Characterization of steroid hormone sensitivity in human breast cancers maintained ex vivo under organotypical culture conditions

 Purpose: The methodology we propose combines the immunohistochemical determination of the oestrogen and progesterone receptors (ER and PgR) with the characterization of the oestradiol- and progesterone-induced influence on cell proliferation in breast cancers in order to characterize their steroid hormone sensitivity at both the “static” and “dynamic” level. Methods: ER and PgR have been immunohistochemically quantified by means of computer-assisted microscopy. Cell proliferation has been determined by means of tritiated thymidine autoradiography in tumour samples maintained in vitro as organotypic cultures. A series of 14 patients was investigated. Results: Of the 14 breast cancers under study, one with an unequivocally “very ER-rich”/“very PgR-rich” immunohistochemical phenotype totally failed to exhibit any modification in its cell proliferation level after both oestradiol and progesterone stimulation. Two cases definitively associated with an “ER-poor”/“PgR-poor” immunohistochemical phenotype nevertheless responded noticeably to the dynamic stimulation of their cell proliferation by oestradiol and progesterone. While our series of cases covers 14 patients only, it suffices to demonstrate the limits of ER and PgR determination in characterizing steroid hormone sensitivity in breast cancer. Discussion: The present work therefore presents an in vitro approach to test growth regulation of human breast cancer by steroid hormones. The clinical value of the present approach should be further determined by showing that steroid hormone-induced modifications in cell proliferation level are actually associated with clinical response. Received: 11 June 1999 / Accepted: 30 November 1999     

Determination of the proliferative potential of human brain tumors using the monoclonal antibody Ki-67

Summary The proliferative activity of 133 human tumors of the nervous system was investigated by means of immunohistochemistry using the monoclonal antibody Ki-67 in order to evaluate the usefulness of this method for histopathological tumor grading. Ki-67 recognizes a proliferation-associated nuclear antigen present in human cells during all active phases of the cell cycle but absent in the G₀ phase [Gerdes J, Schwab U, Lemke H, Stein H (1983) Int J Cancer 31:13–20]. In 28 WHO grade I and II gliomas of all major types Ki-67 indices were generally low with mean values ranging from less than 1% in pilocytic astrocytomas to 4.2% in grade II oligodendrogliomas. Individual cases of grade II astrocytomas and oligodendrogliomas had, however, values up to 8.5%. In 13 primary anaplastic gliomas of WHO grade III consistently higher statistical means were obtained with values ranging from 8.6% for anaplastic astrocytomas to 14.2% for anaplastic mixed gliomas. Interestingly, 18 WHO grade IV glioblastomas demonstrated a mean value of only 7%, which is probably due to the pronounced phenothypic heterogeneity in this tumor group. This heterogeneity results in enormous intraand intertumor variability in Ki-67 indices (range <1%–22.1%). Investigation of 17 recurrent gliomas revealed mean values for Ki-67 ranging from 1.7% for three WHO grade II astrocytomas up to 48.5% obtained in two highly anaplastic recurrent astrocytomas corresponding to WHO grade IV. Other tumors of the nervous system evaluated included 9 medulloblastomas (mean 17.9%, range 5.0%–42.0%), 17 benign meningiomas (mean 1.1%, range 0%–5%), 15 metastatic carcinomas (mean 16.5%, range <1%–46.0%), and individual tumors of various types. Our results indicate that Ki-67 immunohistochemistry can add useful additional information for histopathological grading which, by supplementing and refining the traditional WHO grading system, might lead to a better assessment of the biological behaviour of human tumors of the nervous system.Supported by the Deutsche Forschungsgemeinschaft, SFB 200     

The glutathione-related detoxification system is increased in human breast cancer in correlation with clinical and histopathological features

Purpose: The glutathione detoxification pathway includes glutathione S-transferase (GST) and peroxidase (GPX) isoenzymes as well as glutathione reductase (GSSR). Though well established from cultured cancer cell lines, its involvement in resistance is still unclear in the tumours. This study aimed to describe the parameters that influence the glutathione contents and associated activities in breast cancer. Methods: The components of the glutathione pathway were measured in the tumours from 41 women with primary breast cancer in comparison with those in the matched tumour-free samples. Appropriate statistical studies (regression analysis, Wilcoxon signed rank test) explored the influence of clinical and prognostic factors. Results: Reduced and total glutathione contents were largely increased (P < 0.0001) and all related activities were significantly enhanced in the tumours. Interindividual variations were described, probably due to various parameters (age, menopause, axillary lymph node status, S and G₂ + M cell fractions, ER, cathepsin-D and c-ErbB-2 expressions) that influence particular components of the glutathione pathway, especially the glutathione levels. Conclusions: The breast tumours improved their redox status and detoxification capacities depending on various parameters of significance for cell proliferation and aggressiveness, which supports the involvement of the glutathione pathway in malignant cell resistance to oxidative stress and apoptosis. Received: 24 August 2000 / Accepted: 13 November 2000     

Is this “My’ patient? Development and validation of a predictive model to link patients to primary care providers

BACKGROUND: Evaluating the quality of care provided by individual primary care physicians (PCPs) may be limited by failing to know which patients the PCP feels personally responsible for. OBJECTIVE: To develop and validate a model for linking patients to specific PCPs. DESIGN: Retrospective convenience sample. PARTICIPANTS: Eighteen PCPs from 10 practice sites within an academic adult primary care network. MEASUREMENTS: Each PCP reviewed the records for all outpatients seen over the preceding 3 years (16,435 patients reviewed) and designated each patient as “My Patient” or “Not My Patient.” Using this reference standard, we developed an algorithm with logistic regression modeling to predict “My Patient” using development and validation subsets drawn from the same patient set. Quality of care was then assessed by “My Patient” or “Not My Patient” designation by analyzing cancer screening test rates. RESULTS: Overall, PCPs designated 11,226 patients (68.3%, range per provider 15% to 93%) to be “My Patient.” The model accurately categorized patients in development and validation subsets (combined sensitivity 80.4%, specificity 93.7%, and positive predictive value 96.5%). To achieve positive predictive values of >90% for individual PCPs, the model excluded 19.6% of PCP “My Patients” (range 5.5% to 75.3%). Cancer screening rates were higher among model-predicted “My Patients.” CONCLUSIONS: Nearly one-third of patients seen were considered “Not My Patient” by the PCP, although this proportion varied widely. We developed and validated a simple model to link specific patients and PCPs. Such efforts may help effectively target interventions to improve primary care quality. Presented in part at the annual meeting of the Society of General Internal Medicine, New Orleans, LA in May, 2005. Supported by institutional funding through the Massachusetts General Hospital Primary Care Operations Improvement program.     

Recombinant human erythropoietin increases the radiosensitivity of xenografted human tumours in anaemic nude mice

Purpose: The effect of recombinant human erythropoietin (Epo) on the radiosensitivity of human tumour xenografts growing in anaemic nude mice was studied. Methods and materials: Anaemia was induced by total body irradiation (TBI) of mice prior to tumour transplantation. The development of anaemia was prevented by Epo (1000 U/kg s.c.) given 3 times weekly starting 2 weeks prior to TBI (5 Gy). Epo treatment did not influence the growth rate of the tumours, which were transplanted into the subcutis of the hind leg of mice. Thirteen days after TBI (tumour volume of approx. 40 mm³), a single-dose irradiation (12 Gy) of the tumour was performed resulting in a growth delay with subsequent regrowth of the tumours. Results: In Epo-treated animals the tumour growth delay was significantly longer compared to anaemic mice. However, the radiosensitivity of tumours in non-anaemic animals' (non-Epo-treated) tumours could not fully be restored. Conclusion: These data give evidence for restored radiosensitivity after correction of anaemia with Epo. Received: 24 March 2000 / Accepted: 20 September 2000     

Expression of p16<Superscript>INK4A</Superscript> gene in human pituitary tumours

Pituitary adenomas comprise 10–15% of primary intracranial tumours but the mechanisms leading to tumour development are yet to be clearly established. The retinoblastoma pathway, which regulates the progression through the cell cycle, is often deregulated in different types of tumours. We studied the cyclin-dependent kinase inhibitor p16^INK4A gene expression at mRNA level in human pituitary adenomas. Forty-six tumour specimens of different subtypes, 21 clinically non-functioning, 12 growth hormone-secreting, 6 prolactin-secreting, 6 adrenocorticotropin-secreting, and 1 thyrotropin-secreting tumours were studied. All clinically non-functioning and most of the hormone-secreting tumours were macroadenomas (38/46). The RT–PCR assay and electrophoresis of the PCR-products showed that p16^INK4A mRNA was undetectable in: 62% of non-functioning, 8% of growth hormone-secreting, 17% of prolactin-secreting and 17% of adrenocorticotropin-secreting adenomas. Forty percent of all macroadenomas and 25% of microadenomas had negative p16^INK4A mRNA, the latter results suggest that the absence of p16^INK4A product might be an early event in tumours with no expression of this suppressor gene. Within the non-functioning adenomas 63% were “null cell” and 37% were positive for some hormone, both subgroups showed similar percentage of cases with absence of p16^INK4A mRNA. Our results show that clinically non-functioning macroadenomas have impaired p16^INK4A expression in a clearly higher proportion than any other pituitary tumour subtype investigated. Other regulatory pathways may be implicated in the development of tumours with positive p16^INK4A expression.     

Will older persons and their clinicians use a shared decision-making instrument?

OBJECTIVE: To examine experiences of older persons and their clinicians with shared decision making (SDM) and their willingness to use an SDM instrument. DESIGN: Qualitative focus group study. PARTICIPANTS: Four focus groups of 41 older persons and 2 focus groups of 11 clinicians, purposively sampled to encompass a range of sociodemographic and clinical characteristics. APPROACH AND MAIN RESULTS: Audiotaped responses were transcribed, coded independently, and analyzed by 3 reviewers using the constant comparative method. Patient participants described using informal facilitators of shared decision making and supported use of an SDM instrument to keep “the doctor and patient on the same page.” They envisioned the instrument as “part of the medical record” that could be “referenced at home.” Clinician participants described the instrument as a “motivational and educational tool” that could “customize care for individual patients.” Some clinician and patient participants expressed reluctance given time constraints and unfamiliarity with the process of setting participatory clinical goals. CONCLUSIONS: Participants indicated that they would use a shared decision-making instrument in their clinical encounters and attributed multiple functions to the instrument, especially as a tool to facilitate agreement with treatment goals and plans. The authors have no conflicts of interest to report. Portions of these findings were presented at the national meeting of the American Geriatrics Society, Las Vegas, NV, 2004, and the national meeting of the Society for Medical Decision Making, Chicago, IL, May 2003. This research was supported by a center grant from a joint program of the Hartford and RAND foundations: Building Interdisciplinary Geriatric Health Care Research.     

Distal pancreatectomy withen bloc resection of the celiac artery for carcinoma of the body and tail of the pancreas

Summary Conclusion Combined resection of the celiac artery with a distal pancreatectomy (DP) increases the resectability and improves the overal prognosis of patients with locally advanced ductal cancer of the body and tail of the pancreas. Background Carcinoma of the body and tail of the pancreas is often unresectable because of invasion to adjacent organs. We evaluated a DP including anen bloc resection of the celiac artery (“extended”), for pancreatic cancer that had invaded the common hepatic and/or celiac arteries. Methods Six cases of an “extended” DP were compared with 19 cases of a “standard” DP for pancreatic ductal carcinoma in terms of clinical and pathologic findings, perioperative course, and long-term outcome. We also compared the survival rate of these two groups with a third group consisting of 22 patients with unresectable pancreatic ductal carcinoma. Results The mean operative time, postoperative serum aspartate aminotransferase concentration, and length of hospital stay did not significantly differ between the “extended” and “standard” DP groups. The cumulative 1- and 3-yr accumulated survival rates for the “extended,” “standard,” and unresectable groups were 40.0, 33.3, and 5.4, and 20.0, 16.6, and 0%, respectively. Statistically significant differences (p<0.01) existed between the “extended” and unresected groups.     

Assessing physicians’ orientation toward lifelong learning

BACKGROUND: Despite the importance of lifelong learning as an element of professionalism, no psychometrically sound instrument is available for its assessment among physicians. OBJECTIVE: To assess the validity and reliability of an instrument developed to measure physicians’ orientation toward lifelong learning. DESIGN: Mail survey. PARTICIPANTS: Seven hundred and twenty-one physicians, of whom 444 (62%) responded. MEASUREMENT: The Jefferson Scale of Physician Lifelong Learning (JSPLL), which includes 19 items answered on a 4-point Likert scale, was used with additional questions about respondents’ professional activities related to continuous learning. RESULTS: Factor analysis of the JSPLL yielded 4 subscales entitled: “professional learning beliefs and motivation,” “scholarly activities,” “attention to learning opportunities,” and “technical skills in seeking information,” which are consistent with widely recognized features of lifelong learning. The validity of the scale and its subscales was supported by significant correlations with a set of criterion measures that presumably require continous learning. The internal consistency reliability (coefficient α) of the JSPLL was 0.89, and the test-retest reliability was 0.91. CONCLUSIONS: Empirical evidence supports the validity and reliability of the JSPLL. The authors have no conflict of interest to declare for this article or this research. The study, its findings, and interpretations of the outcomes do not necessarily reflect NBME policy, and NBME support provides no official endorsement.     

Relationship of DNA ploidy to hormone receptor status and proliferation in invasive breast carcinoma

Purpose: In 247 primary invasive breast carcinomas, DNA ploidy was related to hormone receptor status, proliferation, and clinical/histopathologic factors. Methods: DNA ploidy analysis was performed by image analysis using imprints. Estrogen (ER) and progesterone (PR) receptor status was determined immunohistochemically. The proliferative activity of the tumours was assessed by Ki-67 antigen labelling. Total observation time was 3.5 years. Results: DNA ploidy analysis revealed a high fraction of tumours with non-peridiploid patterns (78%). Significant correlations between DNA ploidy and ER/PR receptor status (P < 0.01) were found with increased frequencies of peridiploid DNA results in receptor positive tumours. A significant relationship became manifest between DNA ploidy and Ki-67 index showing high frequencies of non-peridiploid DNA patterns in tumours with Ki-67 index >20% (P < 0.01). There was a strong correlation (P < 0.001) between DNA ploidy and histopathologic grading, while tumour size and lymph node status were not correlated to DNA ploidy. Conclusions: The results of our study on invasive breast carcinoma demonstrate that DNA ploidy measured by image analysis is predominantly associated with markers of cell differentiation. Preliminary outcome data reveal a risk-indicating potential of DNA ploidy primarily in cases with favourable results for other prognostic factors. Received: 18 February 2000 / Accepted: 9 May 2000     

Herbal extract “Songyou Yin” inhibits tumor growth and prolongs survival in nude mice bearing human hepatocellular carcinoma xenograft with high metastatic potential

Purpose  Chinese herbs have become a focus of interest in cancer treatment. This study evaluates the effect of the herbal compound extract “Songyou Yin” (containing Salvia miltiorrhiza Bge.-danshen and other four herbs) on hepatocellular carcinoma (HCC). Methods  Human HCC cell line MHCC97H with high-metastatic potential was employed for in vitro study. In vivo study was conducted in nude mice bearing HCC orthotopic xenograft with MHCC97H. Results  In vitro, “Songyou Yin” caused dramatic attenuation of tumor proliferation by induction of apoptosis that was associated with caspase-3 activation, and inhibit invasiveness of MHCC97H via reducing matrix metalloproteinase-2 (MMP2) activity. In vivo, “Songyou Yin” minimized cancer-related body weight loss of mice bearing tumors without distinct toxicity, and inhibited tumor growth with stepwise increased dosage of “Songyou Yin” and accorded with the expression of proliferating cell nuclear antigen. Moreover, “Songyou Yin” inhibited tumor growth was associated with an increased TUNEL-positive apoptosis as well as a decreased microvessel density and vascular endothelial growth factor (VEGF) abundance, and inhibited tumor invasion via down-regulation of MMP2. The lung metastatic extent was decreased (p < 0.01, compared with control). The life span of nude mice bearing xenografts was 75.0 ± 3.9 days in “Songyou Yin” group, whereas it was 52.0 ± 2.3 days in the control (p < 0.001). Conclusions  Nontoxic herbal compound extract “Songyou Yin” inhibited tumor growth and prolonged survival, via inducing apoptosis and down-regulation of MMP2 and VEGF, which indicated its potential use in patients with advanced HCC.     

Treatment of early stage testicular seminoma

Stage I and IIA/B testicular seminoma represent approximately 45% of all testicular germ cell tumours. Due to the availability of highly efficient salvage treatment, the disease-specific survival in stage I seminoma is approximately 100%, irrespective of the choice of adjuvant treatment. Radiotherapy with 26 Gy to the paraaortic/paracaval lymph nodes yields excellent cure rates of 95–98% with a favourable profile of acute and late toxicity. Likewise, phase-II trials with single-agent carboplatinum systemic treatment have demonstrated a rate of relapse of 3–4% on average. However, carboplatinum chemotherapy has to be regarded as experimental until data of phase-III trials are available. Surveillance in stage I disease is conflicted with a rate of relapse of approximately 20%. However, 80% of the patients will avoid potentially toxic overtreatment by the watch-and-wait policy. In stage IIA/B seminoma, “dogleg” radiotherapy with 30 Gy and 36 Gy, respectively, provides high cure rates of 90–95%. Those patients relapsing will be salvaged in almost 100% of cases. Testicular intraepithelial neoplasia (TIN) is the common precursor lesion of testicular germ cell tumours except for spermatocytic seminoma. In case of TIN in a single testis or bilateral TIN, local radiotherapy with 18 Gy is recommended as standard treatment. Received: 14 December 2000 / Accepted: 18 January 2001     

Proliferation of antigen MIB-1 in metastatic carcinoid tumours removed at liver transplantation: relevance to prognosis

BACKGROUND: Metastatic carcinoid tumours are difficult to manage. In spite of a multidisciplinary approach, including orthotopic liver transplantation, the recurrence rate is high with a poor prognosis. Histopathology generally fails to provide prognostic information, hence it is essential to try to identify markers of prognosis in these tumours before considering orthotopic liver transplantation. The MIB-1 antibody, which detects cell proliferative activity, has been shown to be a useful prognostic marker for a variety of neoplasms. AIMS: To assess the value of MIB-1 immunostaining as a prognostic marker of the duration to recurrence and the survival of patients undergoing orthotopic liver transplantation for metastatic carcinoid/neuroendocrine tumours of the liver. METHODS: Fourteen patients were included in the study. Formalin-fixed, paraffin-embedded tissue sections of the tumours were stained with routine haematoxylin and eosin and chromogranin. The cell proliferative activity was assessed by MIB-1 antibody labelling using the immunoperoxidase method. Results were correlated with the time of tumour recurrence and the length of patients' survival after transplantation. RESULTS: No correlation was found between MIB-1 labelling index and age, gender, clinical and histological type of tumour (i.e. carcinoid, APUDOMA, secreting or non-secreting). The patients with higher MIB-1 indices ( 5%) showed a trend toward earlier recurrence and poorer survival than those with low MIB-1 indices ( 5%). The predictive value of a MIB-1 index of 2 indicating patient survival of 24 months was 83% (five out of six patients). CONCLUSIONS: The correlation between MIB-1 index and patients' survival suggests that a high proliferative rate, as assessed by MIB-1 immunostaining, may detect those tumours with more aggressive biological behaviour. Prospective studies on a larger number of patients will be needed to determine if, in any individual tumour, this method will provide an additional parameter for a rational approach to therapy.     

Statins,inflammation and deep vein thrombosis: a systematic review

Venous thromboembolism (VTE) includes both deep vein thrombosis (DVT) and pulmonary embolism. The 2009 JUPITER trial showed a significant decrease in DVT in non-hyperlipidemic patients, with elevated C-reactive protein (CRP) levels, treated with rosuvastatin. The effects of statins on thrombosis are unclear, prompting this literature review. A literature search was performed (1950 to February 2011) with MEDLINE, EMBASE, and PUBMED databases including the following keywords: “statins”, “hydroxymethylglutaryl-CoA reductase inhibitors”, “VTE”, “PE”, “DVT”, and either “anti-coagulation” or “inflammation”. Editorials, reviews, case reports, meta-analysis and duplicates were excluded. Inflammatory biomarkers of DVT, include interleukin (IL)-6, CRP, IL-8, and monocyte chemotactic protein 1 (MCP-1). Statin therapy reduces IL-6 expression of CRP and MCP-1, usually elevated in VTE. Reduction of IL-6 induced MCP-1 has been linked to vein wall fibrosis, promoting post thrombotic syndrome (PTS) and recurrent DVT in patients. Also, our review suggests that the anti-thrombotic effects are likely exhibited through the anti-inflammatory properties of statins. This work supports that statin therapy has the ability to decrease the incidence and recurrence of VTE and the potential to decrease PTS. This is mainly due to the anti-inflammatory effects of statins and may explain why normolipidemic patients, with elevated CRP, appear to have the greatest reduction in VTE. Given their low risk of bleeding, statins have the potential to serve as a safe adjunctive pharmacological therapy to current treatments in select patients with VTE, however further investigations into this concept are needed and essential.     

Cell-cycle arrest and p53-independent induction of apoptosis in vitro by the new anticancer drugs 5-FdUrd-P-FdCydOct and dCydPam-P-FdUrd in DU-145 human prostate cancer cells

 Purpose: Current therapies have limited impact on the progression of metastatic hormone-refractory prostate cancer. Therefore, we investigated the utility of new heterodinucleoside phosphate dimers of 5-fluorodeoxyuridine (5-FdUrd) in p53-mutated and androgen-independent DU-145 human prostate tumour cells. Methods: The effects of the dimers were assessed in vitro by a cell proliferation assay for cytotoxicity, flow cytometry for cell cycle distribution, confocal laser scanning microscopy for the detection of apoptotic bodies, poly(ADP-ribose) polymerase cleavage for caspase 3 activity and by a thymidylate synthetase assay. Results: The new dimers N ⁴-palmitoyl-2′-deoxycytidylyl-(3′→5′)-5-fluoro-2′-deoxyuridine (dCydPam-P-FdUrd) and 2′-deoxy-5-fluorouridylyl-(3′→5′)-2′-deoxy-5-fluoro-N ⁴-octadecylcytidine (5-FdUrd-P-FdCydOct) caused marked cytotoxicity with IC₅₀ values of 3–4 μM. 5-FdUrd-P-FdCydOct at 200 μM was capable of eradicating 100% of tumour cells whereas 10% of the cells were resistant to 5-FdUrd. Cytotoxicity was caused by a dramatic S-phase arrest, resulting in an increase of this cell population from 34% to 85% with 5-FdUrd-P-FdCydOct and to 81% with dCydPam-P-FdUrd. S-phase arrest was followed by apoptosis, as shown by 85% of the cells staining positive for Apo 2.7 antibody, a six- to eight-fold increased caspase 3 activity and DNA fragmentation. Thymidylate synthase activity was inhibited by 50% at 0.6–0.7 μM dimer concentration. The dimers were hydrolysed in vitro by phosphodiesterase I and human serum to the corresponding nucleosides and nucleoside monophosphates. Conclusions: The new dimers dCydPam-P-FdUrd and 5-FdUrd-P-FdCydOct are effective prodrugs of 5-FdUrd and have potential value for the treatment of p53-mutated and hormone-independent human prostate carcinomas. Received: 20 August 1999 / Accepted: 4 December 1999     

A comparative study of the clinicopathological significance of E-cadherin and catenins (α, β, γ) expression in the surgical management of oral tongue carcinoma

Purpose: E-cadherin and catenins are important epithelial adhesion molecules in normal epithelium. Loss of E-cadherin-catenin adhesion is an important step in the progression of many epithelial cancers. E-cadherin and catenins expression in carcinoma of the tongue were evaluated in relation to their clinicopathological features and prognostic values. Method: Immunohistochemical staining was carried out with E-cadherin and (α, β, γ)-catenin monoclonal antibodies for 85 surgical specimens of oral tongue carcinoma, nine matched metastatic lymph nodes, and seven locally recurrent tumours. Results: There was under-expression in 85% of E-cadherin, 94% of α-catenin, 89% of β-catenin, and 83% of γ-catenin in the primary tumours. There was no correlation of E-cadherin/catenin expression with sex, age, cancer stage, and differentiation. Nodal metastasis was found in 68% of patients with weak expression of γ-catenin compared with 9% with strong expression in primary tumours (chi-square, P=0.02). E-cadherin was a significant prognostic factor for survival and recurrence; patients with weak E-cadherin expression had 53% 5-year survival compared with 85% with strong expression (Wilcoxon, P=0.0159). Conclusions: Both E-cadherin and catenins were highly under-expressed in oral tongue carcinoma, metastatic lymph node, and recurrent tumour. γ-catenin had predictive value for nodal metastasis. E-cadherin was, however, a more important prognostic factor for recurrence and survival. Received: 14 February 2000 / Accepted: 6 June 2000     

Comparison of Mesalazine and Balsalazide in Induction and Maintenance of Remission in Patients with Ulcerative Colitis: A Meta-Analysis

Background 5-Aminosalicylates are the standard treatment for induction and maintenance of remission in mild-to-moderate ulcerative colitis. In recent years, the 5-aminosalicylic acid-containing pro-drug balsalazide has been the focus of attention. Aim To compare the efficacy and tolerance of balsalazide and mesalazine by meta-analysis. Methods Pubmed, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for studies comparing the efficacy and/or tolerance of balsalazide with mesalazine in the management of UC. The search terms were: “mesalazine” or “5-aminosalicylic acid” and “balsalazide” and “ulcerative colitis.” Data were collected from 1966 to 2007 (up to February). There was no language restriction. “Symptomatic remission,” “complete remission,” “relapse rate,” “total adverse events,” and “withdrawals because of adverse events” were the key outcomes of interest. Results Six randomized placebo-controlled clinical trials met our criteria and were included in the meta-analysis. In these “symptomatic remission,” “complete remission,” “relapse rate,” “total adverse events,” and “withdrawals because of adverse events” were evaluated in three, three, two, five, and six of the trials, respectively. They included 653 patients consisting of 55.4% men and 44.6% women randomized to receive either balsalazide or mesalazine. Pooling of three trials for symptomatic remission yielded a significant relative risk (RR) of 1.23 (95% confidence interval of 1.03–1.47, P = 0.02). The summary RR for complete remission in three trials was 1.3 (95% CI of 1.002–1.68, P = 0.048). Pooling of two trials for the outcome of relapse yielded a non-significant RR of 0.77 (95% CI of 0.56–1.07, P = 0.12). Pooling five studies from which data for any adverse events were extracted, yielded a non-significant RR of 0.87 (95% CI of 0.75–1.001, P = 0.53). The summary RR for withdrawals because of adverse events in six trials was 0.69, a non-significant RR (95% CI of 0.37–1.29, P = 0.24). Conclusion Balsalazide is more effective than mesalazine in induction of remission, but balsalazide has no benefit compared with mesalazine in preventing relapse in the population selected. The number of patients with any adverse events and withdrawals because of severe adverse events is similar for mesalazine and balsalazide.