Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial

Aims: Assess the efficacy and safety of saxagliptin added to a submaximal sulphonylurea dose vs. uptitration of sulphonylurea monotherapy in patients with type 2 diabetes and inadequate glycaemic control with sulphonylurea monotherapy. Methods and patients: A total of 768 patients (18–77 years; HbA_1c screening ≥ 7.5 to ≤ 10.0%) were randomised and treated with saxagliptin 2.5 or 5 mg in combination with glyburide 7.5 mg vs. glyburide 10 mg for 24 weeks. Blinded uptitration glyburide was allowed in the glyburide‐only arm to a maximum total daily dose of 15 mg. Efficacy analyses were performed using ANCOVA and last‐observation‐carried‐forward methodology. Results: At week 24, 92% of glyburide‐only patients were uptitrated to a total glyburide dose of 15 mg/day. Saxagliptin 2.5 and 5 mg provided statistically significant adjusted mean decreases from baseline to week 24 vs. uptitrated glyburide, respectively, in HbA_1c (?0.54%, ?0.64% vs. +0.08%; both p < 0.0001) and fasting plasma glucose (?7, ?10 vs. +1 mg/dl; p = 0.0218 and p = 0.002). The proportion of patients achieving an HbA_1c < 7% was greater for saxagliptin 2.5 and 5 mg vs. uptitrated glyburide (22.4% and 22.8% vs. 9.1%; both p < 0.0001). Postprandial glucose area under the curve was reduced for saxagliptin 2.5 and 5 mg vs. uptitrated glyburide (?4296 and ?5000 vs. +1196 mg·min/dl; both p < 0.0001). Adverse event occurrence was similar across all groups. Reported hypoglycaemic events were not statistically significantly different for saxagliptin 2.5 (13.3%) and 5 mg (14.6%) vs. uptitrated glyburide (10.1%). Conclusion: Saxagliptin added to submaximal glyburide therapy led to statistically significant improvements vs. uptitration of glyburide alone across key glycaemic parameters and was generally well tolerated.     

K-ras gene mutational analysis supports a monoclonal origin of biphasic pleomorphic carcinoma of the lung.

We investigated 27 pleomorphic carcinomas of the lung for exon 1 K-ras gene mutations using polymerase chain reaction-single-strand conformation polymophism analysis and direct sequencing. All pleomorphic carcinomas were biphasic, that is, composed of an adeno-, squamous- or large-cell-carcinomatous component associated with a spindle- and/or giant-cell component. Of 27 cases, six (22%) showed K-ras codon 12 mutations, which is a figure higher than that previously reported on in pure sarcoma-like pleomorphic carcinomas. Five tumors displayed the same mutation in both the epithelial and the sarcomatoid components, whereas in one tumor the mutation was restricted to the epithelial component. All mutations occurred in smokers, and were transversions, including GGT (glycine) to TGT (cysteine) change in two cases, to GCT (alanine) in two and to GTT (valine) in two. No significant relationships were found between the occurrence and type of mutations and patients' survival or any other clinicopathological variable, suggesting that K-ras mutations are early events in the development of these tumors. Our results indicate that most, though not all, biphasic pleomorphic carcinomas of the lung are monoclonal in origin, and that cigarette smoking may have a causative role in the development of K-ras alterations in these tumors, as all mutations are transversions.     

MR correlates of cerebral atrophy in patients with multiple sclerosis

Objective To investigate the in-vivo correlates of brain atrophy in patients with multiple sclerosis (MS) by assessing the relationship between normalized measures of brain volume (NBV) and other magnetic resonance (MR) measures of tissue damage. Background Brain atrophy diffusely occurs and progressively increases in patients with MS. Nevertheless, the mechanisms leading to brain atrophy in this disease are not fully understood. Methods MR examinations were performed in 20 patients with relapsing-remitting MS. Conventional MRI was used to assess NBV and total brain T2-hyperintense and T1-hypointense lesion volumes. Proton MR spectroscopic imaging and diffusion tensor MR imaging were also performed for large portions of brain containing mainly normal-appearing tissue to provide indices of tissue damage, including N-acetylaspartate to creatine ratio (NAA/Cr) and mean diffusivity (). Results Values of NBV correlated significantly with those of average brain (r = -0.58, p = 0.007) and NAA/Cr (r = 0.67, p < 0.001). The relationship of these markers of tissue damage to NBV was also found when NAA/Cr and were computed together in a composite MR score (r = 0.70, p < 0.001). In contrast, NBV values did not correlate with measurements of average lesion , T₂ and T₁ weighted total brain MRI lesion volumes. Conclusions This study suggests that brain atrophy in MS is not simply due to axonal loss, but rather reflects a more generalized process that involves various brain tissue components. Damage to the normal-appearing tissue rather than the extent and intrinsic pathology of macroscopic lesions seems to be important in the destructive process leading to MS-related irreversible cerebral atrophy. Received: 13 September 2001 Received in revised form: 18 January 2002 Accepted: 4 March 2002     

A phase II study of biochemotherapy for the treatment of metastatic malignant melanoma

The use of interleukin-2 (IL-2) and interferon-alpha (IFNalpha) in combination with chemotherapy for the treatment of advanced malignant melanoma has generated considerable interest. In particular, the relatively high number of durable complete responses has suggested this may be a significant advance in the treatment of malignant melanoma. We report our experience at the University of Colorado in 43 patients, including many with poor prognostic factors. Patients received cisplatin 20 mg/m2 on days 1-4, vinblastine 1.6 mg/m2 on days 1-4, dacarbazine 800 mg/m2 on day 1, IL-2 9 x 10(6) IU/m2 per day intravenously over 24h on days 1-4 and IFNalpha 5 x 10(6) IU/m2 per day subcutaneously on days 1-5 every 3 weeks. The median follow-up for all patients was 34 months. Responses were seen in 20 patients (47%, 95% confidence interval 31-62%) and comprised five complete responses (CRs) (12%) and 15 partial responses (PRs) (35%). Two patients achieving a CR remain disease free at 45 and 47 months follow-up. In addition three patients who obtained a surgical CR and another with only minor residual changes on computed tomography scan have not progressed at 27, 30, 40 and 27 months, respectively. Toxicity was manageable, but all patients had at least one grade 3 or 4 toxicity, predominantly hypotension and neutropenia. There were no treatment-related deaths. In conclusion, the response rate and duration is within the range previously reported for biochemotherapy. The results of ongoing randomized studies are awaited to better define the value of biochemotherapy in the treatment of advanced melanoma.     

European study on intravenous immunoglobulin in multiple sclerosis: results of magnetization transfer magnetic resonance imaging analysis

BACKGROUND: Magnetization transfer magnetic resonance imaging (MT MRI) can provide in vivo markers reflecting the severity of multiple sclerosis-related brain damage occurring within and outside T2-visible lesions. OBJECTIVE: To investigate the effect of intravenous immunoglobulin (IVIG) treatment on the accumulation of brain damage in patients with secondary progressive multiple sclerosis (SPMS), measured using MT MRI.Design, Patients, and Intervention Seventy patients with SPMS participating in the European, multicenter, randomized, double-blind, placebo-controlled trial of IVIG in SPMS underwent brain T2-weighted and MT MRI at baseline and after 12 and 24 months. The MT MRI scans were post-processed and analyzed to obtain MT ratio values from T2-visible lesions and MT ratio histograms from the normal-appearing brain tissue (NABT). RESULTS: At baseline, a significant difference was found for NABT MT ratio histogram peak height (P =.003) between treated patients and patients receiving placebo. No significant differences between treated patients and those receiving placebo were found for any of the considered MT MRI-derived metrics in terms of treatment x time interaction. Nevertheless, over the 24-month period, the placebo patients experienced a 6.75% reduction of the NABT MT ratio histogram peak height, whereas treated patients experienced only a 0.92% reduction of the NABT MT ratio histogram peak height. CONCLUSIONS: This study did not show any statistically significant effect of IVIG on MT MRI quantities. Nevertheless, the markedly different percentage change of the NABT MT ratio histogram peak height over time between patients receiving placebo and treated patients suggests a possible role of IVIG treatment in preventing the loss of "truly" normal brain tissue in SPMS patients.     

Uterine rupture with the use of PGE2 vaginal inserts for labor induction in women with previous cesarean sections

OBJECTIVE: To analyze the rate of uterine rupture in women with previous cesarean sections undergoing a trial of labor in which a prostaglandin E2 (PGE2) vaginal insert was used. STUDY DESIGN: The study was based on a computerized search and review of pharmacy records, medical records and the pertinent literature. Pharmacy records were correlated with the medical records of all women undergoing a trial of labor after cesarean section over a 33-month period. RESULTS: Between January 1998 and September 2000, 13,544 patients delivered. Of these cases, 790 were vaginal trials of labor after previous cesarean section. A PGE2 vaginal insert was used in 58 of the patients. A total of 6 of these 58 patients (10.3%) experienced uterine rupture. This compares to a rupture rate of 1.1% (8/732) in deliveries not using PGE2 vaginal inserts. CONCLUSION: The risk of uterine rupture was significantly increased in patients undergoing a trial of labor after previous cesarean section when a PGE2 vaginal insert was used. Physicians need to be aware that using a PGE2 vaginal inserts for cervical ripening and/or induction of labor in women with a previous cesarean section might increase the risk of uterine rupture above the standard risk for vaginal birth after cesarean (VBAC) candidates. We recommend that all VBAC patients using a PGE2 vaginal insert be closely monitored for evidence of uterine rupture.     

Primary lymphoepithelioma-like carcinoma of the urinary bladder: Report of one case with review and update of the literature after a pooled analysis of 43 patients

Background and objectives:Lymphoepithelioma-like carcinoma (LELC) is anundifferentiated epithelial tumor with a denseinflammatory infiltrate that resembles thelymphoepithelioma of the nasopharinx occurringin other sites. Primary LELC of the bladder(LELCB) was first reported by Zukerberg et alin 1991. The incidence of LELCB is 0.4%–1.3% of all bladder carcinomas. The mean ageat diagnosis is 69 years. Of the patientpopulation 69% are men. Herein we report onone more case of primary predominant LELCB andreview all the English literature concerningthis subject after performing a pooled analysisof the cases recorded in the Eglish literatureincluding the present one.Materials and methods: The reports of 43patients including the present case of primaryLELCB from the English literature werecollected from 1991 to 2002. Patients wereevaluated for age, sex, primary and adjuvanttreatments, clinical staging, follow-up andoutcome, and disease related survival. Theoverall patient population was separated into 3groups according to the LELCB classification ofAmin. Results: The overall patientpopulation included 31 males and 12 females.Average age was 68.4 years (range 52–84). LELCBhistological subtypes resulted pure in 17cases(40%), predominant in 16 (37%) and focal in10 (23%). Mean follow-up was 37.7 months(range 0–216). Outcome resulted as follows: 26patients (62%) did not show evidence ofdiasease (62%), 11 (26%) died of disease, 1(2%) was alive with metastases, and 4 (10%)died for causes unrelated to the primarydisease. Survival rate related to specificdisease resulted 71%. Mean follow-up was 48.1in the first group (pure LELCB), 32 in thesecond (predominant LELCB), and 30.3 in thethird one (focal LELCB). Patients with notevidence of disease were 13 (81%) in group 1,13 (82%) in group 2, and 0 in group 3.Patients who died of their disease resulted 1(6%) in the first group, 1 (6%) in thesecond, and 9 (90%) in the third one. Patientswho died for disease not related to the primarytumor were 2 (13%) in the first group, 1 (6%)in the second, and 1 (10%) in the third one.One patient (6%) was alive with metastases ingroup 2. Survival rate related to specificdisease resulted 93% in the first group, 93%in the second one, and 0% in the third one.Conclusions:To date, there are no clear guide lines for the treatment of LELCB. Treatments performedinclude both deep transurethral resection ofthe tumor (TUR-B) as well as partial or radicalcystectomy, with or without adjuvant treatmentsincluding systemic chemotherapy andradiotherapy. The prognosis is favorable forpatients presenting with the pure andpredominant forms with a diploid DNA patternand very poor for patients presenting withfocal LELCB. Bladder salvage therapy byperforming both TUR-B alone or combined withadjuvant systemic chemotherapy may be areasonable option for patients with pure orpredominant LELCB, while radical surgery withadjuvant systemic therapy may be indicated forfocal muscle invasive LELCB.