphatic mapping and focused analysis of sentinel lymph nodes in gastrointestinal neoplasms.

Lymph node analysis is essential for staging gastrointestinal (GI) neoplasms. Our group has conducted several studies of intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL) for the staging of GI neoplasms. LM is performed following injection of 0.5-1 ml of isosulfan blue dye, and blue-stained sentinel lymph nodes (SLNs) are analyzed by hematoxylin and eosin (H&E) staining, multiple sectioning, and cytokeratin immunohistochemistry. In feasibility trials, LM identified at least one SLN in 121 of 126 patients. Of the 58 cases with nodal metastasis, 50 (89%) had at least one positive SLN and 24 (42%) had nodal metastasis only in the SLN. In 25 cases, tumor deposits were identified by multiple sectioning (n = 8) or immunohistochemistry (n = 17) only. In 10 cases (8%), LM identified aberrant lymphatic drainage that altered the extent of the lymphadenectomy. Our cumulative experience indicates that focused analysis of the SLNs draining GI neoplasms can increase the detection of micrometastases and may improve selection of patients for adjuvant treatment.

Diagnostic laparoscopy and laparoscopic ultrasonography optimize the staging and resectability of intraabdominal neoplasms.

BACKGROUND: Despite technical improvements, preoperative imaging studies often fail to predict intraoperative findings. We investigated the potential use of diagnostic laparoscopy (DL) and laparoscopic ultrasonography (LUS) for the assessment of disease in patients with abdominal neoplasms. METHODS: Fifty consecutive patients with abdominal neoplasms underwent spiral computed tomography with oral and intravenous contrast using 5-mm contiguous sections. In addition, eight patients underwent ultrasonography, six underwent magnetic resonance imaging, and eight underwent positron emission tomography. All patients then underwent DL and LUS using a 7.5-MHz ultrasound probe. RESULTS: There were 29 men and 21 women with a mean age of 63 years (range, 35-84). Most had a diagnosis of colorectal cancer (19 cases), melanoma (12 cases), or hepatoma (five cases). In nine cases (18%), DL revealed peritoneal metastatic implants not shown on preoperative images. In 18 cases (36%), LUS was more accurate than preoperative imaging. Combined DL and LUS findings radically changed the operative management in 16 patients (32%). CONCLUSION: As compared with preoperative imaging, the combination of DL and LUS provides more accurate information regarding staging and resectability. Moreover, it helps to determine the extent of operation and reduces the number of unnecessary laparotomies. DL and LUS should be used as an adjunct to preoperative imaging studies in patients with primary or metastatic intraabdominal neoplasms.

Laparoscopic radiofrequency ablation of unresectable hepatic malignancies. A phase 2 trial.

BACKGROUND: Radiofrequency ablation (RFA) of hepatic malignancies has been performed successfully via a percutaneous route or at laparotomy. We analyzed the efficacy and utility of laparoscopic intraoperative ultrasound and RFA in patients with unresectable hepatic malignancies. METHODS: Between November 1997 and November 1999, 27 patients with unresectable hepatic malignancies and no evidence of extrahepatic disease were entered in a phase 2 trial of laparoscopic intraoperative ultrasound and RFA. Real-time ultrasonography was used to guide RFA, and lesions were ablated at a temperature of 100 degrees C for 10 min. Overlapping ablations were performed for larger lesions. RESULTS: Additional tumors were identified in 10 (37%) of the 27 study patients by laparoscopy and laparoscopic intraoperative ultrasound despite extensive preoperative imaging. Radiofrequency ablation of 85 hepatic tumors yielded no mortality and only one case of postoperative bleeding. During a mean follow-up period of 14 months, four tumors (4.7%) locally recurred. Of the 27 patients, 11 (41%) remain free of disease at this writing; (22%) are alive with disease; and 10 (37%) have died with disease. CONCLUSION: Laparoscopic RFA and intraoperative ultrasound constitute a safe and accurate method for ablation of unresectable hepatic tumors.

Serum TA90 antigen-antibody complex as a surrogate marker for the efficacy of a polyvalent allogeneic whole-cell vaccine (CancerVax) in melanoma.

INTRODUCTION: TA90 is a tumor-associated 90-kD glycoprotein antigen expressed on most melanoma cells, including those of CancerVax, a polyvalent allogeneic whole-cell vaccine. Previous studies have shown that a TA90 antigen-antibody immune complex (IC) in the serum of patients with melanoma is a marker of subclinical tumor burden and a strong prognostic factor. We hypothesized that the induction of TA90-IC during postoperative adjuvant CancerVax therapy might indicate vaccine-mediated immune destruction of subclinical melanoma cells with release of TA90, and thereby serve as a surrogate marker of vaccine efficacy. METHODS: From 1993 to 1997, 219 melanoma patients were enrolled in a prospective phase II trial of CancerVax plus bacille Calmette-Guerin (BCG) after complete tumor resection. Coded serum samples were prospectively collected and analyzed for TA90-IC before and 2, 4, 8, 12, and 16 weeks after initiation of CancerVax therapy. TA90-IC seroconverters were those patients whose negative TA90-IC values (< .410) became positive (> or = .410) after initiation of CancerVax treatment. RESULTS: Before CancerVax therapy, 51 patients had positive TA90-IC values and 168 patients had negative TA90-IC values. During CancerVax treatment, all 51 positive patients remained positive, 79 (47%) negative patients seroconverted to positive, and 89 (53%) negative patients remained negative. Seroconverters had higher 2-year rates of disease-free survival (59% vs. 32%; P < .006) and overall survival (78% vs. 63%; P < .02) than did patients whose TA90-IC values remained positive. CONCLUSIONS: CancerVax induces TA90-IC in melanoma patients with subclinical disease. TA90-IC seroconverted patients have significantly improved disease-free and overall survival compared with TA90-IC positive patients. TA90-IC is an important prognostic factor that can serve as a surrogate marker for the clinical efficacy of CancerVax.

Validation of lymphatic mapping in colorectal cancer: in vivo, ex vivo, and laparoscopic techniques.

BACKGROUND: The use of lymphatic mapping (LM) is being investigated to improve the staging of colorectal cancer (CRC) and thereby identify patients who might benefit from adjuvant chemotherapy. This study evaluated in vivo, laparoscopic, and ex vivo approaches for the ultrastaging of CRC. METHODS: Seventy-five CRC patients were enrolled in a study of LM with peritumoral injection of isosulfan blue dye. LM was undertaken during open colon resection (OCR) in 64 patients, during laparoscopic colon resection (LCR) in 9 patients, and after specimen removal (ex vivo) in 2 patients. Ex vivo LM was also undertaken in 6 patients after unsuccessful in vivo LM. All nodes were examined by hematoxylin and eosin (H&E) staining; in addition, sentinel lymph nodes (SNs) were multisectioned and examined by immunohistochemical staining with cytokeratin (CK-IHC). RESULTS: At least one SN was identified in 72 patients (96%). In vivo LM identified SNs in 56 of 64 (88%) patients undergoing OCR and in 9 of 9 (100%) patients undergoing LCR. Ex vivo LM was undertaken as the initial mapping procedure in 2 cases of intraperitoneal colon cancer and after in vivo LM had failed in 6 cases of extraperitoneal rectal carcinoma; an SN was identified in 7 of the 8 cases. Focused examination of the SN correctly predicted nodal status in 53 of 56 OCR cases, 9 of 9 LCR cases, and 6 of 7 ex vivo cases. Multiple sections and CK-IHC identified occult micrometastases in 13 patients (17%), representing 10 OCR, 1 LCR, and 2 ex vivo cases. CONCLUSIONS: LM of drainage from a primary CRC can be accurately performed in vivo during OCR or LCR. Ex vivo LM can be applied when in vivo techniques are unsuccessful and may be useful for rectal tumors. During LCR, colonoscopic injection can be used to mark the primary tumor and define the lymphatic drainage so that adequate resection margins are obtained. These LM techniques improve staging accuracy in CRC.

Focused examination of sentinel lymph nodes upstages early colorectal carcinoma.

Approximately 30 per cent of patients with early colorectal carcinoma (CRC) develop systemic disease. A subgroup of these patients may harbor occult micrometastatic disease and might benefit from adjuvant chemotherapy. We investigated sentinel lymph node (SLN) mapping and focused pathologic examination of the SLN as a means of detecting nodal micrometastases. Between 1996 and 2000 SLN mapping was performed in 50 consecutive patients undergoing colectomy for CRC. All lymph nodes in the resection specimen were examined via routine hematoxylin and eosin (H&E) staining. In addition multiple sections of each SLN were examined via both H&E and cytokeratin immunohistochemistry. At least one SLN was identified in 47 patients (94%). In seven patients (14%) SLN mapping identified aberrant drainage that altered the planned resection. The SLN(s) correctly predicted nodal basin status in 44 of 47 (94%) cases; there were three falsely negative SLNs. Sixteen cases had positive SLNs by conventional H&E staining. An additional 10 (20%) cases were upstaged by a focused examination of the SLNs. Micrometastases were identified in three cases by H&E staining of multiple sections of the SLN and in seven only by cytokeratin immunohistochemistry. In nine cases the SLN was the only node containing tumor cells. In this study, SLN mapping demonstrated aberrant nodal drainage patterns that altered the surgical resection in patients with CRC. Focused examination of SLNs may detect micrometastases missed by conventional techniques and thereby identify patients who might benefit from adjuvant therapy.

Arcuate relaxing incisions with a 5.00-mm optical zone for the correction of high postcataract astigmatism.

The purpose of this study was to investigate the efficacy and safety of arcuate cuts with a 5-mm optical zone to correct high postoperative astigmatism after extracapsular cataract extraction. We performed 5-mm optical zone arcuate cuts on 23 eyes of 23 patients with high postoperative astigmatism. Ophthalmic examination included uncorrected visual acuity (UCVA), best spectacle corrected visual acuity (BSCVA) and the amount of the refractive and keratometric cylinder before and 9 months after operation. Surgically induced refractive change was calculated in all cases. A significant reduction in astigmatism was achieved in all cases with minimal axis deviation. No case developed clinically significant irregular astigmatism. The mean magnitude of astigmatism of the surgically induced refractive change calculated from standard keratometry and refractive data was 3.73+/-0.72 and 3.70+/-0.77 dptr, respectively. The mean axis deviation calculated from the keratometric and refractive data was 1.18+/-2.33 and 1.32+/-3.62 degrees, respectively. At the last examination, 78.2% of the eyes had UCVA of 20/40 or better. No eye lost more than two lines of vision, 6 eyes lost one line, 2 eyes gained one and 1 eye gained two lines of BSCVA. The above data show that the 5-mm optical zone arcuate astigmatic keratotomy is an effective and safe method of correcting high postoperative astigmatism.

Lymphatic mapping and focused analysis of sentinel lymph nodes upstage gastrointestinal neoplasms.

BACKGROUND: Lymph node analysis is essential for staging gastrointestinal (GI) neoplasms. Intraoperative lymphatic mapping and sentinel lymphadenectomy were originally described for melanoma but have not yet been investigated for most GI neoplasms. HYPOTHESES: (1) Lymphatic mapping and sentinel lymphadenectomy is feasible in GI neoplasms, (2) the sentinel node (SN) status reflects the regional node status, and (3) focused analysis of the SN improves staging accuracy. DESIGN: Prospective patient series. PATIENTS AND METHODS: Lymphatic mapping was performed in 65 patients with GI neoplasms by injecting 0.5 to 1 mL of isosulfan blue dye around the periphery of the neoplasm. Blue-stained SNs were analyzed by hematoxylin-eosin staining, multiple sectioning, and cytokeratin immunohistochemistry. RESULTS: Lymphatic mapping identified at least 1 SN in 62 patients (95%). Of the 36 cases with nodal metastasis, 32 (89%) had at least 1 positive SN and 15 (42%) had nodal metastasis only in the SN. In 11 cases, tumor deposits were identified by multiple sectioning (n = 2) or immunohistochemistry (n = 9) only. In 5 cases (8%), lymphatic mapping identified aberrant lymphatic drainage that altered the extent of the lymphadenectomy. CONCLUSIONS: Lymphatic mapping and sentinel lymphadenectomy are feasible in GI neoplasms and identify aberrant lymphatic drainage. The SN status accurately reflects the regional node status. Focused analysis of the SN increases the detection of micrometastases and may improve selection of patients for adjuvant treatment.

Cryosurgical ablation and radiofrequency ablation for unresectable hepatic malignant neoplasms: a proposed algorithm.

BACKGROUND: Thermal ablation of unresectable hepatic tumors can be achieved by cryosurgical ablation (CSA) or radiofrequency ablation (RFA). The relative advantages and disadvantages of each technique have not yet been determined. HYPOTHESIS: Radiofrequency ablation of malignant hepatic neoplasms can be performed safely, but is currently limited by size. Cryosurgical ablation, while associated with higher morbidity, is more effective for larger unresectable hepatic malignant neoplasms. DESIGN: Retrospective analysis of prospective patient database. PATIENTS AND METHODS: Between July 1992 and September 1999, 308 patients with liver tumors not amenable to curative surgical resection were treated with CSA and/or RFA (percutaneous, laparoscopic, celiotomy). No patient had preoperative evidence of extrahepatic disease. All patients underwent laparoscopy with intraoperative ultrasound if technically possible. Both RFA and CSA were performed under ultrasound guidance. Resection, as an adjunctive procedure, was combined with ablation in certain patients. RESULTS: Laparoscopy identified extrahepatic disease in 12% of patients, and intraoperative hepatic ultrasound identified additional lesions in 33% of patients, despite extensive preoperative imaging. Radiofrequency ablation alone or combined with resection or CSA resulted in reduced blood loss (P<.05), thrombocytopenia (P<.05), and shorter hospital stay compared with CSA alone (P<.05). Median ablation times for lesions greater than 3 cm were 60 minutes with RFA and 15 minutes with CSA (P<.001). Local recurrence rates for lesions greater than 3 cm were also greater with RFA (38% vs 17%). CONCLUSIONS: Laparoscopy and intraoperative ultrasound are essential in staging patients with hepatic malignant neoplasms. Radiofrequency ablation when combined with CSA reduces the morbidity of multiple freezes. Although RFA is safer than CSA and can be performed via different approaches (percutaneously, laparoscopically, or at celiotomy), it is limited by tumor size (<3 cm). Percutaneous RFA should be considered in high-risk patients or those with small local recurrences.

The effect of lithocholic acid on proliferation and apoptosis during the early stages of colon carcinogenesis: differential effect on apoptosis in the presence of a colon carcinogen.

Lithocholic acid (LCA) is implicated in human and experimental animal carcinogenesis. Its effect on apoptosis and proliferation of the colonic epithelium was studied in a 1,2-dimethylhydrazine (DMH)-induced murine carcinogenesis model. Four groups of mice, control, LCA, DMH and DMH+LCA, were studied for 4 weeks, a period corresponding to early stages of carcinogenesis. Apoptosis (AI) and proliferation (PI) indices in the colon were determined by immunohistochemistry. LCA stimulated apoptosis [AI = 1.2 +/- 0.3% (all values are the mean +/- SEM) versus control 0.5 +/- 0.1%, P < 0. 05], as did DMH (4.3 +/- 0.8%, P < 0.02). DMH increased apoptosis at the base of the crypt nearly 50-fold, with no effect at the lumenal third. In mice receiving DMH, LCA suppressed apoptosis almost completely (0.1 +/- 0.03%); this suppression was complete at the lower two-thirds of the crypt (AI = 0) and 60% at the lumenal third. LCA increased proliferation (PI = 22.2 +/- 4.6% versus 15.4 +/- 1% in controls), but this did not reach statistical significance. DMH increased proliferation (PI = 34.6 +/- 2.3%, P < 0.01). In mice receiving DMH, proliferation (41 +/- 2.9%) was about two-thirds of the additive effect. LCA affected proliferation, mainly in the middle third of the crypt; DMH's effect was similar in distribution, but more pronounced. In mice receiving DMH, LCA shifts proliferation upward, extending it to the lumenal third of the crypt. LCA's main cell kinetic effect in the colon is on apoptosis; this effect differs in normal (stimulation) and pre-malignant colon (nearly complete suppression). LCA does not significantly stimulate proliferation in either normal or pre-malignant colon. The differential effect of LCA on apoptosis in the presence of a carcinogen partially explains its effect as a promoter on colon carcinogenesis in animal models, and may have important implications for human carcinogenesis.

Regression and its mechanisms after laser in situ keratomileusis in moderate and high myopia.

OBJECTIVE: The purpose of the study was to evaluate the degree and mechanism of regression after laser in situ keratomileusis (LASIK) on moderate to highly myopic eyes during the first postoperative year. DESIGN: A prospective, single-center, clinical trial. PARTICIPANTS: A total of 52 eyes of 38 patients were entered in the study; 47 eyes had complete data available at each postoperative visit. INTERVENTION: The intervention was LASIK using the microkeratome to create an 8.5- to 9.0-mm diameter, 130- to 160-micron-thick flap. A spherical midstromal multizone ablation (inner zone, 4.5 mm; outer zone, 5.5-6.0) was then performed using the Summit OmniMed excimer laser (Summit Technology, Inc, Waltham, MA). The mean preoperative refraction was -14.02 diopters (D). Retreatment for undercorrection and regression was performed between postoperative months 3 and 6 on 13 eyes. MAIN OUTCOME MEASURES: Manifest spherical equivalent, mean central corneal power, and central corneal thickness were the parameters measured. RESULTS: At 3 months, follow-up data were available on 47 eyes. The mean refractive regression was -1.07 D (7.6%) from the first week to the third month. During the first postoperative year, the mean regression of manifest spherical equivalent (MSE), increase in corneal power, and increase in corneal thickness were symmetric in magnitude and time course for the 34 eyes that did not require retreatment (-0.96 D, +1.03 D, and 15 microns, respectively). CONCLUSION: Early regression of refractive effect after LASIK appears to be a consequence of an increase in corneal thickness associated with central corneal steepening. No evidence of progressive corneal ectasia was observed during the first year of follow-up. Longer follow-up is required to confirm these trends.

The effect of eicosanoids on the expression of MHC genes in cultured human colon cancer cells and mouse colonocytes in vivo.

Eicosanoids have been implicated in the pathogenesis of cancer and are known to regulate the expression of antigens of the major histocompatibility complex (MHC). In human colon cancer, we have recently observed that: (a) the expression of MHC class I and II antigens are markedly reduced; and (b) the levels of PGE2, but not of PGF2 alpha and LTB4, are elevated compared to histologically normal mucosa. Therefore, we investigated the effect of PGE2, PGF2 alpha and LTB4 on the regulation of MHC class I antigens in two human colon adenocarcinoma cell lines and in a murine model of colon cancer. None of these eicosanoids had any significant effect on the expression of MHC class I antigens in the human colonocytes or the transcription rate of class I genes, with the exception of LTB4 which only modestly suppressed the transcription rate. Similarly, 16, 16-dimethyl-PGE2 had no effect on the expression of MHC class I genes in the colonocytes of BALB/c mice treated with the carcinogen dimethylhydrazine. We conclude that PGE2, PGF2 alpha and LTB4 did not affect the expression of MHC class I antigens in cultured human colon adenocarcinoma cells, and 16, 16-dimethyl PGE2 did not affect their expression in mice, even when mice were treated with a colon carcinogen. Thus, these eicosanoids are an unlikely regulator of the observed underexpression of MHC class I antigens in human colon cancer.

Keratoconus and tapetoretinal degeneration.

In a series of 233 keratoconus cases, electroretinograms (ERGs) and visual evoked responses (VERs) were recorded; the results of this study are discussed. In six cases, the ERGs were extinguished, and the VERs were pathologic. In contrast to this, in four cases, ERGs were normal, but VERs were pathologic. Postoperatively the electrophysiologic findings remained the same, and the ophthalmoscopic examination of the eyes revealed the existence of a diffuse tapetoretinal degeneration or a macular lesion. These data show clearly the coexistence in many cases of keratoconus with diffuse tapetoretinal degeneration or macular lesion. The preoperative value of an electrophysiologic study of keratoconus patients is justified to avoid an unneeded corneal transplant.

Clinical experience with cyanoacrylate tissue adhesive.

In this paper 385 cases treated with cyanoacrylate tissue adhesive during the years 1980-1995 are studied. The indications, outcomes and complications of cyanoacrylate adhesive are investigated and the results are analysed. It is encouraging that except for three cases of ocular hypotony and two cases of microbial infection no other complications occurred. Even in desperate cases with corneal perforation greater than 3 mm and ocular infection, enucleation was avoided. The early use of a bandage contact lens, inserted just after the glue application and the coverage with topical antibiotics switched every 15 days until the removal of the glue, may explain the small incidence of infection. Our experience from the use of cyanoacrylate tissue adhesive in cases with corneal perforation greater than 3 mm is very encouraging. In these cases a running 10.0 nylon suture was used to create a reticulum over the space of the corneal perforation upon which the glue was applied. The use of cyanoacrylate tissue adhesive offers to the clinician a safe technique for healing corneal wounds that avoids tectonic penetrating keratoplasty with its associated complications.

Selected eicosanoids increase the proliferation rate of human colon carcinoma cell lines and mouse colonocytes in vivo.

Eicosanoids have been implicated in colon carcinogenesis, but their role remains unclear. The levels of PGE2 are elevated in colon cancer tissues and in blood draining colon tumors. The effect of eicosanoids on the proliferation of colonic cells is unknown. We studied the effect of several prostaglandins (PGs) and leukotriene (LT)B4 on the proliferation rate of the human colon adenocarcinoma cell lines SW1116 and HT-29 and of 16,16-dimethyl PGE2 (dmPGE2) on the colon of BALB/c mice. PGs E2, F2 alpha, I2, the methyl ester of PGE2, dmPGE2, and LTB4 (10(-10), 10(-8), 10(-6) M), administered for up to 72 h, stimulated cell proliferation in SW1116 cells and all but PGF2 alpha and PGI2 stimulated proliferation in HT-29 cells. The proliferative effect was time- and concentration-dependent. However, in SW1116 cells the response to PGs was 'bell-shaped', being maximal at 10(-8) M, with the 10(-10) and 10(-6) M concentrations being less effective. In HT-29 cells, the addition of methyl groups to the PGE2 molecule increased the proliferative effect. None of these eicosanoids affected the distribution of these cells in the cell cycle or their rate of programmed cell death (apoptosis). dmPGE2 stimulated 3.6-fold the proliferation of colonocytes in normal BALB/c mice. This was determined by bivariate flow cytometric analysis of the expression of proliferating cell nuclear antigen (PCNA) in virtually pure populations of mouse colonocytes. dmPGE2 did not alter the cell cycle distribution of these cells. We conclude that several PGs as well as LTB4 stimulate the proliferation of human colon carcinoma cells in vitro, while dmPGE2 has a similar effect on mouse colonocytes in vivo. These findings raise the possibility that eicosanoids may contribute to colonic carcinogenesis by stimulating the proliferation rate of tumor cells in the colon.

Prostaglandin E2 down-regulates the expression of HLA-DR antigen in human colon adenocarcinoma cell lines.

Prostaglandins (PG) have been implicated in the pathogenesis of cancer and play an important role in immune regulation. Colon cancer is associated with elevated levels of PGE2, while aspirin, the prototypical inhibitor of PG synthesis, appears to reduce the incidence of colon cancer by 50%. We have observed that in human colon cancer the expression of HLA class I and II antigens is reduced or lost; loss of HLA antigens is suspected to be a mechanism by which the malignant cell escapes the immune surveillance. We investigated the effect of these eicosanoids on the expression of HLA antigens in human colon adenocarcinoma cell lines. PGE2 down-regulated the expression of the class II antigen HLA-DR in SW1116 cells (65% reduction at 2.8 x 10(-8) M). This effect was dose- and time-dependent, reversible, and specific (PGF2 alpha and LTB4 had no effect; the expression of carcinoembryonic antigen and class I genes were not affected). Aspirin induced the expression of HLA-DR in HT29 cells, a cell line not expressing constitutively HLA-DR. The reduction of HLA-DR by PGE2 was accompanied by reduced messenger RNA (mRNA) levels of HLA-DR alpha and reduced transcription of the corresponding gene. In contrast to HLA-DR, none of these three eicosanoids affected the expression of HLA class I genes, as assessed via determination of protein expression by fluorescence flow cytometric analysis and evaluation of the corresponding class I mRNA levels. We conclude that PGE2 specifically down-regulates the expression of HLA-DR, while it does not affect the expression of class I antigens.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of bile acids and piroxicam on MHC antigen expression in rat colonocytes during colon cancer development.

The effect of bile acids and piroxicam on the expression of major histocompatibility complex (MHC) antigens in colonocytes was evaluated in rats treated with the colonic carcinogen azoxymethane (AOM). Male Fischer-344 rats were fed a basal diet (AIN-76) supplemented with 0.4% cholic acid, 0.4% ursodeoxycholic acid, 0.2% ursodeoxycholic acid plus 0.2% cholic acid, or 75 p.p.m. piroxicam. Rats were injected subcutaneously once a week for 2 weeks with AOM (15 mg/kg body weight/week) or vehicle, after being fed their respective diets for two weeks. The rats were killed at 16 weeks, while parallel identical groups of rats were killed at 28 weeks, and colon tumours were counted. None of the rats treated with AOM-vehicle developed tumours at 28 weeks, while in the AOM-treated rats the frequency of colonic tumours was as follows: AOM alone 50%, cholic acid 74%, ursodeoxycholic acid 17%, piroxicam 28%, ursodeoxycholic plus cholic acid 46%. The expression of RT1A, RT1B and RT1D was determined in isolated colonocytes by immune fluocytometry. Normal rat colonocytes express all three MHC antigens strongly. Neither the bile acids nor piroxicam affected MHC antigen expression in AOM-vehicle-treated rats. AOM did not effect MHC antigen expression compared to normal controls. Cholic acid had no significant effect on the expression of MHC antigens in AOM-treated rats. Ursodeoxycholic acid alone or in combination with cholic acid increased the expression of RT1A compared to normal controls, of RT1B compared to AOM-treated rats, and of RT1D compared to controls or AOM-treated rats. Piroxicam increased the expression of all three antigens compared to either control or AOM-treated rats. These findings indicate that (1) ursodeoxycholic acid and piroxicam up-regulate colonic MHC antigen expression in the AOM model of colonic carcinogenesis; (2) the colon of rats exposed to AOM responds differently than the normal colon with respect to MHC regulation; and (3) the protective effect of ursodeoxycholic acid and piroxicam on colon tumour formation seems to be paralleled by an increase in MHC antigen expression.

The effect of ethanol on the expression of HLA class I genes in human colon adenocarcinoma cell lines.

The loss of HLA antigens by neoplastic cells may allow tumors to escape immune surveillance. We observed reduced expression of HLA antigens during human colon carcinogenesis. Since ethanol, which is associated with human colonic carcinogenesis, modulates the expression of HLA genes, we examined whether it affects the expression of HLA class I genes in human colon adenocarcinoma cell lines. Ethanol (1.7 x 10(-10) M to 1.7 x 10(-1) M), had no effect on the expression of HLA class I antigens on these colonocytes, the corresponding mRNA levels, or the expression of HLA constructs. Our findings do not support the hypothesis that ethanol may modulate the expression of HLA class I genes in human colon cancer cells.