Yu Shen

THE EFFECT OF CELECOXIB, A CYCLOOXYGENASE-2 INHIBITOR, IN FAMILIAL ADENOMATOUS POLYPOSIS

BACKGROUNDnPatients with familial adenomatous polyposis have a nearly 100 percent risk of colorectal cancer. In this disease, the chemopreventive effects of nonsteroidal antiinflammatory drugs may be related to their inhibition of cyclooxygenase-2.nnnMETHODSnWe studied the effect of celecoxib, a selective cyclooxygenase-2 inhibitor, on colorectal polyps in patients with familial adenomatous polyposis. In a double-blind, placebo-controlled study, we randomly assigned 77 patients to treatment with celecoxib (100 or 400 mg twice daily) or placebo for six months. Patients underwent endoscopy at the beginning and end of the study. We determined the number and size of polyps from photographs and videotapes; the response to treatment was expressed as the mean percent change from base line.nnnRESULTSnAt base line, the mean (+/-SD) number of polyps in focal areas where polyps were counted was 15.5+/-13.4 in the 15 patients assigned to placebo, 11.5+/-8.5 in the 32 patients assigned to 100 mg of celecoxib twice a day, and 12.3+/-8.2 in the 30 patients assigned to 400 mg of celecoxib twice a day (P=0.66 for the comparison among groups). After six months, the patients receiving 400 mg of celecoxib twice a day had a 28.0 percent reduction in the mean number of colorectal polyps (P=0.003 for the comparison with placebo) and a 30.7 percent reduction in the polyp burden (the sum of polyp diameters) (P=0.001), as compared with reductions of 4.5 and 4.9 percent, respectively, in the placebo group. The improvement in the extent of colorectal polyposis in the group receiving 400 mg twice a day was confirmed by a panel of endoscopists who reviewed the videotapes. The reductions in the group receiving 100 mg of celecoxib twice a day were 11.9 percent (P=0.33 for the comparison with placebo) and 14.6 percent (P=0.09), respectively. The incidence of adverse events was similar among the groups.nnnCONCLUSIONSnIn patients with familial adenomatous polyposis, six months of twice-daily treatment with 400 mg of celecoxib, a cyclooxygenase-2 inhibitor, leads to a significant reduction in the number of colorectal polyps.

A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis

Background: Non-selective cyclooxygenase (COX) inhibitors (non-steroidal anti-inflammatory drugs) inhibit large bowel carcinogenesis in patients with familial adenomatous polyposis (FAP). Their role in the duodenum of these patients is less certain. The disease modifying activity of specific COX-2 inhibitors has not been explored in humans. Patients and methods: This was a randomised, double blind, placebo controlled study of celecoxib (100 mg twice daily (n=34) or 400 mg twice daily (n=32)) versus placebo (n=17), given orally twice daily for six months to patients with FAP. Efficacy was assessed qualitatively by blinded review of shuffled endoscopy videotapes comparing the extent of duodenal polyposis at entry and at six months and quantitatively by measurement of the percentage change in duodenal area covered by discrete and plaque-like adenomas from photographs of high and low density polyposis. Results: Shuffled and blinded video review showed a statistically significant effect of 400 mg twice daily celecoxib compared with placebo treatment (p=0.033) with all five independent observers scoring a beneficial effect. Overall, patients taking celecoxib 400 mg twice daily showed a 14.5% reduction in involved areas compared with a 1.4% for placebo (p=0.436). However, patients with clinically significant disease at baseline (greater than 5% covered by polyps) showed a 31% reduction in involved areas with celecoxib 400 mg twice daily compared with 8% on placebo (p=0.049). Conclusions: A panel of five endoscopists found a significant reduction in duodenal polyposis after six months of treatment with celecoxib 400 mg twice daily. COX-2 inhibition may help this otherwise untreatable condition.

Antibiotic Treatment of Gastric Lymphoma of Mucosa-Associated Lymphoid Tissue: An Uncontrolled Trial

Gastric low-grade B-cell lymphoma is related to Helicobacter pylori infection according to histopathologic, epidemiologic, and clinical characteristics. Although normal gastric mucosa does not contain organized lymphoid tissue, lymphoid follicles develop with H. pylori infection (1) and with autoimmune diseases, such as the Sjgren syndrome (2). Low-grade B-cell lymphoma has been postulated to arise within this mucosa-associated lymphoid tissue (MALT) and is often called low-grade MALT lymphoma (3, 4). The incidence of gastric low- and high-grade MALT lymphoma is increased in populations with a high prevalence of H. pylori infection, and H. pylori infection has been reported in up to 90% of patients with low-grade MALT lymphoma (4-6). In addition, investigators have shown that growth of this tumor may depend on antigenic stimulation by H. pylori: They demonstrated that the proliferation of lymphoma B cells in cell culture can be stimulated by H. pylori-specific T cells and related cytokines in the presence of H. pylori (7). On the basis of these findings, trials of antibiotic treatment of gastric low-grade MALT lymphoma have been initiated, and the regression of lymphoma after cure of H. pylori infection has been reported in a high proportion of patients with low tumor burden (8-13). Data on patients with significant tumor infiltration are still forthcoming (13, 14). Because MALT lymphoma has only recently been approached as a distinct clinicopathologic entity (15, 16), its natural history and clinical course are not fully defined. Current data suggest that it is often an indolent tumor with long periods of mild activity and confinement to the stomach. Patients often present with nonspecific upper intestinal discomfort, ulcer-associated symptoms, or gastric bleeding. The endoscopic appearance may suggest benign gastritis, and extensive biopsies may be required for diagnosis. Progression to significant tumor mass, dissemination, or transformation to high-grade, aggressive lymphoma occur in an undefined subset of patients, who may present with early satiety or weight loss. Spontaneous remissions are rare (17-20). Because low-grade MALT lymphoma is an uncommon, often indolent form of cancer with few clinical findings and because the risk for progression to high-grade MALT lymphoma is still unknown (15, 16), definitive data on cure require long-term follow-up of large cohorts from standardized clinical trials. This report presents an interim analysis of an ongoing trial designed to determine the long-term response of low-grade gastric MALT lymphoma to antibiotic treatment and to define criteria for treatment and follow-up. Methods Patients Patients with gastric MALT lymphoma restricted to the stomach and perigastric lymph nodes (modified Ann Arbor stage I and II N1) were eligible for the study. The University of Texas, M.D. Anderson Cancer Center (MDACC), Internal Review Board approved the study, and all patients provided written informed consent. The National Cancer Institute and the institutional review boards of participating institutions approved the multi-institutional protocol. To enable a follow-up period of at least 18 months, only patients treated before May 1997 were included in this analysis. Study Design and Treatment The interim data are derived from an ongoing, prospective, uncontrolled treatment trial with third-party patient registry. Patients were studied at four participating centers. Pathologic diagnosis and resolution of MALT lymphoma were confirmed at MDACC, and all but one patient were examined endoscopically at MDACC. Study design included 1) tumor staging with bilateral bone marrow biopsies and aspirates and computed tomography of the abdomen and pelvis done at baseline and yearly; 2) endoscopy at baseline, at weeks 6 to 8, at 3- to 4-month intervals thereafter until resolution of MALT lymphoma was seen on two consecutive endoscopies, at 6-month intervals thereafter for 2 years, and then yearly thereafter; and 3) endoscopic ultrasonography at baseline and at each endoscopy until resolution of masses or infiltration of the muscularis propria, if present (defined as thickness>2 mm or obliteration of wall architecture), and then at 6- to 12-month intervals. The treatment protocol consisted of two of the following three oral antibiotic regimens1] amoxicillin, 750 mg three times daily, and clarithromycin, 500 mg three times daily; 2) tetracycline, 500 mg four times daily, and clarithromycin, 500 mg three times daily; or 3) tetracycline, 500 mg four times daily, and metronidazole, 500 mg three times dailyadministered sequentially for 21 days at baseline and at 8 weeks along with a proton-pump inhibitor (lansoprazole, 30 mg twice daily [n=29], or omeprazole, 20 mg twice daily [n=5]), and bismuth subsalicylate, two tablets four times daily. Patients who were allergic to penicillin received the tetracycline-based regimens. Tumor Staging Tumors were staged endoscopically to separate superficial gastritis from significant ulcers and infiltration and from mass lesions. A modified Ann Arbor staging system that incorporated changes proposed by Blackledge, Musshoff, and Rohatiner and their coworkers was used initially (21-23). The TNM (tumor, node, metastasis) classification of the American Joint Committee on Cancer and Union Internationale Contre le Cancer (24, 25), which corresponds to the modified Ann Arbor staging, was subsequently adapted and applied (Table 1). The extent of tumor (T) infiltration through the stomach wall and to adjacent organs corresponds to T staging of gastric cancer. Modified Ann Arbor stage I corresponds to stage I T1-4 N0 M0. Modified Ann Arbor stage II1 (22) (involvement of perigastric lymph nodes) corresponds to stage II T1-4 N1 M0. Modified Ann Arbor stage II2 (22) (involvement of distant lymph nodes caudal to the diaphragm, including para-aortic and retroperitoneal lymph nodes) corresponds to stage II T1-4 N2 M0. Ann Arbor stage III (lymph node involvement on both sides of the diaphragm) is designated by stage III T1-4 N3 M0. Ann Arbor stage IV (organ metastasis or involvement of a second extranodal site) is designated by stage IV T1-4 N0-3 M1. Table 1. Staging of Gastric Lymphoma of Mucosa-Associated Lymphoid Tissue Criteria for Response Response to treatment was evaluated at 3- to 4-month intervals beginning with the fifth month after treatment. Treatment was considered to have failed if patients did not meet criteria for improvement; these patients were removed from the study. In stage I T2, I T3, and II N1 tumors, improvement was defined as regression to a lower stage, 30% reduction in abnormal wall thickness, or 30% reduction in the size of the tumor mass (product of the greatest diameters). These patients remained in the study if sequential improvement was evident at each 3-month interval. Patients with persistent mucosal disease (stage I T1) documented by histopathology were formally reviewed at 12-month intervals; a consensus on withdrawal from or continuation in the study was based on clinical considerations, current knowledge, and patient preference. Initially, patients with persistent stage I T1 disease were withdrawn from the study at 12 months (n=2). Subsequently, patients with persistent stage I T1 disease were observed for more than 36 months if improvement was documented at 12-month intervals. Criteria for improvement in stage I T1 disease included reduction in the number of affected gastric sites or affected biopsy specimens or improved histologic score (8), endoscopic appearance of progressive atrophy and scarring, or resolution of abnormal wall thickness on endoscopic ultrasonography. Complete remission was defined as the absence of histopathologic evidence of lymphoma and an endoscopic appearance of gastritis or better. Partial remission was defined as a reduction in endoscopic stage in stage I T2 disease or at least 50% reduction in the size of the mass lesions in stage I T3 or II T3 N1 disease. In stage I T1 disease, partial remission was defined as at least 75% reduction in the number of gastric sites or biopsy specimens showing lymphoma. Treatment was considered to have failed in patients who met criteria for failure or who were withdrawn from the study before complete remission occurred. Endoscopy and Biopsies The gastric mapping protocol included 2 or more maximum-capacity biopsies from each of 7 to 12 areas of the gastric map (26) and at least 6 biopsies from 2 or more of the most abnormal areas. The more extensive mapping was done at baseline and at clinically relevant time points. Studies, done at defined intervals, included routine histopathology, H. pylori testing by Genta stain, rapid urease test (CLO-test, Delta West, Bentley, Australia) or serology, Southern blot or polymerase chain reaction (PCR) for immunoglobulin gene rearrangement analysis, and immunoglobulin light-chain immunocytochemistry. Diagnostic Criteria Low-grade B-cell MALT lymphoma was diagnosed by established histologic criteria [15, 27], including 1) a dense diffuse infiltrate of marginal-zone centrocyte-like B cells with round to slightly irregular nuclear contours, often with abundant pale cytoplasm; 2) presence of lymphoepithelial lesions, characterized by infiltration and disruption of gastric glands or crypts by groups of neoplastic lymphoid cells; and 3) absence of any areas where large cells predominate. Minor criteria supporting but not essential for diagnosis included presence of immunoglobulin light-chain restriction; presence of residual secondary follicle centers with or without intact mantles; and presence of follicular colonization, defined as replacement of follicle centers by neoplastic lymphoid cells. Immunophenotypic expression of pan-B-cell antigens, such as CD20, and lack of expression of CD5 or CD10 supported the diagnosis. Patients with foci of large-cell transformation were excluded from the study. Southern Blot and Polymerase Chain Reaction High-molec

Hexaminolevulinate Guided Fluorescence Cystoscopy Reduces Recurrence in Patients With Nonmuscle Invasive Bladder Cancer

PURPOSEnWe assessed the impact that improved detection of nonmuscle invasive bladder cancer with hexaminolevulinate fluorescence cystoscopy may have on early recurrence rates.nnnMATERIALS AND METHODSnThis prospective, randomized study enrolled 814 patients suspected of having bladder cancer at increased risk for recurrence. All patients underwent white light cystoscopy and mapping of lesions, followed by transurethral resection of the bladder when indicated. Patients in the fluorescence group also received intravesical hexaminolevulinate solution at least 1 hour before cystoscopy to induce fluorescence of cancerous lesions, and underwent additional inspection with blue light before and after transurethral resection of the bladder. Adjuvant intravesical therapy was based on risk. Followup cystoscopy at 3, 6 and 9 months was conducted with white light.nnnRESULTSnDetection was performed as a within patient comparison in the fluorescence group. In this group 286 patients had at least 1 Ta or T1 tumor (intent to treat). In 47 patients (16%) at least 1 of the tumors was seen only with fluorescence (p = 0.001). During the 9-month followup (intent to treat) there was tumor recurrence in 128 of 271 patients (47%) in the fluorescence group and 157 of 280 (56%) in the white light group (p = 0.026). The relative reduction in recurrence rate was 16%.nnnCONCLUSIONSnHexaminolevulinate fluorescence cystoscopy significantly improves the detection of Ta and T1 lesions and significantly reduces the rate of tumor recurrence at 9 months.

Correlation between CpG methylation profiles and hormone receptor status in breast cancers

IntroductionAberrant DNA methylation has been found frequently in human breast cancers, associated with the loss of expression of a number of regulatory genes for growth and correlated to clinical outcomes. The present study was undertaken to determine whether methylation of a set of growth-suppressor genes would correlate to the expression of estrogen receptors (ERs) and progesterone receptors (PRs).MethodsWe used a pyrosequencing methylation analysis to study the methylation of 12 known growth-suppressor genes in 90 pairs of malignant/normal breast tissues. We also examined the expression of ERs and PRs in those specimens by immunohistochemistry. Mutations of p53 in tumor cells were detected by direct sequencing.ResultsTwelve tumor-suppressor genes: ARHI, RASSF1A, HIN-1, RARβ2, hMLH1, 14-3-3 σ, RIZ1, p16, E-cadherin, RIL, CDH13, and NKD2 were selected for this methylation study. Five of them (RIL, HIN-1, RASSF1A, CDH13, and RARβ2) were frequently methylated in breast cancers (57%, 49%, 58%, 44%, and 17%, respectively) but not the normal breast (0–4%). Two panels of methylation profiles were defined. The methylation of the HIN-1/RASSFIA panel strongly correlated to the expression of ERs, PRs, and hormone receptors (HRs; which were defined as positive if ERs and/or PRs were positive; p < 0.001). Conversely, the methylation of the RIL/CDH13 panel strongly correlated to negative ER, PR, and HR expression (p = 0.001, 0.025, and 0.001, respectively). The subset of triple-negative breast cancers (in other words, those with negative ER, PR, and HER-2/neu status) was positively associated with the methylation of the RIL/CDH13 panel and negatively associated with the HIN-1/RASSF1A panel. Mutations of p53 were found in nine breast tumors (11%), seven of which lacked methylation in both panels.ConclusionWe have defined two panels (HIN-1/RASSFIA, and RIL/CDH13) of methylation profiles, which correlated, either positively or negatively, to HR status.

Increased apoptosis in metastatic human colonic adenocarcinomas

Recent work suggests that apoptosis is disrupted during the progression of many solid tumors. Isogenic metastatic colon adenocarcinoma cells displayed significantly higher levels of staurosporine-induced apoptosis compared to their nonmetastatic counterparts in vitro. In addition, analysis of 15 matched primary tumors and liver metastases demonstrated that the levels of apoptosis were significantly higher in the metastases, and this increased cell death was associated with significantly lower levels of Bcl-2 protein expression. Our data demonstrate that the molecular events associated with acquisition of the metastatic phenotype sensitize colon cancer cells to some pro-apoptotic stimuli.

OVX1, macrophage-colony stimulating factor, and CA-125-II as tumor markers for epithelial ovarian carcinoma: A critical appraisal

Ovarian carcinoma remains the leading cause of death from gynecologic malignancy in Australia, the Netherlands, and the United States. CA‐125‐II, the most widely used serum marker, has limited sensitivity and specificity for detecting small‐volume, early‐stage disease. Therefore, a panel of three serum tumor markers—OVX1, CA‐125‐II, and macrophage‐colony stimulating factor (M‐CSF)—has been used to evaluate the sensitivity and specificity of multiple markers for the detection of early‐stage ovarian carcinoma.

High-dose chemotherapy in high-risk myelodysplastic syndrome: Covariate-adjusted comparison of five regimens

Antileukemic chemotherapy has been used for two decades to treat high‐risk myelodysplastic syndrome (refractory anemia with excess of blasts [RAEB] and RAEB in transformation into acute leukemia [RAEB‐t]) patients. Because the results of standard regimens have been disappointing, high‐dose chemotherapeutic regimens were investigated recently. In the absence of randomized trials, the relative merits of various treatment regimens are unknown.

Physician variation in management of low-risk prostate cancer: a population-based cohort study.

IMPORTANCEnUp-front treatment of older men with low-risk prostate cancer can cause morbidity without clear survival benefit; however, most such patients receive treatment instead of observation. The impact of physicians on the management approach is uncertain.nnnOBJECTIVEnTo determine the impact of physicians on the management of low-risk prostate cancer with up-front treatment vs observation.nnnDESIGN, SETTING, AND PARTICIPANTSnRetrospective cohort of men 66 years and older with low-risk prostate cancer diagnosed from 2006 through 2009. Patient and tumor characteristics were obtained from the Surveillance, Epidemiology, and End Results cancer registries. The diagnosing urologist, consulting radiation oncologist, cancer-directed therapy, and comorbid medical conditions were determined from linked Medicare claims. Physician characteristics were obtained from the American Medical Association Physician Masterfile. Mixed-effects models were used to evaluate management variation and factors associated with observation.nnnMAIN OUTCOMES AND MEASURESnNo cancer-directed therapy within 12 months of diagnosis (observation).nnnRESULTSnA total of 2145 urologists diagnosed low-risk prostate cancer in 12,068 men, of whom 80.1% received treatment and 19.9% were observed. The case-adjusted rate of observation varied widely across urologists, ranging from 4.5% to 64.2% of patients. The diagnosing urologist accounted for 16.1% of the variation in up-front treatment vs observation, whereas patient and tumor characteristics accounted for 7.9% of this variation. After adjustment for patient and tumor characteristics, urologists who treat non-low-risk prostate cancer (adjusted odds ratio [aOR], 0.71 [95% CI, 0.55-0.92]; P =u2009.01) and graduated in earlier decades (P =u2009.004) were less likely to manage low-risk disease with observation. Treated patients were more likely to undergo prostatectomy (aOR, 1.71 [95% CI, 1.45-2.01]; P <u2009.001), cryotherapy (aOR, 28.2 [95% CI, 19.5-40.9]; P <u2009.001), brachytherapy (aOR, 3.41 [95% CI, 2.96-3.93]; P <u2009.001), or external-beam radiotherapy (aOR, 1.31 [95% CI, 1.08-1.58]; P =u2009.005) if their urologist billed for that treatment. Case-adjusted rates of observation also varied across consulting radiation oncologists, ranging from 2.2% to 46.8% of patients.nnnCONCLUSIONS AND RELEVANCEnRates of management of low-risk prostate cancer with observation varied widely across urologists and radiation oncologists. Patients whose diagnosis was made by urologists who treated prostate cancer were more likely to receive up-front treatment and, when treated, more likely to receive a treatment that their urologist performed. Public reporting of physicians cancer management profiles would enable informed selection of physicians to diagnose and manage prostate cancer.

Liposomal amphotericin B versus the combination of fluconazole and itraconazole as prophylaxis for invasive fungal infections during induction chemotherapy for patients with acute myelogenous leukemia and myelodysplastic syndrome.

Fungal infections are a major cause of morbidity and mortality in patients undergoing induction chemotherapy for acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). The authors evaluated the efficacy and toxicity of liposomal amphotericin B (L‐AmB) compared with a combination of fluconazole plus itraconazole (F+I) as prophylaxis in this setting.