Análisis del comportamiento clínico-patológico del cáncer de mama mucinoso: primer estudio multicéntrico en México. Revisión a 10 años / Analysis of the clinical-pathological behaviour of mucinous carcinoma of the breast: First multicentre study in Mexico-review at 10 years

Introducción El carcinoma mucinoso de mama es una histología poco frecuente, al que se le ha atribuido buen pronóstico, sin embargo, hay pocos datos sobre su comportamiento en población mexicana. Material y métodos Estudio retrospectivo, descriptivo y observacional de tres centros oncológicos de referencia en México, se analizaron características clínicas e histopatológicas de pacientes con carcinoma mucinoso de mama en el periodo comprendido de 2007 a 2017. Resultados Se diagnosticaron 152 pacientes con carcinoma mucinoso puro de mama. Mediana de edad de 56 años. Se encontró asociación entre el tamaño tumoral (p = 0,002) y la afección ganglionar (p < 0,001) con la supervivencia global. Para supervivencia libre de enfermedad, se identificó como factor asociado la afección ganglionar y el inmunofenotipo; con una media de supervivencia libre de enfermedad (SLE) de 143,5 meses para luminal A, 115,4 meses para luminal B, 81 meses para triple negativo y 16 meses para Her 2, p < 0,001. Conclusiones La afección ganglionar es un factor de riesgo para recurrencia de cáncer de mama mucinoso. El tamaño tumoral y una mayor afección ganglionar se relacionaron con un pronóstico adverso en la supervivencia global. (AU)

Introduction Mucinous carcinoma of the breast is an infrequent histological type. Prognosis is believed to be good but there are few data on its behaviour in the Mexican population. Material and methods Retrospective, descriptive, observational study performed in 3 oncological referral centres in Mexico. We analysed the clinical and histopathological characteristics of patients with mucinous carcinoma of the breast between 2007 and 2017. Results A total of 152 patients were diagnosed with pure mucinous breast carcinoma. The median age was 56 years. An association was found between tumoural size (p = 0.002) and lymph node involvement (p < 0.001) with overall survival. The factors associated with disease-free survival were lymph node involvement and immunophenotype. Mean disease-free survival was 143.5 months for luminal A, 115.4 months for luminal B, 81 months for triple negative and 16 months for Her 2, p < 0.001. Conclusions Lymph node involvement is a risk factor for recurrence of mucinous carcinoma of the breast. Tumoural size and greater lymph node involvement are related to worse overall survival. (AU)

Genistein Prevents Development of Spontaneous Ovarian Cancer and Inhibits Tumor Growth in Hen Model.

Genistein, the major isoflavone in soybean, has been reported to exert anticancer effects on various types of cancer including ovarian cancer; however, its chemopreventive effects and mechanisms of action in ovarian cancer have not been fully elucidated in spontaneously developing ovarian cancer models. In this study, we demonstrated the preventive effects and mechanisms of genistein in the laying hen model that develops spontaneous ovarian cancer at high incidence rates. Laying hens were randomized to three groups: control (3.01 mg/hen, n = 100), low (52.48 mg/hen n = 100), and high genistein supplementation (106.26 mg/hen/day; per group). At the end of 78 weeks, hens were euthanized and ovarian tumors were collected and analyzed. We observed that genistein supplementation significantly reduced the ovarian tumor incidence (P = 0.002), as well as the number and size of the tumors (P = 0.0001). Molecular analysis of the ovarian tumors revealed that genistein downregulated serum malondialdehyde, a marker for oxidative stress and the expression of NFκB and Bcl-2, whereas it upregulated Nrf2, HO-1, and Bax expression at protein level in ovarian tissues. Moreover, genistein intake decreased the activity of mTOR pathway as evidenced by reduced phosphorylation of mTOR, p70S6K1, and 4E-BP1. Taken together, our findings strongly support the potential of genistein in the chemoprevention of ovarian cancer and highlight the effects of the genistein on the molecular pathways involved in ovarian tumorigenesis.

Analgesic medication use and risk of epithelial ovarian cancer in African American women.

BACKGROUND: Existing literature examining analgesic medication use and epithelial ovarian cancer (EOC) risk has been inconsistent, with the majority of studies reporting an inverse association. Race-specific effects of this relationship have not been adequately addressed. METHODS: Utilising data from the largest population-based case-control study of EOC in African Americans, the African American Cancer Epidemiology Study, the relationship between analgesic use (aspirin, non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen) and risk of EOC was estimated by multivariate logistic regression. The association of frequency, duration, and indication of analgesic use on EOC risk was also assessed. RESULTS: Aspirin use, overall, was associated with a 44% lower EOC risk (OR=0.56; 95% CI=0.35-0.92) and a 26% lower EOC risk was observed for non-aspirin NSAID use (OR=0.74; 95% CI=0.52-1.05). The inverse association was strongest for women taking aspirin to prevent cardiovascular disease and women taking non-aspirin NSAIDs for arthritis. Significantly decreased EOC risks were observed for low-dose aspirin use, daily aspirin use, aspirin use for <5 years, and occasional non-aspirin NSAID use for a duration of ⩾5 years. No association was observed for acetaminophen use. CONCLUSIONS: Collectively, these findings support previous evidence that any NSAID use is inversely associated with EOC risk.

RPS7 inhibits colorectal cancer growth via decreasing HIF-1α-mediated glycolysis.

Ribosomal protein S7 (RPS7) acts as a tumor suppressor in primary tumorigenesis but its role in cancer metabolism remains unclear. In this study, we demonstrate that RPS7 inhibits the colorectal cancer (CRC) cell glycolysis by suppressing the expression of hypoxia-inducible transcription factor-1α (HIF-1α) and the metabolic promoting proteins glucose transporter 4 (GLUT4) and lactate dehydrogenase B (LDHB). Further study found that the enhanced expression of HIF-1α abrogates the overexpression effects of RPS7 on CRC. In vivo assays also demonstrate that RPS7 suppresses colorectal cancer tumorigenesis and glycolysis. Clinically, the tissue microarray (TMA) analysis discloses the negative regulatory association between RPS7 and HIF-1α in colorectal cancer. Meanwhile, overexpression of RPS7 in colorectal cancer tissues predicts good overall survival and progression-free survival, but high expression level of HIF-1α indicates poor overall survival and progression-free survival. Overall, we reveal that RPS7 inhibits colorectal cancer glycolysis through HIF-1α-associated signaling and may be a promising biomarker for prognosis prediction and a potential target for therapeutic treatment.

Dietary phyto-oestrogens and the risk of ovarian and endometrial cancers: findings from two Australian case-control studies.

Phyto-oestrogens have been suggested to have a protective effect on hormone-sensitive cancers. However, few studies have investigated the association between dietary phyto-oestrogens and gynaecological cancers. In the present study, we analysed data from two population-based case-control studies of ovarian (1366 cases and 1414 controls) and endometrial (1288 cases and 1435 controls) cancers. Dietary intake information was obtained using a 135-item FFQ, and phyto-oestrogen intake was estimated using published food composition databases. Unconditional logistic regression was used to estimate adjusted OR and 95% CI. In multivariable analyses, there was a suggestive pattern of inverse associations between increasing intakes of total phyto-oestrogens, isoflavones and enterolignans and the risk of ovarian cancer. However, the results only reached statistical significance for the lignan compounds matairesinol and lariciresinol, where the OR for the highest v. the lowest intake category was 0.72 (95% CI 0.54, 0.96; P for trend = 0.02) for matairesinol and 0.72 (95% CI 0.55, 0.96; P for trend = 0.03) for lariciresinol. When the risk of ovarian cancer was assessed by subtype, there was an indication that increasing intakes of phyto-oestrogens may be associated with a decreased risk of mucinous (cases n 158) ovarian tumours (OR for the highest v. the lowest intake category: 0.47 (95% CI 0.24, 0.93); P for trend = 0.04). However, there were no significant associations with other histological subtypes. In contrast, dietary phyto-oestrogens (total or any subclass) were unrelated to the risk of endometrial cancer cases overall or by subtype.

Prior appendectomy does not protect against subsequent development of malignant or borderline mucinous ovarian neoplasms.

BACKGROUND: Due to concern that mucinous malignant or borderline ovarian neoplasms (MON) may represent metastatic deposits from appendiceal primaries, gynecologic oncologists routinely perform appendectomy in these cases. However, a multidisciplinary critique of this practice is lacking. METHODS: The New England Case-Control study database was utilized to compare the effect of prior appendectomy against known risk factors for MON. Pathology and operative reports of local cases of MON were reviewed to estimate the frequency of microscopic mucinous lesions in the appendix. Protein expression patterns among mucinous ovarian, colorectal, and appendiceal cancers were compared by immunohistochemistry. RESULTS: From the New England Case-Control study, 287 cases of MON were compared against 2339 age-matched controls. Prior appendectomy did not reduce the risk of MON (OR 1.28, 95% CI 0.83-1.92, p = 0.23), while prior tubal ligation, parity, and breastfeeding were each protective against MON. Active smoking (OR 2.04, 95% CI 1.48-2.80, p < 0.001) was associated with an increased risk of MON. Among 196 mucinous adnexal tumors, appendectomy did not reclassify any MON as appendiceal in origin. By immunohistochemistry, mucinous ovarian carcinomas tended to be CK7+/CK20-/MUC2-/CDX2-, whereas mucinous colorectal and appendiceal adenocarcinomas were typically CK7-/CK20+/MUC2+/CDX2+, although with some overlap in immunophenotype. Additionally, PAX8 was positive in a subset of MOC and negative in all appendiceal carcinomas. CONCLUSION: Prior appendectomy is not protective against development of malignant or borderline MON. Routine appendectomy during surgery for MON seldom reveals an unsuspected GI primary in early stage tumors but may aid in final diagnosis in advanced stage cases. FUNDING: National Cancer Institute grants P50-CA105009 and R21 CA-156021; The Honorable Tina Brozman 'Tina's Wish' Foundation; the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF); Dana-Farber Cancer Institute - Susan Smith Center for Women's Cancers; Robert and Deborah First Fund; The Gamel Family Fund; Mary Kay Foundation; Sandy Rollman Ovarian Cancer Foundation; Arthur Sachs/Fulbright/Harvard; La Fondation Philippe; La Fondation de France.

Potential effect of the risk of ovarian cancer algorithm (ROCA) on the mortality outcome of the Prostate, Lung, Colorectal and Ovarian (PLCO) trial.

Recently, the Prostate, Lung, Colorectal and Ovarian (PLCO) Trial reported no mortality benefit for annual screening with CA-125 and transvaginal ultrasound (TVU). Currently ongoing is the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), which utilizes the risk of ovarian cancer algorithm (ROCA), a statistical tool that considers current and past CA125 values to determine ovarian cancer risk. In contrast, PLCO used a single cutoff for CA125, based on current levels alone. We investigated whether having had used ROCA in PLCO could have, under optimal assumptions, resulted in a significant mortality benefit by applying ROCA to PLCO CA125 screening values. A best-case scenario assumed that all cancers showing a positive screen result earlier with ROCA than under the PLCO protocol would have avoided mortality; under a stage-shift scenario, such women were assigned survival equivalent to Stage I/II screen-detected cases. Updated PLCO data show 132 intervention arm ovarian cancer deaths versus 119 in usual care (relative risk, RR = 1.11). Forty-three ovarian cancer cases, 25 fatal, would have been detected earlier with ROCA, with a median (minimum) advance time for fatal cases of 344 (147) days. Best-case and stage-shift scenarios gave 25 and 19 deaths prevented with ROCA, for RRs of 0.90 (95% CI: 0.69-1.17) and 0.95 (95% CI: 0.74-1.23), respectively. Having utilized ROCA in PLCO would not have led to a significant mortality benefit of screening. However, ROCA could still show a significant effect in other screening trials, including UKCTOCS.

RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation.

We previously identified Hop as over expressed in invasive pancreatic cancer cell lines and malignant tissues of pancreatic cancer patients, suggesting an important role for Hop in the biology of invasive pancreatic cancer. Hop is a co-chaperone protein that binds to both Hsp70/Hsp90. We hypothesised that by targeting Hop, signalling pathways modulating invasion and client protein stabilisation involving Hsp90-dependent complexes may be altered. In this study, we show that Hop knockdown by small interfering (si)RNA reduces the invasion of pancreatic cancer cells, resulting in decreased expression of the downstream target gene, matrix metalloproteinases-2 (MMP-2). Hop in conditioned media co-immunoprecipitates with MMP-2, implicating a possible extracellular function for Hop. Knockdown of Hop expression also reduced expression levels of Hsp90 client proteins, HER2, Bcr-Abl, c-MET and v-Src. Furthermore, Hop is strongly expressed in high grade PanINs compared to lower PanIN grades, displaying differential localisation in invasive ductal pancreatic cancer, indicating that the localisation of Hop is an important factor in pancreatic tumours. Our data suggests that the attenuation of Hop expression inactivates key signal transduction proteins which may decrease the invasiveness of pancreatic cancer cells possibly through the modulation of Hsp90 activity. Therefore, targeting Hop in pancreatic cancer may constitute a viable strategy for targeted cancer therapy.

Greater vegetable and fruit intake is associated with a lower risk of breast cancer among Chinese women.

The effect of vegetable and fruit consumption on breast cancer risk is controversial. We examined the association between vegetable and fruit intake and breast cancer risk in a hospital-based case-control study conducted in Guangdong, China. Four hundred and thirty-eight cases were frequency matched to 438 controls by age (5-year interval) and residence (rural/urban). Dietary intake was assessed by face-to-face interviews using a validated food frequency questionnaire. Multivariate logistic regression was used to estimate the odds ratios (ORs) and 95% confidence interval (CI) after adjusting for various potential confounders. Total vegetable and fruit intake was found to be inversely associated with breast cancer risk. The ORs of the highest quartile relative to the lowest quartile of total vegetable and fruit intake were 0.28 (95% CI 0.18-0.43) and 0.53 (95% CI 0.34-0.82), respectively. Consumption of individual vegetable and fruit groups such as dark green leafy vegetables, cruciferous vegetables, carrots and tomatoes, banana, watermelon/papaya/cantaloupe were all inversely and significantly related with breast cancer risk. An inverse association was also observed for vitamin A, carotene, vitamin C, vitamin E, and fiber intake. These data indicate that greater intake of vegetables and fruits is associated with a decreased risk of breast cancer among Chinese women residing in Guangdong.

The use of sodium hyaluronate-carboxymethylcellulose (HA-CMC) barrier in gynecologic malignancies: a retrospective review of outcomes.

Concerns exist regarding the safety of sodium hyaluronate-carboxymethylcellulose (HA-CMC, Seprafilm) adhesion barrier in regard to cancer survival as a result of in vitro data demonstrating that hyaluronan, a component of HA-CMC, may promote tumor growth. We sought to determine whether use of HA-CMC is associated with duration of disease-free or overall survival and rates of immediate complication in patients with gynecologic malignancies. We identified 202 consecutive patients with epithelial ovarian, fallopian tube, and primary peritoneal cancer who underwent initial surgical staging or interval debulking at the University of Minnesota between January 2001 and December 2004. Information on patients' demographics, medical history, surgical procedures, postoperative complications, disease stage, histology, adjuvant therapy, and disease-free and overall survival was collected from medical records. Survival curves were compared between patients receiving or not receiving HA-CMC by stratified Cox regression models, log rank, and Wilcoxon tests. The level of significance was set to alpha = .05 for each test. Eighty patients received intraoperative placement of HA-CMC and 122 did not. Immediate postoperative complication rates were equivalent in both groups. Median follow-up was 2.1 years. There was no difference in disease-free survival (5-year estimate 23.6% vs. 33.3%, P = .80) or overall survival (5-year estimate 29.7% vs. 40.3%, P = .75) between those who received HA-CMC and those who did not. Our retrospective analysis suggests that HA-CMC adhesion barrier does not affect disease-free survival or overall survival; nor does it increase the immediate postoperative complication rates in patients undergoing abdominal surgery for ovarian, fallopian tube, and primary peritoneal carcinomas.

[Anal mucinous adenocarcinoma arising in long standing fistula-in-ano].

Perianal mucinous adenocarcinoma is an unusual but well described malignancy constituting approximately 3 to 11% of all anal carcinoma. The pathology is thought to develop from one of three types, the distal part of the rectum, the mucin-secreting columnar epithelium of the anal glands, and from chronic fistula-in-ano. The association of carcinoma with anal fistula may manifest itself in several ways: a fistula may be associated with cancer elsewhere in the colon; cancer may present as a fistula; or cancer may develop in anal fistula. Mucinous adenocarcinoma of the anus supervening on a long-standing chronic anal fistula is an extremely rare disease with less then 150 cases reported in the literature, mainly single patient reports. The key to long-term survival seems to be a high index of suspicion in those patients with longstanding perianal fistula. Chemotherapy in combination with external beam radiation followed by abdomino-perineal resection seems to be the most appropriate therapy.

Green tea consumption enhances survival of epithelial ovarian cancer.

Our study investigates whether tea consumption can enhance the survival of patients with epithelial ovarian cancer, a prospective cohort study was conducted in Hangzhou, China. The cohort comprised 254 patients recruited during 1999-2000 with histopathologically confirmed epithelial ovarian cancer and was followed up for a minimum of 3 years. Two hundred forty four (96.1%) of the cohort or their close relatives were traced. The variables examined included their survival time and the frequency and quantity of tea consumed post-diagnosis. The actual number of deaths was obtained and Cox proportional hazards models were used to obtain hazard ratios and associated 95% confidence intervals (CI), adjusting for age at diagnosis, locality, BMI, parity, FIGO stage, histologic grade of differentiation, cytology of ascites, residual tumour and chemotherapeutic status. The survival experience was different between tea drinkers and non-drinkers (p < 0.001). There were 81 (77.9%) of 104 tea-drinkers who survived to the time of interview, compared to only 67 women (47.9%) still alive among the 140 non-drinkers. Compared to non-drinkers, the adjusted hazard ratios were 0.55 (95% CI = 0.34-0.90) for tea-drinkers, 0.43 (95% CI = 0.20-0.92) for consuming at least 1 cup of green tea/day, 0.44 (95% CI = 0.22-0.90) for brewing 1 batch or more of green tea/day, 0.40 (95% CI = 0.18-0.90) for consuming more than 500 g of dried tea leaves/year, and 0.38 (95% CI = 0.15-0.97) for consuming at least 2 g of dried tea leaves/batch. The corresponding dose-response relationships were significant (p < 0.05). We conclude that increasing the consumption of green tea post-diagnosis may enhance epithelial ovarian cancer survival.

Biology of epithelial ovarian cancer: implications for screening women at high genetic risk.

PURPOSE: Our aim was to analyze the clinicopathologic features of screen-detected ovarian cancers identified in women, either at general population risk or high genetic risk of ovarian cancer, who have participated in screening studies. METHODS: Studies published between 1988 and April 2003 were categorized by the population screened and the primary screening modalities used. Each report was examined with reference to the histologic type, stage, and grade of screen-detected cancers. Reports of studies of prophylactically removed ovaries from women at high risk of ovarian cancer were also reviewed. RESULTS: Of the stage I tumors detected by screening women at population risk, almost half were borderline ovarian tumors, granulosa-cell tumors, or germ-cell tumors, which is disproportionate to their frequency. Furthermore, of the stage I invasive epithelial cancers diagnosed in women at population risk, the majority were endometrioid, clear-cell, and mucinous histologic subtypes. Most ovarian cancers that occur in women at high genetic risk are high-grade serous cancers, and these are infrequently screen detected at an early stage. CONCLUSION: The clinicopathologic features of screen-detected ovarian cancers suggest that screening may not reduce mortality in women at increased genetic risk. Prospective screening studies are required in genetically high-risk populations to answer this important question. Women electing surveillance should be aware of the lack of proven benefit and the low likelihood of detecting early stage serous cancers. Bilateral salpingo-oophorectomy appears to be the most effective approach to decrease the risk of ovarian cancer and thereby reduce mortality in high-risk women.

Pronounced inhibition by a natural anthocyanin, purple corn color, of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-associated colorectal carcinogenesis in male F344 rats pretreated with 1,2-dimethylhydrazine.

The potential of purple corn color (PCC), a natural anthocyanin, to modify colorectal carcinogenesis was investigated in male F344/DuCrj rats, initially treated with 1,2-dimethylhydrazine (DMH), receiving 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the diet. After DMH initiation, PCC was given at a dietary level of 5.0% in combination with 0.02% PhIP until week 36. No PCC-treatment-related changes in clinical signs, body weight and food consumption were found. Incidences and multiplicities of colorectal adenomas and carcinomas in rats initiated with DMH were clearly increased by PhIP. In contrast, lesion development was suppressed by PCC administration. Furthermore, in the non-DMH initiation groups, induction of aberrant crypt foci by PhIP tended to be decreased by the PCC supplementation. The results thus demonstrate that while PhIP clearly exerts promoting effects on DMH-induced colorectal carcinogenesis, these can be reduced by 5.0% PCC in the diet, under the present experimental conditions.

Characteristics of metachronous colorectal carcinoma occurring despite colonoscopic surveillance.

PURPOSE: Metachronous colorectal cancer still occurs in a small percentage of patients, despite colonoscopic surveillance. Cancers in hereditary nonpolyposis colorectal cancer for which there is a high risk of metachronous cancer show distinctive DNA changes termed replication errors (RER+). Ten to 20 percent of sporadic colorectal cancers are also RER+. The aim of this study was to identify factors predictive of metachronous colorectal cancer, despite colonoscopic surveillance. Clinicopathologic characteristics and RER status of cancers were examined. METHODS: Colorectal cancer patients, who entered into a surveillance program of being examined with colonoscopy within six months of surgery and then at intervals of three years thereafter, were reviewed. The 433 patients compliant with the protocol who had had more than one colonoscopy had been followed up for a mean of 3.8 +/- 2.2 years. DNA was extracted from archival paraffin-embedded cancer tissue for determination of RER status. RESULTS: Ten cases of metachronous cancer were identified, giving a rate of 0.61 percent per year. The site of the index cancer in patients who later developed metachronous cancer was predominantly proximal (P = 0.0007), and these cancers were more likely to have mucinous histology (P < 0.0005). Three of 10 (30 percent) index cancers were RER+, which was not significantly different from unselected series of control colorectal cancers in which 20 of 108 (18.5 percent) were RER+. DISCUSSION: This study documents the rate of metachronous cancer among patients compliant with a defined colonoscopic screening program and suggests that the risk is highest in patients with a proximal mucinous cancer. RER status does not appear to be a very strong predictive factor, and this study does not support its use as a guide to the frequency of surveillance colonoscopy. More data would be required to determine if RER positivity conferred a relative risk of 3.3 or less.

Reduction of cell proliferative activities of gastric stump adenomatous hyperplasias after bile reflux diversion in rats.

Previously we reported the majority of lesions induced by bile reflux, in the absence of chemical carcinogens, in the rat remnant stomach to consist primarily of gastric type and secondarily of intestinal type cells, and that they are reversible after diversion of bile reflux. The present study was designed to evaluate changes in proliferative activities in cells of each type under these conditions. The frequency of adenomatous hyperplasia (AH) induced in the gastric stump mucosa by duodenal content reflux after Billroth II partial gastrectomy (BII) increased until the 54th week of the experiment. Roux-en-Y (RY) surgical procedure which prevents duodenal reflux performed at the 24th or 36th week after BII led to a decrease in AH. Cell content of the lesions was analyzed using routine H&E staining, immunohistochemical staining for pepsinogen isoenzyme 1 and histochemical procedures for mucins (paradoxical concanavalin A, galactose oxidase Schiff and sialidase galactose oxidase Schiff reactions) and proliferation in each compartment evaluated by an immunohistochemical method using bromodeoxyuridine (BrdU) and a monoclonal antibody against BrdU. At the 54th week the number of BrdU-labeled cells per normal pyloric column was significantly (P < 0.05) increased to 10.63/pit after the BII operation, while it diminished to 5.23/pit after RY diversion, this being the same level as with the RY procedure alone. AH maintained a high rate of BrdU incorporation at 12.7% after BII operation, which was also significantly reduced (P < 0.01) to 7.0% by the RY surgery. The intestinal type cell showed highest (22.2%), the surface mucous type cell showed the next (16.5%) and the pyloric gland type cell showed lowest (5.2%) BrdU labeling indices after BII operation. All the cell types in AH showed similar proportional decreases in BrdU incorporation after RY diversion. Thus surgical intervention reverses the cell proliferation caused by bile reflux in the gastric stump.