Inhibition of growth and reduction in tumorigenicity of UCI-107 ovarian cancer by antagonists of growth hormone-releasing hormone and vasoactive intestinal peptide

PURPOSE: To evaluate the tumor inhibitory activities of antagonists of growth hormone-releasing hormone (GH-RH) and vasoactive intestinal peptide (VIP) in UCI-107 human ovarian cancer model, and to investigate the role of the insulin-like growth factor (IGF) system in the response. METHODS: In the present study we investigated the effects of GH-RH antagonist JV-1-36 and VIP antagonist JV-1-52, on the growth and tumorigenicity of UCI-107 ovarian cell carcinoma xenografted into nude mice. Studies on the effects of hGH-RH(1-29)NH2, IGF-I, IGF-II, JV-1-36, and JV-1-52 on the proliferation of UCI-107 cells cultured in vitro were also performed. RESULTS: After 22 days of therapy with JV-1-36 or JV-1-52 at the dose of 20 microg/day, the final volume of UCI-107 tumors was significantly (P<0.05) decreased by 50.5% and 56%, respectively, compared to controls. The concentration of IGF-II in tumors was reduced by 66% in the JV-1-36-treated group and by 62% in the group given JV-1-52 (both P < 0.05). Exposure in vitro to 1 microM concentrations of JV-1-36 or JV-1-52 for 24 h decreased the tumorigenicity of UCI-107 cells in nude mice. All ten mice injected with cells treated with medium alone developed tumors within 23 days after cell inoculation, while only eight of ten and four of ten mice injected with cells exposed to JV-1-36 or JV-1-52, respectively, had tumors. In vitro exposure of UCI-107 cells to 5-35 ng/ml IGF-II produced a significant suppression in the rate of cell proliferation (P < 0.01). CONCLUSION: Our results suggest that GH-RH and VIP antagonists inhibit the growth of UCI-107 ovarian cell carcinoma by mechanisms that appear to involve direct effects on the cancer cells.     

Four-year follow-up of imprisoned male heroin users and methadone treatment: mortality, re-incarceration and hepatitis C infection

AIMS: To examine the long-term impact of methadone maintenance treatment (MMT) on mortality, re-incarceration and hepatitis C seroconversion in imprisoned male heroin users. DESIGN, SETTING AND PARTICIPANTS: The study cohort comprised 382 imprisoned male heroin users who had participated in a randomized controlled trial of prison-based MMT in 1997/98. Subjects were followed-up between 1998 and 2002 either in the general community or in prison. MEASUREMENTS: All-cause mortality, re-incarceration, hepatitis C and HIV serostatus and MMT retention. FINDINGS: There were no deaths recorded while subjects were enrolled in MMT. Seventeen subjects died while out of MMT, representing an untreated mortality rate of 2.0 per 100 person-years (95% CI, 1.2-3.2). Re-incarceration risk was lowest during MMT episodes of 8 months or longer (adjusted hazard ratio 0.3 (95% CI, 0.2-0.5; P < 0.001), although MMT periods 2 months or less were associated with greatest risk of re-incarceration (P < 0.001). Increased risk of hepatitis C seroconversion was significantly associated with prison sentences of less than 2 months [adjusted hazard ratio 20 (95% CI, 5-76; < P = 0.001)] and MMT episodes less than 5 months [adjusted hazard ratio 4.2 (95% CI, 1.4-12.6; P = 0.01)]. Subjects were at greatest risk of MMT dropout during short prison sentences of 1 month or less (adjusted hazard ratio 10.4 (95% CI, 7.0-15.7; P < 0.001). HIV incidence was 0.3 per 100 person-years (95% CI, 0.03-0.99). CONCLUSIONS: Retention in MMT was associated with reduced mortality, re-incarceration rates and hepatitis C infection. Prison-based MMT programmes are integral to the continuity of treatment needed to ensure optimal outcomes for individual and public health.     

Effect on gallbladder function subsequent to truncal vagotomy and gastrojejunostomy for chronic duodenal ulcer.

The effect of truncal vagotomy on gallbladder function and on the incidence of lithogenesis has remained controversial. A prospective and retrospective investigational study was undertaken to evaluate the effect of truncal vagotomy and gastrojejunostomy on gallbladder function. The study included a total of 76 patients and 77 controls. In Group I (Prospective group), 32 consecutive patients with chronic duodenal ulcer and gastric outlet obstruction undergoing truncal vagotomy and gastrojejunostomy were included. Group II included 25 age and gender matched controls (prospective group). Group III included 44 patients who had undergone truncal vagotomy and gastrojejunostomy 3 years or more prior to presentation (Retrospective group) and Group IV included 52 age and gender matched controls for the retrospective group. The patients in the prospective groups were followed up for a period of 1 year. An alkaline tide test was done in the prospective and retrospective group to assess for the completeness of vagotomy. Gallbladder contractile response to fatty meal and the presence of stones and sludge were noted in all the four groups by ultrasonography. There were 30 patients in the prospective group and 40 in the retrospective group after excluding patients with incomplete vagotomy. On ultrasound examination, there was no significant difference in the gallbladder volume and contractility of the study group when compared with the controls. Gallbladder sludge was found in 16 to 25% of patients in the prospective group (group I) during follow up, where as similar finding was documented in 8% of the matched control (group II (P>0.1). However, in the retrospective (group III) 10% (4 out of 40) had calculi and 20% of patients demonstrated sludge which was significantly higher when compared with the controls (p = 0.001). Truncal vagotomy and gastrojejunostomy did not affect gallbladder contractility, but it might predispose to the formation of sludge and subsequent calculi in a proportion of patients in long term.     

The perception of cancer risk in patients with prevalent Barrett's esophagus enrolled in an endoscopic surveillance program

BACKGROUND & AIMS: Patients with Barrett's esophagus (BE) have a risk of esophageal adenocarcinoma of approximately 0.5% per year. Patients may have difficulty understanding this risk. This study assessed the perceived risk of cancer in patients with BE, and correlated their risk estimates with their health care use behaviors. METHODS: We performed a survey of patients with BE participating in an endoscopic surveillance program at 2 sites: a university teaching hospital and a Veterans' Administration hospital. A questionnaire also elicited their demographics as well as their sources of health information. Health care behaviors, including physician visits and endoscopic surveillance behaviors, were assessed. Patients were classified as either overestimators or nonoverestimators of risk. Characteristics of overestimators, as well as health care use patterns, were assessed. RESULTS: One hundred eighteen patients met entry criteria, and 92 (78%) completed all the questionnaires. Sixty-eight percent of patients overestimated their 1-year risk of cancer, with a mean estimated 1-year cancer risk being 13.6%. The lifetime risk also was overestimated by 38% of patients. Patients who overestimated risk were more likely to be Veterans' Administration medical center patients, have more symptomatic reflux, and were more likely to use the Internet to get health care information. There was no significant difference in physician visits between overestimators and nonestimators (1.2 visits per year vs 1.0, P = .20), nor in endoscopy use (5.7 endoscopies per 5-year period vs 5.0, P = .42). CONCLUSIONS: The majority of patients with prevalent BE participating in an endoscopic surveillance program overestimated their chances of developing adenocarcinoma of the esophagus. Efforts to improve education of such patients with BE are warranted.     

Obesity-induced inflammation in white adipose tissue is attenuated by loss of melanocortin-3 receptor signaling

Metabolic syndrome, a complex of highly debilitating disorders that includes insulin resistance, hypertension, and dyslipidemia, is associated with the development of obesity in humans as well as rodent models. White adipose tissue (WAT) inflammation, caused in part by macrophage infiltration, and fat accumulation in the liver are both linked to development of the metabolic syndrome. Despite large increases in body fat, melanocortin 3-receptor (MC3-R)-deficient mice do not get fatty liver disease or severe insulin resistance. This is in contrast to obese melanocortin 4-receptor (MC4-R)-deficient mice and diet-induced obese (DIO) mice, which show increased adiposity, fatty liver disease, and insulin resistance. We hypothesized that defects in the inflammatory response to obesity may underlie the protection from metabolic syndrome seen in MC3-R null mice. MC4-R mice fed a chow diet show increased proinflammatory gene expression and macrophage infiltration in WAT, as do wild-type (WT) DIO mice. In contrast, MC3-R-deficient mice fed a normal chow diet show neither of these inflammatory changes, despite their elevated adiposity and a comparable degree of adipocyte hypertrophy to the MC4-R null and DIO mice. Furthermore, even when challenged with high-fat chow for 4 wk, a period of time shown to induce an inflammatory response in WAT of WT animals, MC3-R nulls showed an attenuated up-regulation in both monocyte chemoattractant protein-1 (MCP-1) and TNFalpha mRNA in WAT compared with WT high-fat-fed animals.     

Multicenter phase 2 trial of thalidomide in relapsed/refractory multiple myeloma: adverse prognostic impact of advanced age

Relapsed or refractory multiple myeloma has a poor outlook. Some patients respond to thalidomide; however, criteria for predicting response have not been conclusively identified. We initiated a prospective multicenter phase 2 trial in patients with relapsed/refractory myeloma using thalidomide up to the maximum dose, 800 mg/d. Interferon-alpha-2B (1.5-3.0 x 10(6) U, subcutaneously, 3 times per week) was added at week 12 if disease was responsive or stable. Patients intolerant of interferon continued thalidomide alone. Thalidomide with or without interferon was continued until disease progression. Objectives were to determine toxicity, response rate (RR), progression-free survival (PFS), and overall survival (OS) and to elucidate relevant prognostic factors. We enrolled 75 patients, with median age 64 years (range, 36-83 years). Median individual maximum-tolerated dose of thalidomide was 600 mg/d; 41% reached 800 mg/d. Overall RR was 28%, and 55% stable disease (SD). The only predictor for response was age 65 years or younger (38% versus 17%; P =.043). At 18 months median follow-up, the actuarial median PFS and OS were 5.5 and 14.6 months, respectively. Multivariate analysis for OS demonstrated age exceeding 65 years (median, 9.2 months versus longer than 26 months; P =.011), raised serum lactate dehydrogenase (P =.002), and raised serum creatinine (P =.007) predicted inferior outcomes. Nineteen patients received interferon. Ten discontinued owing to toxicity. Four of 12 patients who received interferon for longer than 4 weeks were converted from SD to partial response. Our findings confirm substantial activity of thalidomide in relapsed/refractory myeloma. Interferon may improve response in selected patients, but is often not tolerated. The inferior outcome demonstrated in those with the identified prognostic factors is important in planning management for such patients.     

Asthma‐specific quality of life questionnaires in children: Are they useful and feasible in routine clinical practice?

This study used well-validated quality of life (QOL) instruments to compare the QOL scores achieved by children aged 7-17 years with the views of their parents of the effects of their child's asthma on family life. Also, a comparison was made between the child's QOL scores and the judgment of the clinician in charge in regard to asthma control.There was poor correlation between the overall scores of the children and the overall caregiver's score (r = 0.19, P = 0.18), and no correlation between the child's score and assessment of control given by the clinician in charge of the case (r = 0.02, P = 0.98).It is important to recognize that there may be little relationship between the concerns of the child regarding his or her asthma, the effects on the family as reported by a parent, and the clinician's view of asthma control. This recognition may significantly affect treatment planning with the family. The administration of the QOL instrument used in this study was straightforward and quite quick, with a mean time to completion of about 8 min.     

How often is a positive faecal occult blood test the result of coeliac disease?

BACKGROUND AND AIMS: It has been reported that occult gastrointestinal bleeding as detected by faecal occult blood (FOB) testing can occur in coeliac disease. This study examines whether a positive FOB is a feature of coeliac disease and whether FOB-positive subjects need investigation for coeliac disease. METHODS: First, the records of patients on the Nottingham Register for Coeliac Disease were reviewed for positive FOB testing. Second, the Nottingham colorectal cancer screening trial database was also reviewed to examine how many coeliac patients on the Register had participated and to examine their FOB results. Finally, sera from 309 screening trial participants who were FOB-positive but had no colonic abnormality were screened for immunoglobulin A (IgA) gliadin and IgA endomysial and human tissue transglutaminase (tTG) IgA antibodies. RESULTS: Five of 590 patients on the Register had had FOB tests at the time of diagnosis; four had positive tests during investigation of diarrhoea and/or anaemia. Of 21 patients on the Register who had participated in the colorectal cancer screening trial, one had a positive FOB test and was found to have a rectal tubulo-villous adenoma. Of the 309 FOB-positive patients, 7% (22 subjects) were positive for IgA gliadin antibodies, but none had IgA endomysial antibodies detected and two subjects had positive human tTG antibody assays for coeliac disease. CONCLUSIONS: Occult gastrointestinal bleeding occurs in a small number of symptomatic coeliac disease patients before diagnosis, but is no more frequent in treated and undetected coeliac disease patients than in the general population. Unless there are other indications, coeliac disease does not need to be considered in the investigation of a positive FOB test.     

Nurse‐led prostate assessment clinics – are they fit for purpose?

Nurse‐led prostate assessment clinics (PACs) have been shown to be both cost‐effective and reduce the workload of urologists. We set out to determine how closely guidelines were adhered to in our PAC and whether the outcomes of these clinics, as determined by set protocols, were producing effective management strategies. The notes of 100 consecutive patients who attended the PAC at a single institution were retrospectively analysed. The presenting symptoms, examination findings, investigations performed and their results were documented, and the consultation outcome was recorded. In particular, we assessed whether the guidelines for investigations and management were followed and whether there were any changes in these following consultant review. Of the 100 patients (mean age 67 years), 79 were referred from primary care. The most common presenting symptoms were frequency and nocturia. Ninety‐two per cent of patients were appropriately assigned to the PAC. Eighty‐two per cent had a complete assessment according to the clinic guidelines. Patient management was appropriate and based on clinic guidelines in 81%. Following consultant review, 78% had no change in their management, while 26% were discharged. Nurse‐led PACs are fit for purpose. Guidelines for assessment and management are closely followed with minimal changes to treatment at consultant review.     

Accuracy of genotyping for HPV16 and 18 to triage women with low-grade squamous intraepithelial lesions: a pooled analysis of VALGENT studies

Background: Genotyping for the most carcinogenic human papillomavirus (HPV) types (HPV16/HPV18) can identify high risk of underlying cervical precancer and guide further management.

Research design and methods: A pooled analysis was performed of the clinical accuracy of high-risk HPV (hrHPV) testing and HPV16/18 genotyping in triage of women with low-grade squamous intraepithelial lesions (LSIL). Data regarding 24 assays evaluated in four VALGENT validation panels were used.

Results: In women with LSIL, hrHPV had a pooled sensitivity for CIN2+ of 95.5% (95% CI: 91.0–97.8%) and a specificity of 25.3% (95% CI: 22.2–28.6%). HPV16/18 genotyping had a sensitivity and specificity for CIN2+ of 52.9% (95% CI: 48.4–57.4%) and 83.5% (95% CI: 79.9–86.5%), respectively. The average risk of CIN2+ was 46.1% when HPV16/18-positive, 15.5% in women who were HPV16/18-negative but positive for other hrHPV types and 4.3% for hrHPV-negative women.

Conclusions: Triage of women with LSIL with HPV16/18 genotyping increases the positive predictive value compared to hrHPV testing but at the expense of lower sensitivity. Arguably, women testing positive for HPV16/18 need further clinical work-up. Whether colposcopy referral or further surveillance is recommended for women with other hrHPV types may depend on the post-test risk of precancer and the local risk-based decision thresholds.