Patients In USA Research Articles

Polymyalgia rheumatica: What's new?

Currently, only 25% of all polymyalgia rheumatica (PMR) patients are referred to specialists. An expert committee has recently recommended confirmation of diagnosis by specialist care. This can help to avoid misdiagnoses and hospital stays and can result in lower glucocorticoid doses.Using ultrasound, magnetic resonance imagining (MRI), or positron emission tomography-computed tomography (PET-CT), typical periarticular inflammatory changes are observed, especially in the shoulder and pelvic girdle area. However, for clinical use, ultrasound is usually sufficient.In 20-25% of newly diagnosed PMR patients without symptoms of giant cell arteritis (GCA), GCA can be detected through vascular ultrasound. These patients require higher glucocorticoid doses in analogy to GCA therapy. There is growing awareness of a joint GCA-PMR spectrum disease.Glucocorticoids remain the primary treatment. The interleukin-6 inhibitor Sarilumab has recently been approved in the USA for patients with recurrent PMR. Studies have also demonstrated the effectiveness of Tocilizumab in PMR.

Abstract B011: Phase 2, multicenter, open-label basket trial of nab-sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1 and TSC2 (PRECISION I)

Abstract Introduction/objective: PRECISION I (NCT05103358) is an ongoing trial of nab-sirolimus in advanced cancers harboring pathogenic inactivating alterations in TSC1 or TSC2. TSC1 and TSC2 alterations have been observed in patients with various cancers, including the most common cancer of the female reproductive organs, endometrial cancer, where ~3% contain TSC1 and/or TSC2 alterations. nab-Sirolimus, approved in the USA for patients with advanced malignant perivascular epithelioid cell tumor (PEComa), is an albumin-bound mTOR inhibitor (mTORi) that inhibits the mTOR pathway via suppression of the mTORC1 complex. When TSC1 or TSC2 is inactivated via mutation or loss, the mTOR pathway may be aberrantly activated. In an exploratory analysis of AMPECT (NCT02494570), a pivotal trial of nab-sirolimus in advanced malignant PEComa, 64.3% (9/14) of patients with pathogenic inactivating TSC2 or TSC1 alterations had a confirmed response. Most treatment-related adverse events in AMPECT were grade 1/2 (none were grade ≥4) and were consistent with mTORi-class adverse events. Based on the clinical observations from AMPECT and the underlying mechanism of action of nab-sirolimus, the PRECISION I trial was designed to assess the safety and efficacy of nab-sirolimus in a tumor-agnostic study of patients with advanced cancers with TSC1 or TSC2 inactivating alterations. Patients with endometrial cancer are expected to be enrolled based on the frequency of TSC1 and TSC2 inactivating alterations. Methods: Eligible patients are ≥12 years old and mTORi-naïve, possess advanced or metastatic malignant solid tumors with TSC1 or TSC2 inactivating alterations identified using next-generation sequencing (NGS) in tumor tissue or liquid biopsy (confirmed by central review of NGS reports), and have received appropriate standard treatments, per investigator. nab-Sirolimus 100 mg/m2 is given intravenously over 30 min on days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using Response Evaluation Criteria in Solid Tumors v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Trial Status: Enrollment began in March 2022 and is expedited through collaboration with leading NGS providers; ongoing study access is facilitated through a just-in-time approach to trial location activation. Citation Format: Debra L. Richardson, Gopa Iyer, Li Ding, Anita N. Schmid, Willis Navarro, David Kwiatkowski, Jordi Rodon Ahnert. Phase 2, multicenter, open-label basket trial of nab-sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1 and TSC2 (PRECISION I) [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B011.

Tyrosine Kinase Inhibitors for Radioactive Iodine Refractory Differentiated Thyroid Cancer.

Patients with differentiated thyroid cancer usually present with early-stage disease and undergo surgery followed by adjuvant radioactive iodine ablation, resulting in excellent clinical outcomes and prognosis. However, a minority of patients relapse with metastatic disease, and eventually develop radioactive iodine refractory disease (RAIR). In the past there were limited and ineffective options for systemic therapy for RAIR, but over the last ten to fifteen years the emergence of tyrosine kinase inhibitors (TKIs) has provided important new avenues of treatment for these patients, that are the focus of this review. Currently, Lenvatinib and Sorafenib, multitargeted TKIs, represent the standard first-line systemic treatment options for RAIR thyroid carcinoma, while Cabozantinib is the standard second-line treatment option. Furthermore, targeted therapies for patients with specific targetable molecular abnormalities include Latrectinib or Entrectinib for patients with NTRK gene fusions and Selpercatinib or Pralsetinib for patients with RET gene fusions. Dabrafenib plus Trametinib currently only have tumor agnostic approval in the USA for patients with BRAF V600E mutations, including thyroid cancer. Redifferentiation therapy is an area of active research, with promising initial results, while immunotherapy studies with checkpoint inhibitors in combination with tyrosine kinase inhibitors are underway.

Cracking the Hip: Does Protocol Matter? A Retrospective Cohort Study Investigating the Effect of Protocol Implementation.

IntroductionApproximately 300 000 hip fractures occur annually in the USA in patients >65 years old. Early intervention is key in reducing morbidity and mortality. Our institution implemented a collaborative hip fracture protocol, streamlining existing processes to reduce time to OR (TTO) and hospital length of stay (LOS). Our aim was to determine if this protocol improved these outcomes.Study DesignWe conducted a retrospective cohort study using our level-1 trauma center’s trauma registry, comparing outcomes for patients >60 years old with isolated hip fractures pre-and post-hip protocol implementation in May 2018. Our primary outcomes were TTO and in-hospital mortality. Secondary outcomes included LOS and postoperative complications. Univariate analysis was done using chi-square and T-test.ResultsWe identified 176 patients with isolated hip fractures: 69 post- and 107 pre-protocol. Comparing post- to pre-protocol, TTO decreased by 18hrs (39 vs 57h; P = .013) and patients had fewer postoperative complications (9 vs 23%; P = .016) despite post-protocol patients being more likely to have diabetes (42 vs 27%, P < .05), elevated BMI (22 vs 25; P < .001), and to be current smokers (9 vs 2%; P < .05). LOS and in-hospital mortality also decreased (11 vs 20d; P = .312, 4.3 vs 7.5%; P = .402). Post-protocol patients were more likely to go to the OR within 24hrs of presentation (39 vs 16%; P < .001) and to go straight from ED to OR (32 vs 4%; P < .001).ConclusionTTO, LOS, and postoperative complications for isolated hip fracture patients were lower post-protocol. Though not all statistically significant, this trend indicates that the protocol was helpful in improving hip fracture outcomes but may require further improvement and institution-wide education.

Zanubrutinib for the Treatment of B-cell Malignancies

Selective Bruton's tyrosine kinase (BTK) inhibition is an important therapeutic approach for B-cell malignancies. Ibrutinib, a first-in-class, oral, irreversible BTK inhibitor, has a toxicity profile attributed to off-target inhibition of kinases structurally related to BTK. A highly potent and selective next-generation BTK inhibitor, zanubrutinib, was designed to address intolerance and toxicity concerns associated with ibrutinib. Zanubrutinib provides complete and sustained BTK occupancy in peripheral blood mononuclear cells and lymph nodes, with reduced toxicity compared with ibrutinib. Zanubrutinib received accelerated approval in the USA for patients with previously treated mantle cell lymphoma (2019) and relapsed/refractory (R/R) marginal zone lymphoma (2021) and was approved for Waldenström's macroglobulinaemia (WM) in 2021. Key clinical trials evaluating the efficacy and safety of zanubrutinib include the ASPEN study in patients with WM (ClinicalTrials.gov identifier: NCT03053440), the ALPINE study in patients with R/R chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL; ClinicalTrials.gov identifier: NCT03734016) and the SEQUOIA study in treatment-naïve patients with CLL/SLL with and without del(17p) mutation (ClinicalTrials.gov identifier: NCT03336333). The more selective BTK binding profile, high potency, favourable pharmacokinetic and pharmacodynamic profile, and minimal cardiovascular toxicity of zanubrutinib compared with ibrutinib suggest that zanubrutinib may be an important treatment option when prescribed in accordance with guidelines.

Clinical Features Associated with Long-Term Ruxolitinib Exposure in Myelofibrosis and Predictive Role of Neutrophils

Clinical Features Associated with Long-Term Ruxolitinib Exposure in Myelofibrosis and Predictive Role of Neutrophils

Role of Anti-PCSK9 Antibodies in the Treatment of Patients with Statin Intolerance.

Statin intolerance is usually defined as the inability of a patient to tolerate statintreatment due to muscle-related complaints. While randomised trials show that these complaints occure with similar frequency in patients receiving placebo, namely in up to ~5% of the subjects, and data from registries as well as clinical experience indicate a much higher frequency of up to ~30%. The lack of standard definition or of a diagnostic marker of statin intolerance confounds the problem. The diagnosis remains subjective based on the symptoms the patient reports. Therefore, a large number of patients who need a statin are not receiving it, or receiving only very-low and/or intermittent doses unable to achieve a robust decrease in low-density lipoprotein cholesterol (LDL-C), leaving patients at high or very high risk for cardiovascular events requiring an alternative form of lipid-lowering therapy. Until recently, the only available alternatives were niacin, ezetimibe, bile-acid sequestrants and fibrates that decrease LDL-C concentrations by up to 15-20%. Recently the fully human monoclonal antibodies against proprotein convertase subtilisin/kexin 9 (PCSK9), alirocumab (Praluent®) and evolocumab (Repatha®), which have been shown to decrease LDL-C by up to 70% have been approved in Europe for use in patients with primary hypercholesterolemia not at LDL-C target while on maximally tolerated lipid-lowering therapy and specifically for patients with statin intolerance and in the USA for patients with atherosclerotic cardiovascular disease or familial hypercholesterolemia requiring additional LDL-C lowering. Ongoing large clinical trials with cardiovascular endpoints will provide a definitive answer for the role of anti-PCSK9 antibodies in clinical practice.

Association of aortic valve disease with intestinal angioectasia: data from the Nationwide Inpatient Sample.

Since the description of a correlation between aortic stenosis and angioectasia, controversy has persisted about whether these diseases are truly associated or coincidental findings of older age. Our objective was to determine the association of aortic valve disease and bleeding intestinal angioectasia from a large database. We used the 2011 Nationwide Inpatient Sample database to identify hospitalizations in the USA in patients with bleeding intestinal angioectasia. International Classification of Diseases, 9th revision, Clinical Modification codes were used to identify patients with aortic valve disease, mitral valve disease, and known risk factors for angioectasia (including diagnosed von Willebrand disease, left ventricular assist device, and chronic kidney disease). Univariate and multivariate logistic regression were used to determine the odds of association between the valvular diseases and angioectasia. A total of 32 079 intestinal angioectasia-related hospitalizations were identified of which 7.02% (n=2253) cases had coexistent aortic valve disease. The unadjusted odds of aortic valve disease in association with bleeding intestinal angioectasia versus those without bleeding angioectasia was 4.95 [95% confidence interval: (CI): 4.43-5.54, P<0.001]. The association of intestinal angioectasia with mitral valve disease was not significant (odds ratio=1.56, 95% CI: 0.59-4.14, P=0.38). When adjusted for age and known risk factors, the odds of aortic valve disease in bleeding intestinal angioectasia was still significant (odds ratio=2.37, 95% CI: 2.10-2.66, P<0.001). Our findings support an important association between aortic valve disease and bleeding intestinal angioectasia, not identified in valvular heart valvular diseases with lower shear stress (mitral valve disease).

Hypotension during induction of anaesthesia is neither a reliable nor a useful quality measure for comparison of anaesthetists’ performance

BackgroundIdentification of statistically reliable outcomes for comparison among anaesthetists is challenging. Time-weighted intraoperative mean arterial pressure <65 mm Hg (AUC65) is associated with increased odds for myocardial damage. We explored retrospectively whether such hypotension before incision was statistically reliable for peer comparison. MethodsWe retrieved electronic data between 2006 and 2015 at a tertiary care, academic hospital in the USA for patients at risk for myocardial damage (inpatient after surgery, ASA physical status ≥III, ≥50 yr of age, and case duration ≥60 min). We determined the percentage of anaesthetists comparable based on caseload and case-mix. The AUC65 was compared amongst anaesthetists supervising ≥100 cases involving at-risk patients during the last 12 months. ResultsOnly 14.1% [95% confidence interval (CI) 13.6–14.5%] of cases involved patients who were ‘at risk’ during the 10 yr study period. A yearly average of 49 (sd 6) anaesthetists supervised ≥100 cases of any type, of whom only 52% (95% CI 47.1–56.0%) supervised ≥100 cases involving at-risk patients. Thus, nearly half the anaesthetists would have been excluded from peer comparison. During the last 12 months, there were two outliers among 34 evaluable anaesthetists (P<0.05, controlling for false discovery). However, their contribution to total hypotension amongst cases for all patients was small, because hypotension was widely distributed (e.g. 80% of hypotension attributable to 61.8% of anaesthetists, 95% CI 59.8–63.7%). There was no relationship between the AUC65 and propofol induction dose. ConclusionsThe AUC65 of time-weighted pre-incision hypotension is not a suitable metric for comparing anaesthetists. There were few at-risk patients, half the anaesthetists were not evaluable because of their case-mix and caseload, and hypotension was widely distributed.

Daratumumab: First Global Approval.

Daratumumab (Darzalex™) is a first-in-class, humanized IgG1κ monoclonal antibody that targets the CD38 epitope and was developed by Janssen Biotech and Genmab. Intravenous daratumumab was recently approved via an accelerated approval programme in the USA for patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent. The drug is in preregistration for this indication in the EU and Canada. In a phase II trial in patients with previously treated (as described above) relapsed or refractory multiple myeloma, monotherapy with daratumumab 16mg/kg achieved an overall response rate of approximately 30%. This article summarizes the milestones in the development of daratumumab leading to this first approval for multiple myeloma.

Memantine ER/Donepezil: A Review in Alzheimer's Disease.

A once-daily, fixed-dose combination of memantine extended-release (ER)/donepezil 28/10mg (Namzaric™) is available in the USA for patients with moderate to severe Alzheimer's disease (AD) on stable memantine and donepezil therapy. The fixed-dose formulation is bioequivalent to coadministration of the individual drugs. In a 24-week, phase III trial in patients with moderate to severe AD, addition of memantine ER 28mg once daily to stable cholinesterase inhibitor (ChEI) therapy was more effective than add-on placebo on measures of cognition, global clinical status, dementia behaviour and semantic processing ability, although between-group differences on a measure of daily function did not significantly differ. In subgroup analyses in donepezil-treated patients, add-on memantine ER was more effective than add-on placebo on measures of cognition, dementia behaviour and semantic processing, although there were no significant between-group differences on measures of global clinical status and daily function. Memantine ER plus ChEI combination therapy was generally well tolerated in the phase III trial, with diarrhoea, dizziness and influenza occurring at least twice as often with add-on memantine ER as add-on placebo in donepezil-treated patients. Thus, memantine ER plus donepezil combination therapy is an effective and well tolerated treatment option for patients with moderate to severe AD. The fixed-dose combination is potentially more convenient than coadministration of the individual agents.

Combination of romidepsin with cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated patients with peripheral T-cell lymphoma: a non-randomised, phase 1b/2 study

Romidepsin is a histone deacetylase inhibitor approved in the USA for patients with recurrent or refractory peripheral T-cell lymphoma and has shown activity in this setting with mainly haematological and gastrointestinal toxicity. Although it has limited efficacy, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy is widely used for treatment of de-novo peripheral T-cell lymphoma. We aimed to assess the safety, tolerability, and activity of romidepsin combined with CHOP in patients with previously untreated disease. We enrolled patients aged 18-80 years with histologically proven, previously untreated, peripheral T-cell lymphoma (Eastern Cooperative Oncology Group performance status ≤2) into a dose-escalation (phase 1b) and expansion (phase 2) study at nine Lymphoma Study Association centres in France. In the dose-escalation phase, we allocated consecutive blocks of three participants to receive eight 3 week cycles of CHOP (intravenous cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1.4 mg/m(2) [maximum 2 mg] on day 1 and oral prednisone 40 mg/m(2) on days 1-5) in association with varying doses of romidepsin. The starting dose was 10 mg/m(2) intravenously on days 1 and 8 of each cycle, and we used a 3 + 3 design. We assessed dose-limiting toxicities only during the first two cycles. The primary endpoint was to determine the recommended dose for the combination. For the phase 2 study, we aimed to increase the cohort of patients receiving the recommended dose to a total of 25 patients. Patients were assessed for safety outcomes at least twice per cycle according to the Common Terminology Criteria for Adverse Events, version 4.0. Safety analyses included all patients who received at least one dose of romidepsin and CHOP. This trial is registered at the European Clinical Trials Database (EudraCT), number 2010-020962-91 and ClinicalTrials.gov, number NCT01280526. Between Jan 13, 2011, and May 21, 2013, we enrolled 37 patients (18 treated in phase 1b and 19 patients in phase 2). Three of six patients initially treated at 10 mg/m(2) had a dose-limiting toxicity. The dose-escalation committee decided to modify the study protocol to redefine dose-limiting toxicities with regard to haematological toxicity. Three patients were treated with 8 mg/m(2) of romidepsin, an additional three at 10 mg/m(2) (one dose-limiting toxicity), and six patients at 12 mg/m(2) (three dose-limiting toxicities). We chose romidepsin 12 mg/m(2) as the recommended dose for phase 2. Of the 37 patients treated, three had early cardiac events (two myocardial infarctions and one acute cardiac failure). No deaths were attributable to toxicity. 25 (68%) of 37 patients had at least one serious adverse event. Overall, the most frequent serious adverse events were febrile neutropenia (five [14%] of 37 patients), physical health deterioration (five [14%]), lung infection (four [11%]), and vomiting (three [8%]). 33 (89%) of patients had grade 3-4 neutropenia, and 29 (78%) had grade 3-4 thrombocytopenia. Romidepsin can be combined with CHOP but this combination should now be tested in comparison to CHOP alone in a randomised trial. Celgene.

Preclinical evaluation of efficacy and safety of an improved lentiviral vector for the treatment of β-thalassemia and sickle cell disease.

A previously published clinical trial demonstrated the benefit of autologous CD34+ cells transduced with a self-inactivating lentiviral vector (HPV569) containing an engineered β-globin gene (βA-T87Q-globin) in a subject with β-thalassemia major. This vector has been modified to increase transduction efficacy without compromising safety. In vitro analyses indicated that the changes resulted in both increased vector titers (3 to 4 fold) and increased transduction efficacy (2 to 3 fold). An in vivo study in which 58 β-thalassemic mice were transplanted with vector- or mock-transduced syngenic bone marrow cells indicated sustained therapeutic efficacy. Secondary transplantations involving 108 recipients were performed to evaluate long-term safety. The six month study showed no hematological or biochemical toxicity. Integration site (IS) profile revealed an oligo/polyclonal hematopoietic reconstitution in the primary transplants and reduced clonality in secondary transplants. Tumor cells were detected in the secondary transplant mice in all treatment groups (including the control group), without statistical differences in the tumor incidence. Immunohistochemistry and quantitative PCR demonstrated that tumor cells were not derived from transduced donor cells. This comprehensive efficacy and safety data provided the basis for initiating two clinical trials with this second generation vector (BB305) in Europe and in the USA in patients with β-thalassemia major and sickle cell disease.

Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial

The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis. We did a multicentre, double-blind, placebo-controlled, parallel group, randomised clinical trial at medical centres in the USA in patients with non-cirrhotic, non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally (25 mg daily) or placebo for 72 weeks. Patients were randomly assigned 1:1 using a computer-generated, centrally administered procedure, stratified by clinical centre and diabetes status. The primary outcome measure was improvement in centrally scored liver histology defined as a decrease in non-alcoholic fatty liver disease activity score by at least 2 points without worsening of fibrosis from baseline to the end of treatment. A planned interim analysis of change in alanine aminotransferase at 24 weeks undertaken before end-of-treatment (72 weeks) biopsies supported the decision to continue the trial (relative change in alanine aminotransferase -24%, 95% CI -45 to -3). A planned interim analysis of the primary outcome showed improved efficacy of obeticholic acid (p=0·0024) and supported a decision not to do end-of-treatment biopsies and end treatment early in 64 patients, but to continue the trial to obtain the 24-week post-treatment measures. Analyses were done by intention-to-treat. This trial was registered with ClinicalTrials.gov, number NCT01265498. Between March 16, 2011, and Dec 3, 2012, 141 patients were randomly assigned to receive obeticholic acid and 142 to placebo. 50 (45%) of 110 patients in the obeticholic acid group who were meant to have biopsies at baseline and 72 weeks had improved liver histology compared with 23 (21%) of 109 such patients in the placebo group (relative risk 1·9, 95% CI 1·3 to 2·8; p=0·0002). 33 (23%) of 141 patients in the obeticholic acid developed pruritus compared with nine (6%) of 142 in the placebo group. Obeticholic acid improved the histological features of non-alcoholic steatohepatitis, but its long-term benefits and safety need further clarification. National Institute of Diabetes and Digestive and Kidney Diseases, Intercept Pharmaceuticals.

Trends in breast cancer treatment in United States from 2000 to 2011: Consequences of 2004 National Comprehensive Cancer Network (NCCN) guidelines change.

69 Background: In 2004, the NCCN, changed the guidelines for the treatment of stage 1, HR+, &gt; 70 years(y) breast cancer patients, based mainly on the CALGB/RTOG trial, which showed that in these patients, the addition of radiotherapy (RT) to surgery and tamoxifen did not improve overall survival, but significantly decreased local relapse at 5 y. Methods: Retrospective analysis about trends in breast cancer treatment in USA from years 2000 to 2011, searching the National Cancer Data Base, reviewing 458.386 cases of breast cancer stage I, HR+, with special focus in patients &gt;70y. Chi square test was used. Results: Between years 2000-2011, in the group reviewed, mastectomy (MT) increased in women &lt;40y (+25%) and between 40-69y (+13%), while RT decreased in both groups (-20%, -3%). In women &gt;70y, MT decreased (-27%) progressively along these years, but radiotherapy increased until year 2003 (+3%), and begun to decrease in 2004 (-4%), with a final difference between 2003 and 2011 of -9%. In patients &gt;70 y, chemotherapy (CH) treatments, increased progressively (+3%) from year 2000 to 2011 (p&lt;0.001). Conclusions: Changes in NCCN breast cancer guidelines made in 2004, seem to have changed trends of breast cancer treatment in USA in patients &gt; 70y, stage I, HR+. Since then, less aggressive “local” treatments (-4% for MT and -9% for RT) are been performed. Despite this trend for less local therapy chemotherapy utilization has increased even though the risk of systemic disease is very low. The main risk for these patients is local failure with the associated physical, psychological and family impact as well as cost of re-staging. Local RT has demonstrated a significant reduction of this risk. Today's life expectancy for a 70 y/o woman is &gt;10y consequently local relapses and its consequences are expected. New RT techniques, such as partial breast irradiation delivered in few days are convenient and associated with very low toxicity and no mortality. Perhaps a re-look of the NCCN guidelines might be in order. [Table: see text]

Ruxolitinib: long-term management of patients with myelofibrosis and future directions in the treatment of myeloproliferative neoplasms.

Considerable clinical experience regarding the long-term efficacy and safety of ruxolitinib has been gathered since the drug was approved in the USA for patients with intermediate or high-risk myelofibrosis (MF) in November 2011. Findings from the pivotal phase 3 COMFORT studies showed that ruxolitinib-associated reductions in MF-related splenomegaly and symptom burden occur rapidly and in the majority of patients. Two- and 3-year follow-up data further suggest that the benefits of ruxolitinib are durable and associated with a survival advantage compared with conventional therapies. However, careful management of treatment-related thrombocytopenia and anemia with dose modifications and supportive care is critical to allow chronic therapy. Based on preliminary evidence, ruxolitinib also allows spleen size and symptom reduction before allogeneic stem cell transplantation without negative effect on engraftment or outcomes. In recent studies, ruxolitinib provided effective management of hematologic parameters and symptoms in patients with polycythemia vera refractory to or intolerant of hydroxyurea.

Telaprevir-containing regimen for treatment of hepatitis C virus infection in patients with hepatocellular carcinoma awaiting liver transplantation: a case series.

In patients who undergo liver transplantation (LT), allograft failure secondary to hepatitis C virus (HCV) recurrence after LT accounts for two-thirds of graft failures and deaths. Achievement of sustained virologic response before LT eliminates the risk of HCV recurrence. Only a limited number of studies have evaluated the role of antiviral treatment before LT. No published data are available regarding the use of HCV protease inhibitors before LT. We report our experience using the combination of telaprevir, pegylated interferon alfa-2a (PegIFN alfa-2a), and ribavirin in three patients with HCV-associated hepatocellular carcinoma (HCC) awaiting LT. Two patients had not received, and one had had a partial response to HCV therapy (PegIFN alfa-2a plus ribavirin). All three patients had genotype 1b and were started on telaprevir and full doses of PegIFN alfa-2a and ribavirin. Treatment was planned to be continued until the day of LT or 48 weeks total, whichever came first. One patient still had detectable HCV RNA after 24 weeks of antivirals and was, therefore, excluded from further analysis. The other two patients had undetectable HCV RNA at the end of antiviral therapy. In one of these patients, HCV RNA remained undetectable after LT; the other patient experienced viral relapse. HCV therapy was tolerated by all patients; no patient required permanent discontinuation of therapy because of toxic effects. All three patients experienced hematologic toxic effects. Only one patient required treatment discontinuation, due to progression of HCC. The use of telaprevir-containing regimens appears to be safe in selected patients with HCV-associated HCC awaiting LT, but more studies are warranted to evaluate the safety and efficacy of this treatment combination to prevent post-LT viral recurrence.

Autoinjectors for administration of interferon beta-1b in multiple sclerosis: patient preferences and the ExtaviPro™ 30G and Betacomfort® devices.

BackgroundThe ExtaviPro™ 30G autoinjector has been developed for self-administration of interferon beta-1b (Extavia®), which is used as a first-line, parenteral, disease-modifying therapy in multiple sclerosis (MS). The aim of this survey was to investigate patients’ perceptions of the importance of different general attributes of autoinjectors, and patient preferences when comparing the ExtaviPro™ 30G and Betacomfort® autoinjectors.MethodThe survey was conducted in France, Germany, Italy, and the USA in patients with relapsing-remitting MS who had been using an autoinjector for at least 1 year. Participants examined the ExtaviPro™ 30G and Betacomfort® devices, viewed fact sheets, and watched a video of these autoinjectors in use, then scored nine prespecified attributes of autoinjectors in terms of importance on a scale of 1–7 (1 = not at all important; 7 = extremely important). They then indicated which device they preferred, both overall and by individual attribute.ResultsAmong the 201 participants who completed the survey, being reliable to use was considered the most important general attribute of autoinjectors, followed by attributes associated with convenience (ease of operation, one-handed injection, ease of reach of injection sites, ergonomic shape). For each of the nine attributes, a significantly higher proportion of participants (74%–94% by attribute; P < 0.05 for each) preferred ExtaviPro™ 30G to the Betacomfort® autoinjector, and 173 (86%) participants indicated that they preferred ExtaviPro™ 30G overall (P < 0.05).ConclusionThe results of this survey suggest that patients with MS rate reliability and convenience as the most important general attributes of autoinjectors, and are more likely to prefer ExtaviPro™ 30G to the Betacomfort® autoinjector for routine self-administration of interferon beta-1b.

Biomarkers to predict response to sunitinib therapy and prognosis in metastatic renal cell cancer

Sunitinib is an orally-administered, multitargeted tyrosine kinase inhibitor. The main targets are vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-α, and PDGFR-β. Among therapeutic targeting agents, it is the best available in the USA for patients with metastatic renal cell cancer (RCC). Well-constructed clinical trials have led to the worldwide approval of various agents for RCC. However, in clinical practice, it remains difficult to determine the best treatment strategy with these agents. Therefore, the identification of biomarkers to predict response and side-effects and to select optimal dosages is urgently needed. Potential mechanisms of action and resistance need to be understood in order to make accurate predictions. This article briefly reviews candidate biomarkers of sunitinib therapy in terms of clinical variables, genetic factors, and circulating proteins and endothelial cells. Although further validation and implementation is necessary, if validated, biomarkers will help measure the therapeutic response in individual patients and establish treatment strategies for metastatic RCC.

Benefits of once-daily therapies in the treatment of hypertension

In patients with hypertension, 24-hour blood pressure control is the major therapeutic goal. The number of daily doses is one characteristic of an antihypertensive agent that may affect the adequacy of 24-hour control. One measure of therapeutic coverage is the 24-hour trough-to-peak ratio, which determines the suitability of an agent for once-daily administration. The closer an agent is to a 100% trough-to-peak ratio, the more uniform the 24-hour coverage and therefore blood pressure control. High trough-to-peak ratio, long-acting antihypertensive medications lower blood pressure more gradually, which reduces the likelihood of adverse events attributable to abrupt drug action that occurs with shorter-acting agents. In hypertension, the natural diurnal variation of blood pressure may be altered, including elevated nighttime pressures. An optimal once-daily hypertension therapy would not only lower blood pressure but also normalize any blunted circadian variations in blood pressure. The benefits of once-daily agents with sustained therapeutic coverage may also be explained, in part, by increased patient adherence to simpler regimens as well as lower loss of blood pressure control during virtually inevitable intermittent noncompliance. Studies have demonstrated that once-daily antihypertensive agents have the highest adherence compared with twice-daily or multiple daily doses, including greater adherence to the prescribed timing of doses.