Ancestry-specific hereditary cancer panel yields: Moving toward more personalized risk assessment.

Healthcare disparities in genomic medicine are well described. Despite some improvements, we continue to see fewer individuals of African American, Asian, and Hispanic ancestry undergo genetic counseling and testing compared to those of European ancestry. It is well established that variant of uncertain significance (VUS) rates are higher among non-European ancestral groups undergoing multi-gene hereditary cancer panel testing. However, pathogenic variant (PV) yields, and genomic data in general, are often reported in aggregate and derived from cohorts largely comprised of individuals of European ancestry. We performed a retrospective review of clinical and ancestral data for individuals undergoing multi-gene hereditary cancer panel testing to determine ancestry-specific PV and VUS rates. An ancestry other than European was reported in 29,042/104,851 (27.7%) of individuals. Compared to Europeans (9.4%), individuals of Middle Eastern ancestry were more likely to test positive for one or more pathogenic variants (12.1%, p = .0025), while African Americans were less likely (7.9%, p < .0001). Asian and Middle Eastern individuals were most likely (34.8% and 33.2%, respectively) to receive a report with an overall classification of VUS, while individuals of Ashkenazi Jewish and European ancestry were least likely (17.1% and 20.4%, respectively). These data suggest that in addition to higher VUS rates, there may be ancestry-specific PV yields. Providing aggregate data derived from cohorts saturated with European individuals does not adequately reflect genetic testing outcomes in minority groups, and interrogation of ancestry-specific data is a step toward a more personalized risk assessment.

Age-adjusted association of homologous recombination genes with ovarian cancer using clinical exomes as controls.

BACKGROUND: Genes in the homologous recombination pathway have shown varying results in the literature regarding ovarian cancer (OC) association. Recent case-control studies have used allele counts alone to quantify genetic associations with cancer. METHODS: A retrospective case-control study was performed on 6,182 women with OC referred for hereditary cancer multi-gene panel testing (cases) and 4,690 mothers from trios who were referred for whole-exome sequencing (controls). We present age-adjusted odds ratios (ORAdj) to determine association of OC with pathogenic variants (PVs) in homologous recombination genes. RESULTS: Significant associations with OC were observed in BRCA1, BRCA2, RAD51C and RAD51D. Other homologous recombination genes, BARD1, NBN, and PALB2, were not significantly associated with OC. ATM and CHEK2 were only significantly associated with OC by crude odds ratio (ORCrude) or by ORAdj, respectively. However, there was no significant difference between ORCrude and ORAdj for these two genes. The significant association of PVs in BRIP1 by ORCrude (2.05, CI = 1.11 to 3.94, P = 0.03) was not observed by ORAdj (0.87, CI = 0.41 to 1.93, P = 0.73). Interestingly, the confidence intervals of the two effect sizes were significantly different (P = 0.04). CONCLUSION: The lack of association of PVs in BRIP1 with OC by ORAdj is inconsistent with some previous literature and current management recommendations, highlighted by the significantly older age of OC onset for BRIP1 PV carriers compared to non-carriers. By reporting ORAdj, this study presents associations that reflect more informed genetic contributions to OC when compared to traditional count-based methods.

Clinical validity assessment of genes frequently tested on hereditary breast and ovarian cancer susceptibility sequencing panels.

PURPOSE: Several genes on hereditary breast and ovarian cancer susceptibility test panels have not been systematically examined for strength of association with disease. We employed the Clinical Genome Resource (ClinGen) clinical validity framework to assess the strength of evidence between selected genes and breast or ovarian cancer. METHODS: Thirty-one genes offered on cancer panel testing were selected for evaluation. The strength of gene-disease relationship was systematically evaluated and a clinical validity classification of either Definitive, Strong, Moderate, Limited, Refuted, Disputed, or No Reported Evidence was assigned. RESULTS: Definitive clinical validity classifications were made for 10/31 and 10/32 gene-disease pairs for breast and ovarian cancer respectively. Two genes had a Moderate classification whereas, 6/31 and 6/32 genes had Limited classifications for breast and ovarian cancer respectively. Contradictory evidence resulted in Disputed or Refuted assertions for 9/31 genes for breast and 4/32 genes for ovarian cancer. No Reported Evidence of disease association was asserted for 5/31 genes for breast and 11/32 for ovarian cancer. CONCLUSION: Evaluation of gene-disease association using the ClinGen clinical validity framework revealed a wide range of classifications. This information should aid laboratories in tailoring appropriate gene panels and assist health-care providers in interpreting results from panel testing.

Germline pathogenic variants identified in women with ovarian tumors.

OBJECTIVE: The recognition of genes implicated in ovarian cancer risk beyond BRCA1, BRCA2, and the Lynch syndrome genes has increased the variety of testing options available to providers and patients. We report the frequency of pathogenic variants identified among individuals with ovarian cancer undergoing clinical genetic testing via a multi-gene hereditary cancer panel. METHODS: Genetic testing of up to 32 genes using a hereditary cancer panel was performed on 4439 ovarian cancer cases, and results were analyzed for frequency of pathogenic variants. Statistical comparisons were made using t-tests and Fisher's exact tests. RESULTS: The positive yield was 13.2%. While BRCA1/2 pathogenic variants were most frequent, one third (33.7%) of positive findings were in other homologous recombination genes, and accounted for over 40.0% of findings in endometrioid and clear cell cases. Women with a personal history of breast cancer (22.1%), who reported a family history of ovarian cancer (17.7%), and/or serous histology (14.7%) were most likely to harbor a pathogenic variant. Those with very early onset (<30 years) and late onset (≥70 years) ovarian cancer had low positive yields. CONCLUSIONS: Our study highlights the genetic heterogeneity of ovarian cancer, showing that a large proportion of cases are not due to BRCA1/2 and the Lynch syndrome genes, but still have an identifiable hereditary basis. These findings substantiate the utility of multi-gene panel testing in ovarian cancer care regardless of age at diagnosis, family history, or histologic subtype, providing evidence for testing beyond BRCA1/2 and the Lynch syndrome genes.

Synchronous Bilateral Tubal Serous Carcinomas in a Patient With Exon 13 Duplication and Loss of Function of BRCA1.

We report the first case of distinct, synchronous serous carcinomas of the adnexa arising in a patient with a family history of breast and ovarian cancer and a germline loss of function mutation in BRCA1. Illustrating an exceedingly rare phenomenon of synchronous high-grade carcinomas with distinct histomorphologic, immunohistochemical and cytogenetic features, the case serves as a point of departure for the discussion of phenotypic patterns of carcinomas arising in BRCA1 mutation carriers. We also review patient management, including the importance of risk-reducing salpingo-oophorectomy in women with deleterious BRCA1 mutations, as well as the potential need for an intraoperative pathologic assessment to find occult, high-grade carcinomas in this setting.

Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2.

BACKGROUND: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). METHODS: We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10(-12)). CONCLUSIONS: On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.

Degarelix: a review of its use in patients with prostate cancer.

Degarelix (Firmagon(®); Gonax(®)) is a gonadotropin-releasing hormone receptor antagonist that is approved for the treatment of advanced (hormone-dependent) prostate cancer in the US and EU and the treatment of prostate cancer in Japan. In a pivotal randomized, controlled, 12-month phase III study, degarelix (initial subcutaneous dose of 240 mg followed by monthly dosages of 80 mg) was noninferior to leuprolide (monthly intramuscular dosages of 7.5 mg) in patients with prostate cancer of any stage for which endocrine treatment was indicated (except neoadjuvant hormonal therapy) with regard to suppression of testosterone to castration levels (i.e. ≤0.5 ng/mL). Suppression of testosterone and prostate-specific antigen (PSA) levels was faster with degarelix than with leuprolide, and no testosterone surges or microsurges were seen in degarelix recipients. Suppression of testosterone and PSA levels was maintained for the 12-month study duration and continued for up to 5 years in an extension to the main trial (including in patients switching from leuprolide to degarelix in the extension). The drug was generally well tolerated, with most adverse events being mild to moderate in severity. Injection-site reactions and events reflecting the expected effects of testosterone suppression (e.g. hot flushes, weight increase) were the most common treatment-emergent adverse events. Thus, degarelix is a useful option for the treatment of prostate cancer in patients for whom endocrine treatment is indicated.

Regorafenib: a review of its use in previously treated patients with progressive metastatic colorectal cancer.

Regorafenib (Stivarga) is an inhibitor of multiple protein kinases, including those involved in oncogenesis, tumour angiogenesis and maintenance of the tumour microenvironment. The drug is approved as monotherapy for the treatment of metastatic colorectal cancer (mCRC) in patients who have previously received all standard systemic anticancer treatments (US, EU and Canada) or in patients with unresectable, advanced or recurrent colorectal cancer (Japan). In the randomized, controlled COloRectal cancer treated with REgorafenib or plaCebo after failure of standard Therapy (CORRECT) trial, regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle plus best supportive care (BSC) was associated with a significantly longer median overall survival than placebo plus BSC in patients with previously treated, progressive mCRC. The drug was also associated with significantly longer progression-free survival and better disease control rates than placebo, although objective response rates were similar in both treatment groups. Regorafenib did not appear to compromise health-related quality of life over the study duration and had a generally acceptable tolerability profile. The introduction of regorafenib expands the currently limited range of effective treatment options in patients with previously treated, progressive mCRC.

Inhaled glycopyrronium bromide: a review of its use in patients with moderate to severe chronic obstructive pulmonary disease.

Inhaled glycopyrronium bromide (Seebri(®) Breezhaler(®) capsules; NVA237) is a once-daily, long-acting muscarinic receptor antagonist (LAMA) that is approved in several countries, including the EU, as a maintenance bronchodilator for the symptomatic treatment of adult patients with chronic obstructive pulmonary disease (COPD). In the randomized, controlled, phase III GLOW (GLycopyrronium bromide in chronic Obstructive pulmonary disease airWays clinical study)-1 and -2 trials, treatment with inhaled glycopyrronium bromide 50 µg once daily was associated with significantly better lung function than placebo in patients with moderate to severe COPD in terms of the trough forced expiratory volume in one second (FEV1) at 12 weeks (primary endpoint). Significant between-group differences in trough FEV1 in favour of inhaled glycopyrronium bromide were maintained for up to 52 weeks. Dyspnoea scores, health status and exacerbation rates were also improved to a greater extent in the inhaled glycopyrronium bromide than placebo groups in these trials. In the randomized, controlled, phase III GLOW3 trial, inhaled glycopyrronium bromide was associated with a significantly longer exercise endurance time than placebo after 3 weeks' treatment in patients with moderate to severe COPD. The drug was generally well tolerated over the 26-week (GLOW1) or 52-week (GLOW2) study duration, and had a tolerability profile that was generally similar to that of tiotropium bromide. Serious adverse events were consistent with those expected in patients with moderate to severe COPD. In conclusion, inhaled glycopyrronium bromide is a once-daily LAMA that is an effective bronchodilator for use in the treatment of patients with moderate to severe COPD.

Rivaroxaban: a review of its use in the prevention of stroke and systemic embolism in patients with atrial fibrillation.

Rivaroxaban (Xarelto(®)), a direct factor Xa inhibitor, is approved for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF) in Canada or those with nonvalvular AF (NVAF) in the EU, US and Japan. It is administered at a fixed oral dose and generally does not require routine monitoring of coagulation parameters. In the ROCKET AF trial in patients with NVAF and a moderate to high risk of stroke, oral rivaroxaban 20 mg once daily (15 mg once daily in patients with moderate renal impairment) was noninferior to oral dose-adjusted warfarin once daily in preventing primary endpoint events (i.e. stroke and systemic embolism) in the per-protocol population (primary noninferiority analysis) and superior in the on-treatment safety population (primary superiority analysis). Several ROCKET AF subgroup analyses indicated that the treatment effect of rivaroxaban was consistent across patient subgroups stratified according to baseline factors, including the presence or absence of previous stroke or transient ischaemic attack. Patients with moderate renal impairment receiving the reduced rivaroxaban dosage (15 mg once daily) showed a treatment effect consistent with that seen with rivaroxaban 20 mg once daily in patients with normal renal function. The tolerability profile of rivaroxaban was generally acceptable in ROCKET AF, with no significant difference between rivaroxaban and warfarin in the incidence of major or nonmajor clinically-relevant bleeding events (primary safety endpoint). In the Japanese ROCKET AF trial, rivaroxaban 15 mg once daily (10 mg once daily in patients with moderate renal impairment) was noninferior to oral dose-adjusted warfarin once daily in the incidence of major or nonmajor clinically-relevant bleeding (primary study outcome). Thus, rivaroxaban is a reasonable alternative to warfarin for the prevention of stroke and systemic embolism in patients with NVAF.

Multicomponent meningococcal serogroup B vaccine (4CMenB; Bexsero(®)): a review of its use in primary and booster vaccination.

Multicomponent meningococcal serogroup B vaccine (4CMenB; Bexsero(®)) is a unique vaccine containing four main immunogenic components: three recombinant proteins combined with outer membrane vesicles derived from meningococcal NZ98/254 strain. After three doses of 4CMenB (administered at 2, 3, and 4 months or 2, 4, and 6 months of age) in vaccine-naive infants, the majority of infants had seroprotective human complement serum bactericidal assay (hSBA) antibody titers against the meningococcal serogroup B test strains selected to be specific for the vaccine antigens in randomized, open-label or observer-blind, multicenter, phase IIb or III trials. In extensions to the phase III trial, two doses of 4CMenB administered between 12 and 15 months of age in vaccine-naive infants, and a single booster dose of 4CMenB administered at 12 months of age in vaccine-experienced infants, also elicited robust immunogenic responses. In a phase IIb/III trial, the majority of adolescents (aged 11-17 years) achieved seroprotective hSBA antibody titers against meningococcal serogroup B test strains after two doses of 4CMenB, and a third dose did not appear to add any extra protection. In adults who were potentially at an increased risk of occupational exposure to meningococcal isolates, seroprotection rates were high after one dose of 4CMenB and increased further after two or three doses in a small noncomparative, two-center, phase II trial. The reactogenicity of 4CMenB was generally acceptable in clinical trials. However, the vaccine was associated with more solicited systemic adverse events (particularly fever) in infants when coadministered with routine infant vaccines than when these vaccines were administered alone. In conclusion, 4CMenB effectively elicited immune responses against meningococcal serogroup B test strains selected to be specific for the vaccine antigens in infants, adolescents, and adults.

Bilastine: in allergic rhinitis and urticaria.

Bilastine is an orally administered, second-generation antihistamine used in the symptomatic treatment of seasonal or perennial allergic rhinoconjunctivitis and urticaria. In two well designed phase III trials, 14 days' treatment with bilastine was associated with a significantly lower area under the effect curve (AUEC) for the reflective total symptom score (TSS) than placebo in patients with symptomatic seasonal allergic rhinitis. Additionally, reflective nasal symptom scores were significantly lower in bilastine than placebo recipients in patients with a history of seasonal allergic rhinitis who were challenged with grass pollen allergen in a single-centre, phase II study. Neither bilastine nor cetirizine was effective in the treatment of perennial allergic rhinitis with regard to the mean AUEC for reflective TSS in another well designed phase III trial. However, results may have been altered by differences in some baseline characteristics and placebo responses between study countries. In another well designed phase III trial, compared with placebo, bilastine was associated with a significantly greater change from baseline to day 28 in the mean reflective daily urticaria symptom score in patients with chronic urticaria. There were no significant differences in primary endpoint results between bilastine and any of the active comparators used in these trials (i.e. cetirizine, levocetirizine and desloratadine). Bilastine was generally well tolerated, with a tolerability profile that was generally similar to that of the other second-generation antihistamines included in phase III clinical trials.

Live attenuated influenza vaccine (Fluenz™): a guide to its use in the prevention of seasonal influenza in children in the EU.

Live attenuated influenza vaccine (LAIV).[Fluenz™] has a convenient intranasal route of administration. In the EU, it is indicated for the prevention of influenza disease caused by the influenza virus strains contained in the vaccine in children and adolescents aged 2 years to <18 years. The vaccine elicits a high immunogenic response, is protective against seasonal influenza infection and is associated with the development of herd immunity. LAIV is generally well tolerated, with the safety of the vaccine in the approved pediatric population generally considered to be similar to that of placebo based on clinical trials and extensive experience involving more than 39 million vaccine doses.

Extended-release intramuscular paliperidone palmitate: a review of its use in the treatment of schizophrenia.

Extended-release intramuscular paliperidone palmitate (Xeplion®; Invega® Sustenna®) [henceforth referred to as intramuscular paliperidone palmitate] is a long-acting injectable (LAI) formulation of the well established atypical antipsychotic agent paliperidone (9-hydroxyrisperidone), which is the major active metabolite of risperidone. This article reviews, from an EU perspective, the therapeutic efficacy and tolerability of intramuscular paliperidone palmitate in the treatment of adults with schizophrenia, and the pharmacology of paliperidone that is relevant to the intramuscular formulation. Intramuscular paliperidone palmitate 25-150 mg equivalents (mg eq.) effectively reduced symptoms of schizophrenia in most short-term (9-13 weeks) placebo-controlled trials, as demonstrated by improvements in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to endpoint that were significantly greater in intramuscular paliperidone palmitate than placebo recipients. The onset of clinical response was 8 days in patients who received the recommended initial 150 mg eq. dose of intramuscular paliperidone palmitate into the deltoid muscle on day 1. In a longer-term (24-week maintenance phase and variable length double-blind phase) placebo-controlled trial, intramuscular paliperidone palmitate was associated with a significantly longer time to relapse than placebo in patients with schizophrenia at a preplanned interim analysis conducted after 68 relapse events. Because of these favourable results, the study was terminated early. In two 13-week trials, one of which was conducted in Chinese patients, intramuscular paliperidone palmitate administered using the recommended initiation dosage regimen was noninferior to LAI-risperidone in patients with schizophrenia in terms of the between-group treatment difference (intramuscular paliperidone palmitate vs LAI-risperidone) for the mean change from baseline to endpoint in PANSS total score. The tolerability of intramuscular paliperidone palmitate was generally acceptable in clinical trials of schizophrenia. No new safety concerns were revealed compared with oral paliperidone, except for injection site-related reactions. In conclusion, intramuscular paliperidone palmitate is a useful option for the treatment of patients with schizophrenia.

Pirfenidone: in idiopathic pulmonary fibrosis.

Pirfenidone is an orally administered pyridine that has orphan designation for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF) in the EU. Pirfenidone 2403 mg/day for 72 weeks administered to patients with IPF was associated with a significantly lower mean decline in the percent predicted forced vital capacity than placebo (primary endpoint) according to data from one of two randomized, double-blind, multinational trials (studies 004 and 006 [also known as the CAPACITY trials]), and data from a pooled analysis of both trials. In another randomized, double-blind, multicentre Japanese trial, the adjusted mean in the change in vital capacity from baseline to week 52 was significantly lower in patients with IPF who received pirfenidone 1800 mg/day (considered to be comparable to the 2403 mg/day dose in studies 004 and 006 on a weight-normalized basis) than in those who received placebo (primary endpoint). Pirfenidone had an acceptable tolerability profile in clinical trials, with most adverse events being mild to moderate in severity.

Live attenuated influenza vaccine (FluMist®; Fluenz™): a review of its use in the prevention of seasonal influenza in children and adults.

Live attenuated influenza vaccine (LAIV) is an intranasally administered trivalent, seasonal influenza vaccine that contains three live influenza viruses (two type A [H1N1 and H3N2 subtypes] and one type B). LAIV was effective in protecting against culture-confirmed influenza caused by antigenically matched and/or distinct viral strains in children aged ≤71 months enrolled in three phase III trials. LAIV was superior to trivalent inactivated influenza vaccine (TIV) in protecting against influenza caused by antigenically-matching viral strains in a multinational phase III trial in children aged 6-59 months. LAIV was also significantly more effective than TIV in decreasing the incidence of culture-confirmed influenza illness in two open-label studies (in children with recurrent respiratory tract illnesses aged 6-71 months and in children and adolescents with asthma aged 6-17 years). LAIV did not differ significantly from placebo in preventing febrile illnesses in adults (primary endpoint) enrolled in a phase III trial. However, LAIV significantly reduced the incidence of febrile upper respiratory tract illnesses (URTI), severe febrile illnesses, febrile URTI-related work absenteeism and healthcare provider use. In another well designed trial in adults, LAIV significantly reduced the incidence of symptomatic, laboratory-confirmed influenza compared with placebo (but not intramuscular TIV). LAIV was generally well tolerated in most age groups, with the majority of adverse events being mild to moderate in severity, and runny nose/nasal congestion being the most common. In a large phase III trial, LAIV, compared with TIV, was associated with an increased incidence of medically significant wheezing in vaccine-naive children aged <24 months and an increased incidence of hospitalization in children aged 6-11 months; LAIV is not approved for use in children <24 months. LAIV was not always associated with high rates of seroconversion/seroresponse, particularly in older children and adults, or in subjects with detectable levels of haemagglutination-inhibiting antibodies at baseline. However, LAIV did elicit mucosal (nasal) IgA antibody responses and strong cell-mediated immunity responses. Only one confirmed case of LAIV virus transmission to a placebo recipient (who did not become ill) occurred in a transmission study conducted in young children. The immunogenic response to LAIV in young healthy children was not affected by concomitant administration with other commonly administered childhood vaccines. In conclusion, intranasal LAIV seasonal influenza vaccine is effective and well tolerated in children, adolescents and adults. LAIV was more effective than TIV in children, although this advantage was not seen in adults. In the US, LAIV is indicated for the active immunization of healthy subjects aged 2-49 years against influenza disease caused by virus subtypes A and type B contained in the vaccine.

Rosuvastatin: a review of its use in the prevention of cardiovascular disease in apparently healthy women or men with normal LDL-C levels and elevated hsCRP levels.

Rosuvastatin (Crestor®) is an HMG-CoA reductase inhibitor (statin) that has both lipid-lowering and anti-inflammatory effects. The drug has various indications in the US, including the primary prevention of cardiovascular disease (CVD) in patients with no clinical evidence of coronary heart disease who are at increased risk of CVD based on their age, a high-sensitivity C-reactive protein (hsCRP) level of ≥2 mg/L, and at least one other CVD risk factor. The efficacy of rosuvastatin in apparently healthy women (aged ≥60 years) or men (aged ≥50 years) with normal low-density lipoprotein cholesterol (LDL-C) levels and elevated hsCRP levels was demonstrated in the large, randomized, double-blind, multinational, JUPITER trial. Relative to placebo, rosuvastatin 20 mg once daily for a median follow-up of 1.9 years significantly reduced the occurrence of first major cardiovascular events in this trial (primary endpoint). A between-group difference in favor of rosuvastatin was also demonstrated for various other endpoints, including overall deaths and the nonatherothrombotic endpoint of venous thromboembolism. Rosuvastatin remained more effective than placebo when primary endpoint results were stratified according to various baseline factors, including in patient subgroups thought to be at low risk of CVD. In addition, rosuvastatin was associated with reductions in LDL-C and hsCRP levels, and these reductions appeared to occur independently of each other. The greatest clinical benefit was observed in rosuvastatin recipients achieving an LDL-C level of <1.8 mmol/L (<70 mg/dL) and an hsCRP level of <2 mg/L or, even more so, <1 mg/L. Rosuvastatin was well tolerated in the JUPITER trial, with most adverse events being mild to moderate in severity. Myalgia, arthralgia, constipation, and nausea were the most commonly occurring treatment-related adverse events, and the incidence of monitored adverse events and laboratory measurements was generally similar in the rosuvastatin and placebo groups. It is not yet known whether the mechanism of benefit of rosuvastatin is via lipid effects, anti-inflammatory effects, or a mixture of both, and the use of rosuvastatin solely on the basis of elevated hsCRP levels is controversial. Nonetheless, the drug remains an important pharmacologic option in the prevention of CVD, and has demonstrated efficacy in preventing major cardiovascular events in apparently healthy women (aged ≥60 years) or men (aged ≥50 years) with normal LDL-C levels and elevated hsCRP levels.

Glatiramer acetate: a review of its use in relapsing-remitting multiple sclerosis and in delaying the onset of clinically definite multiple sclerosis.

Glatiramer acetate is a synthetic analogue of the multiple sclerosis (MS)-associated antigen, myelin basic protein. It is indicated in the EU, US and many other countries to reduce the frequency of relapses in patients with relapsing-remitting MS (RRMS), and for the treatment of patients who have experienced a well defined first clinical episode and are at high risk of developing clinically definite MS or have features of MS on MRI. The efficacy of glatiramer acetate in patients with RRMS has been shown in two randomized, double-blind, multicentre phase III trials. In one trial, glatiramer acetate was associated with a significantly lower mean relapse rate than placebo after 24 months' treatment (primary endpoint). In an ongoing open-label extension to this trial, glatiramer acetate was associated with a sustained reduction in the relapse rate at the 6-, 8- and 15-year follow-ups. In the other trial, the mean cumulative number of gadolinium-enhancing lesions on T1-weighted MRI images was significantly lower in glatiramer acetate versus placebo recipients after 9 months' treatment (primary endpoint). Glatiramer acetate also had generally similar efficacy to subcutaneous interferon (IFN)-beta-1a or IFNbeta-1b in two large randomized, open-label, multicentre phase III trials conducted over 96 weeks or >or=2 years. These data were supported by those from a smaller randomized, open-label phase IV trial that utilized a unique imaging protocol to evaluate the efficacy of glatiramer acetate versus that of IFNbeta-1b over >or=2 years. In these trials, there was no significant difference between glatiramer acetate and IFNbeta recipients in any of the clinical endpoints at study end (e.g. time to first relapse [primary endpoint of the REGARD trial] or risk of relapse [primary endpoint of the BEYOND trial]). Moreover, there was no significant difference between glatiramer acetate and IFNbeta-1b recipients in the median number of combined active lesions per patient per monthly MRI scan during the first 12 months of treatment (primary endpoint of the BECOME trial). In general, there was no significant between-group difference in the majority of other MRI-assessed endpoints in any of the trials. The efficacy of glatiramer acetate in patients with clinically isolated syndrome (CIS) was established in a randomized, double-blind, double-dummy, multicentre phase III trial (the PreCISe trial). In this study, glatiramer acetate was associated with a significantly longer time to conversion to clinically definite MS than placebo (primary endpoint). Glatiramer acetate was generally well tolerated in clinical trials, with most adverse events being mild to moderate in severity. Injection site-related reactions and immediate post-injection systemic reactions were the most frequently observed adverse events associated with glatiramer acetate in clinical studies. In conclusion, glatiramer acetate is a valuable first-line option in the treatment of RRMS, as well as being an option in the treatment of CIS.

OROS hydromorphone prolonged release: a review of its use in the management of chronic, moderate to severe pain.

OROS hydromorphone prolonged release (OROS hydromorphone) [Jurnista] is a once-daily formulation of the opioid agonist hydromorphone that utilizes OROS (osmotic-controlled release oral delivery system) technology to deliver the drug at a near constant rate, thereby providing consistent analgesia over a 24-hour period. It is indicated for use in patients with severe pain and contraindicated in those with acute or post-operative pain. In several, randomized, multicentre, phase III trials, oral OROS hydromorphone administered once daily for up to 52 weeks was generally effective in the treatment of patients with chronic, moderate to severe cancer or nonmalignant/noncancer pain with regard to improvements from baseline to endpoint in patient-assessed measures of pain intensity, pain relief and/or functional impairment. Pharmacoeconomic analyses suggest that OROS hydromorphone provides greater cost utility than other opioids in this patient population. In addition, OROS hydromorphone was generally well tolerated in clinical trials, with most adverse events being mild to moderate in severity and similar to those seen with other opioids. Thus, OROS hydromorphone is an effective and useful alternative to other opioids for the treatment of patients with severe pain.

Trabectedin: a review of its use in soft tissue sarcoma and ovarian cancer.

Trabectedin (Yondelis) is a tetrahydroisoquinoline molecule that was originally derived from a marine organism. It is indicated in the EU and many other countries for use in patients with advanced soft-tissue sarcoma (STS) who have progressed despite receiving previous treatment with anthracyclines and ifosfamide or in those who are unable to receive these agents. It is also approved in the EU in combination with pegylated liposomal doxorubicin for the treatment of platinum-sensitive, recurrent ovarian cancer. In addition, trabectedin holds orphan drug status for the treatment of advanced, recurrent STS in the US, Switzerland and Korea, and for the treatment of advanced, recurrent ovarian cancer in the US and Switzerland. Clinical trials showed that intravenous trabectedin was effective in chemotherapy-experienced patients with advanced, recurrent liposarcoma or leiomyosarcoma, and results from a retrospective analysis suggest that the drug may be particularly effective in patients with advanced myxoid liposarcoma. In addition, coadministration of trabectedin with pegylated liposomal doxorubicin was associated with a significantly longer progression-free survival (6 weeks) than pegylated liposomal doxorubicin monotherapy in patients with recurrent ovarian cancer after failure of first-line, platinum-based chemotherapy. The tolerability profile of trabectedin was manageable in clinical trials, and the tolerability profile of concomitant trabectedin and pegylated liposomal doxorubicin was generally consistent with that of each agent alone. Results to date indicate that trabectedin is a valuable addition to the group of second-line antineoplastic agents available for the treatment of advanced, recurrent STS, and that it is a beneficial treatment for recurrent ovarian cancer after failure of first-line, platinum-based chemotherapy when administered in conjunction with pegylated liposomal doxorubicin.