Second-line Option In Patients Research Articles

Роль ритуксимаба в терапии эндокринной офтальмопатии

Endocrine ophthalmopathy (EOP) is a vision-threatening and disfiguring extrathyroid manifestation of Graves' disease, which often impairs the quality of life of patients and causes severe social and psychological consequences. Currently, intravenous glucocorticosteroids are the first line treatment for EOP. However, their effectiveness in these patients is frequently unsatisfactory, whereas the recurrence rate of EOP is high. Rituximab (RТX) is a chimeric monoclonal antibody directed against CD20, a surface antigen present on B cells. Numerous clinical studies of RТX in patients with EOP have shown promising results. RТX is currently considered an acceptable second-line option in patients who do not respond to previous treatments or present with relapse of the disease. This review summarizes the available data on the efficacy and safety of RTX in EOP patients, including the results of two randomized controlled trials. The potential benefits as well as limitations of RТX therapy are discussed.

Predictors of response to immune checkpoint inhibitors (ICI) rechallenge post-disease progression in solid tumors: A systematic review and meta-analyses.

2612 Background: Rechallenge with the same or different ICI has been proposed as a second line option in patients who progress on an initial ICI course. Considering rechallenge risks of limited benefit and further toxicity, identifying predictors for patients benefiting from rechallenge would provide much needed guidance for practice. We present a systematic review and meta-analyses of response predictors to ICI rechallenge after disease progression in solid tumors. Methods: A systematic search of PubMed, Cochrane database and ASCO meeting library was done for studies published up to Jan 2022 evaluating the efficacy of ICI rechallenge in patients with advanced solid tumors after disease progression on initial ICI. Predictors of interest included duration of the initial ICI course using a cutoff point of 6 months, and best overall response (BOR) to initial ICI: stratified into responders (complete or partial response or stable disease) and non-responders (progressive disease). Odds ratios (OR) for ICI rechallenge response were calculated & pooled in reference to initial ICI duration and its BOR using the fixed effects model. ORs with a 95% confidence interval [CI] not overlapping the null value (1) were considered statistically significant. Results: A total of 56 studies reporting on ICI rechallenge upon progression, comprising 3579 patients, of which 31 studies have switched their second ICI regimen. Initial ICI was anti-PD-1 in 37 studies, anti-CTLA-4 in 14 studies, and anti-PD-L1 in 10 studies. Involved solid cancers included melanoma (n = 30), NSCLC (n = 15), RCC (n = 6), and others (n = 5). Pooled objective response rate for rechallenge was 18.4% ([15.4-21.4], I2 = 84.6%), with the highest being among melanoma patients (21.2% [17.2-25.2], I2= 83.4%). For BOR, no significant difference was found for the entire cohort (OR = 1.34 [0.86 - 2.09], I2 = 27.1%). In melanoma studies, response to ICI rechallenge was significantly higher in patients responding to the initial ICI prior to progression (OR = 1.87 [1.03-3.39], I2 = 24.5%). For treatment duration, there was no difference in the entire cohort concerning ICI rechallenge (OR = 1.54 [0.86-2.75], I2 = 14.2%), yet melanoma patients showed a significant difference favoring those who had longer response durations on initial ICI (OR = 2.05 [1.01-4.16], I2 = 0.0%). Conclusions: Response to rechallenge in advanced melanoma patients was more common in initial ICI responders with a longer course duration ( > 6 months). More homogeneous studies are needed to validate our findings and investigate other potential markers for rechallenge such as PD-L1 status & mutational burden. [Table: see text]

Results from the INMUNOSUN-SOGUG trial: a prospective phase II study of sunitinib as a second-line therapy in patients with metastatic renal cell carcinoma after immune checkpoint-based combination therapy

BackgroundThe INMUNOSUN trial had the objective of prospectively evaluating the efficacy and safety of sunitinib as a pure second-line treatment in patients with metastatic renal cell carcinoma (mRCC) who have progressed to first-line immune checkpoint inhibitor (ICI)-based therapies.Patients and methodsA multicenter, phase II, single-arm, open-label study was carried out in patients with a histologically confirmed diagnosis of mRCC with a clear-cell component who had progressed to a first-line regimen of ICI-based therapies. All patients received sunitinib 50 mg once daily orally for 4 weeks, followed by a 2-week rest period following package insert instructions. The primary outcome was the objective response rate.ResultsTwenty-one assessable patients were included in the efficacy and safety analyses. Four patients [19.0%, 95% confidence interval (CI) 2.3% to 35.8%] showed an objective response (OR), and all of them had partial responses. Additionally, 14 (67%) patients showed a stable response, leading to clinical benefit in 18 patients (85.7%, 95% CI 70.7% to 100%). Among the four assessable patients who showed an OR, the median duration of the response was 7.1 months (interquartile range 4.2-12.0 months). The median progression-free survival (PFS) was 5.6 months (95% CI 3.1-8.0 months). The median overall survival (OS) was 23.5 months (95% CI 6.3-40.7 months). Patients who had better antitumor response to first-line ICI-based treatment showed a longer PFS and OS with sunitinib. The most frequent treatment-emergent adverse events were diarrhea (n = 11, 52%), dysgeusia (n = 8, 38%), palmar–plantar erythrodysesthesia (n = 8, 38%), and hypertension (n = 8, 38%). There was 1 patient who exhibited grade 5 pancytopenia, and 11 patients experienced grade 3 adverse events. Eight (38%) patients had serious adverse events, four of which were considered to be related to sunitinib.ConclusionAlthough the INMUNOSUN trial did not reach the pre-specified endpoint, it demonstrated that sunitinib is active and can be safely used as a second-line option in patients with mRCC who progress to new standard ICI-based regimens.

Opicapone: Once-Daily COMT Inhibitor for the Treatment of Wearing Off in Parkinson's Disease.

Objective To provide a review of opicapone as a treatment for end-of-dose wearing off associated with long-term levodopa therapy in patients with Parkinson's disease (PD). Data Sources PubMed, Web of Science, and Google Scholar were searched for relevant literature using the following terms: management, treatment, opicapone, BIA 9-1067, entacapone, and tolcapone. Current guidelines and the manufacturer's package inserts were also reviewed. Study Selection/Data Extraction Recent literature and published studies of opicapone in the management of wearing off. Data Synthesis Long-term use of levodopa is associated with known complications of motor fluctuations and dyskinesia. The addition of a drug with fewer daily administrations may reduce the complexity of the current medication regimen, improve adherence, and reduce the risk of adverse events in older people with PD. The Food and Drug Administration (FDA) approved a new catechol-O-methyltransferase (COMT) inhibitor opicapone in combination with levodopa/carbidopa to treat wearing off in PD patients on April 24, 2020. Conclusion Opicapone offers patients with PD a once-daily option with a favorable side effect profile, increased exposure to levodopa, and reduction in "off" time. It may be an appropriate second line option in patients who are intolerant or do not respond with entacapone.

A phase II study of nivolumab in patients with advanced refractory biliary tract cancers (BTC).

4097 Background: Biliary tract cancers (BTC) are often typically diagnosed at an advanced stage. There is no established second line option for patients with advanced BTC who have failed one prior systemic therapy. The phase II study evaluated safety and efficacy of nivolumab, anti PD-1 antibody in refractory BTC patients. Methods: Pts with histologically proven BTC who progressed on at least one line but no more than three lines of systemic therapy received nivolumab 240mg IV q2weeks for 16 weeks and then 480 mg IV every 4 weeks until disease progression or unacceptable toxicity. The primary endpoint of the study was objective response rate (ORR) by RECIST 1.1 every 8 weeks. The Simon two staged design was used to assess ORR.18 patients were accrued and if one response was seen, the plan was to accrue additional 34 patients. Secondary endpoints were PFS, OS and safety profile. Results: At data cutoff (Jan 14, 2018), 54 patients with BTC (female: 50%, Median age: 65 years) were enrolled. The primary sites of tumor were intrahepatic cholangiocarcinoma (63%) extrahepatic (11%), and gallbladder (26%). 30 pts (56%) failed 1 line of therapy and 24 (44%) failed more than one line of therapy. 45 pts (1 pt withdrew consent, 1pt just enrolled prior to data cutoff and 7 pts came off the study due to clinical progression) were evaluable for response rate. Out of 45 pts, 10 pts (22%) achieved PR (1 unconfirmed PR) and 17 pts (37.8%) achieved SD. DCR was 60%. All patients who responded were microsatellite stable. For evaluable 45 pts with median follow up of 13.34 months, median PFS was 3.98 months (95% CI: 2.33-5.98) and the median OS was 14.22 months (95% CI: 6.64-NA). 6 and 12month OS was 71.4 and 52.3% and 6 and 12 month PFS was 35.2% and 24.1% respectively. Most common treatment related AEs (TRAE) was alkaline phosphatase increased (24.5%). Grade III/IV TRAEs were seen in 11 pts (20.4%); most common were hyponatremia (3 pts) and elevated alkaline phosphatase (2 pts). No treatment related AEs led to discontinuation of the study drug. Tissue samples were collected in all pts with planned correlative studies underway including the PDL 1 status. Conclusions: Nivolumab was well tolerated and has shown promising efficacy in refractory BTC including durable responses lasting 2 years. Further randomized trial is warranted in refractory BTC. Clinical trial information: NCT02829918.

Crisaborole: A Novel Nonsteroidal Topical Treatment for Atopic Dermatitis.

Objective: To review the efficacy and safety of crisaborole and its place in therapy for the management of mild to moderate atopic dermatitis (AD). Data Sources: A literature search of PubMed (data inception to February 2019) was performed using the search terms crisaborole and atopic dermatitis. Supplementary sources included the Journal of the American Academy of Dermatology Guidelines of Care for the Management of Atopic Dermatitis, clinicaltrials.gov data, manufacturer prescribing information, and article bibliographies. Study Selection and Data Extraction: Relevant English-language studies and those conducted in humans were considered and reviewed. Abstracts from clinical trials and drug reviews were reviewed. Phases I, II, III, and long-term safety studies were included. Data Synthesis: Data from multiple clinical trials have demonstrated the effectiveness and safety of crisaborole topical ointment. Patients treated with crisaborole experienced improvement in AD symptoms based on improvement in the Investigator's Static Global Assessment and the AD Severity Index scores. Crisaborole has a limited adverse event profile and low systemic absorption. Relevance to Patient Care and Clinical Practice: Crisaborole is the first topical phosphodiesterase 4 inhibitor indicated for the treatment of mild to moderate AD. Its place in therapy is along with topical calcineurin inhibitors as a second-line option for patients who are recalcitrant to or unable to use topical corticosteroids. Conclusions: Crisaborole is a safe and efficacious second-line option for the treatment of mild to moderate AD in patients 2 years of age and older.

Radioembolization with Yttrium-90 Microspheres for the Treatment of Liver Metastases of Pancreatic Adenocarcinoma: A Multicenter Analysis

PurposeTo retrospectively assess the efficacy and safety of radioembolization with yttrium-90 (90Y) resin microspheres as a second-line option in patients with liver metastases from pancreatic adenocarcinoma. Materials and MethodsThirty-three patients with metastatic pancreatic adenocarcinoma that progressed despite systemic chemotherapy and other treatments directed at primary tumors and metastases were treated with 90Y radioembolization at 1 of 3 institutions from 2011 through 2017. Data from laboratory and imaging studies at 2, 4, 8, and 12 weeks after treatment were analyzed. Tumor response was assessed with Response Evaluation Criteria In Solid Tumors version 1.1 and adverse events with Common Terminology Criteria for Adverse Events version 4.0. ResultsImaging results showed partial response in 8 patients (42%), stable disease in 7 (37%), and progressive disease in 4 (21%). Median overall survival times after radioembolization and diagnosis of the primary tumor were 8.1 (95% CI, 4.8–12.5) and 20.8 (95% CI, 14.2–29.0) months, respectively. Radioembolization did not produce major hepatic toxicity, and changes in liver enzyme levels were rarely grade ≥ 3 during the 12-week follow-up. The exceptions were 3 patients with grade 3 increased alkaline phosphatase (week 2) and bilirubin levels (week 4), increased bilirubin level (week 12), and decreased albumin level (week 12), respectively. Most reported complications were grade ≤ 2, with 2 patients showing short-term radioembolization-related grade 3 abdominal distention, abdominal pain, fatigue, or ascites. ConclusionsYttrium-90 radioembolization provided a meaningful survival benefit in patients with liver metastases from pancreatic adenocarcinoma that progressed despite previous therapies. Adverse events and liver toxicity were tolerable and only occasionally severe (grade ≥ 3).

29] Time of onset of symptom relief after intraoperative detrusor injection of botulinum toxin A in patients with neurogenic and non-neurogenic overactive bladder syndrome

ObjectiveTo investigate the controversy that still exists regarding the time of onset of symptom relief after intraoperative detrusor injection of botulinum toxin A (BOTOX) in patients with neurogenic and non-neurogenic overactive bladder syndrome (OAB), as intra-detrusor injection of botulinum toxin has emerged as a second-line option for patients with neurogenic and non-neurogenic OAB who are refractory to first-line treatment modalities.

PIN45 - A Cost-Utility Analysis of Atovaquone-Proguanil vs. Artemether-Lumefantrine for the Treatment of Uncomplicated Malaria in the United States

To understand the cost-effectiveness of atovaquone-proguanil (AP) versus artemether-lumefantrine (AL) for the treatment of uncomplicated malaria in the United States, a non-endemic country. A cost-utility analysis was conducted to compare treatment with atovaquone-proguanil versus artemether-lumefantrine, with possible risks of adverse events and no response to treatment. We designed a decision tree model simulation to evaluate the relative cost-effectiveness of our two treatment strategies. The sample population represented Americans who traveled to chloroquine-resistant endemic countries and returned to the United States with a diagnosis of uncomplicated malaria from P. falciparum species. Input parameters were obtained from reported outcomes previously published in comparative effectiveness studies, preference-mapping studies, and randomized control trials. The main outcomes of interest were incremental costs, incremental quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). A one-way sensitivity analysis was performed on all relevant parameters. The base-case scenario showed that initiating therapy with atovaquone-proguanil versus artemether-lumefantrine resulted in an ICER of -$487.67 per QALY. As such, atovaquone-proguanil was less costly and more effective compared to artemether-lumefantrine; and thus, was the dominant strategy. Results from the sensitivity analysis suggested that the probability of experiencing no adverse events from atovaquone-proguanil was the main driver of the model. The analysis revealed that starting treatment with atovaquone-proguanil in non-endemic countries, such as the United States, was a dominant strategy compared to initiating treatment with artemether-lumefantrine in uncomplicated malaria patients. Although it is not cost-effective to initiate treatment with artemether-lumefantrine, its use could be considered as a second-line option in patients who do not respond to or cannot tolerate the side effects of atovaquone-proguanil. Due to the rapidly changing drug resistance patterns of malaria, both physicians and travelers must remain informed to avoid the costs and risks of this potentially severe, but easily preventable, infectious disease.

Perspectives in Head and Neck Medical Oncology.

The modern treatment of locoregionally advanced disease often requires a multimodality combination approach. A number of chemotherapeutic agents can be combined with radiation, but the platinum agent cisplatin, a potent radiation sensitizer, is best studied in head and neck cancer. Newer agents such as cetuximab can be used in combination with radiation therapy for those patients who cannot tolerate cisplatin. For chemotherapy-naïve patients with metastatic head and neck cancer who demonstrate a good performance status, platinum doublet regimens are commonly used. Doublet regimens generally improve response rates compared to single-agent chemotherapies, although they have not demonstrated a survival benefit over single agents and they have added toxicity. Immunotherapies, alternative cytotoxic chemotherapies, and targeted therapies are second-line options for patients with disease that has progressed on platinum-based therapy. Immunotherapy, in particular, has gained focus by enhancing the ability of the immune system to recognize and destroy malignant cells. When multimodal approaches are used, as in combined chemotherapy and radiation therapy, toxicities are increased. It is imperative that patients are followed closely in order to maximize treatment benefit while minimizing complications.

The Use of Cyclosporine A in Rheumatology: a 2016 Comprehensive Review.

Cyclosporine A, an inhibitor of calcineurin, exerts an immunomodulator action interfering with T cell activation. Even though novel therapeutic tools have emerged, CyA still represents a suitable option in several clinical rheumatology settings. This is the case of refractory nephritis and cytopenias associated with systemic lupus erythematosus. Furthermore, CyA is a valued therapeutic tool in the management of uveitis and thrombophlebitis in course of Behçet's disease. Topical CyA has been proven to be beneficial in the dry eye of Sjogren's syndrome, whereas oral treatment with CyA can be considered for the severe complications of adult onset Still's disease. CyA provides a therapeutic option in psoriatic arthritis, being rather effective in skin disease. CyA is currently regarded as a second-line option for patients with inflammatory myopathies refractory to standard regimen. CyA is used even in paediatric rheumatology, in particular in the management of juvenile dermatomyositis and macrophage activation syndrome associated with systemic juvenile idiopathic arthritis. Importantly, CyA has been shown to suppress the replication of HCV, and it can thus be safely prescribed to those patients with chronic hepatitis C. Noteworthy, CyA can be administered throughout the gestation course. Surely, caution should be paid to CyA safety profile, in particular to its nephrotoxicity. Even though most evidence comes from small and uncontrolled studies with few randomised controlled trials, CyA should be still regarded as a valid therapeutic tool in 2016 rheumatology.

Ibrutinib for treatment of chronic lymphocytic leukemia.

The pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of ibrutinib are described. Ibrutinib is a first-in-class oral inhibitor of Bruton tyrosine kinase (BTK) approved for treatment of relapsed chronic lymphocytic leukemia (CLL). Ibrutinib blocks downstream signaling of the B-cell receptor, disrupting stromal microenvironment interactions and B-cell cytokine signaling. BTK inhibition has been shown to be effective in relapsed or refractory CLL. A recent Phase III study evaluated ibrutinib (420 mg daily) versus ofatumumab (consistent with labeling) in relapsed or refractory CLL with a primary endpoint of progression free survival (PFS, n = 391). After a median follow-up period of 9.4 months, a PFS was not attained in ibrutinib-treated individuals with and without deletion 17p. In contrast, ofatumumab-treated individuals experienced a PFS of 8.1 months and those with deletion 17p experienced a PFS of 5.8 months. Major hemorrhage was reported in 2 (1%) patients treated with ibrutinib, and a total of 8 (4%) patients discontinued treatment due to toxicity or adverse reactions. Partial response or partial response with lymphocytosis was achieved in 63% of ibrutinib-treated individuals as determined by independent assessments. Overall, ibrutinib reduced the rate of mortality by 57%. Ibrutinib is a first-in-class, orally active, irreversible BTK inhibitor with a novel mechanism of action. This unique mechanism of action and high overall response rates observed in clinical trials make ibrutinib an attractive second-line option in patients who have disease progression while receiving monoclonal antibody therapy or chemoimmunotherapy.

Non HCV-related infectious cryoglobulinemia vasculitis: Results from the French nationwide CryoVas survey and systematic review of the literature

In patients with infectious cryoglobulinemia vasculitis (CryoVas) in the absence of hepatitis C virus infection, data on presentation, therapeutic management and outcome are lacking. We conducted a nationwide survey that included patients with HCV-negative CryoVas. We describe here the presentation, therapeutic management and outcome of 18 patients with non-HCV infectious CryoVas and 27 additional patients identified form a systematic review of the literature. We included 18 patients, mean age 57.9±13.5 years. Infectious causes were viral infections in 8 patients [hepatitis B virus (HBV) in 4, and cytomegalovirus, Epstein Barr virus, parvovirus B19 and human immunodeficiency virus in one case each], pyogenic bacterial infection in 6 patients, parasitic infection in 2 patients, and leprosy and candidiasis in one case each. Baseline manifestations were purpura (78%), glomerulonephritis (28%), arthralgia (28%), peripheral neuropathy (22%), skin necrosis (22%), cutaneous ulcers (17%), and myalgia (11%). Cryoglobulinemia was type II in 2/3 of cases. Most cases received specific anti-infectious therapy as first-line therapy, sometimes associated with corticosteroids, achieving sustained remission in the majority of cases. Refractory or relapsing patients, frequently related to HBV infection, showed a complete remission after rituximab in addition to antiviral therapy. In contrast, corticosteroids and/or immunosuppressive agents used in the absence of anti-infectious agents were frequently associated with refractory CryoVas. Viral and pyogenic bacterial infections represent the main causes of non-HCV infectious CryoVas. Antimicrobial therapy is commonly associated with sustained remission. Immunosuppressive agents should be considered only as a second-line option in patients with refractory vasculitis.

Effect of the addition of platinum to gemcitabine on outcome in patients with advanced pancreatic cancer who progress on gemcitabine: A comprehensive analysis of published trials.

275 Background: Pancreatic cancer is one of the deadliest cancers with an estimated 5 years survival rate of 5%. Until recently gemcitabine had been considered the first line treatment for locally advanced or metastatic disease. Although many chemotherapy regimens have been used there is no standard of care for second line therapy. The aim of this analysis was to identify superior regimen in the second line setting. Methods: We conducted a general search on PubMed for “second line therapy in advanced pancreatic cancer”. We limited our search to trials published in English from 2000 through 2012. Studies presented as abstracts in major meetings were also included. Trials that used targeted therapy other than erlotinib were excluded. We compared in an exploratory fashion the RR, PFS and OS of BSC and each of the following regimens to the rest of the treatments: 5FU+platinum, gemcitabine+platinum, taxol, erlotinib. In addition, we compared the combinations of platinum with either 5FU or gemcitabine. Finally, we explored the trend of these treatments outcomes over time. Results: Forty-four trialswere identified, of which 34 trials (T) met the inclusion criteria treating 1503 patients (N). There was a trend toward an improved overall survival with treatments (T: 33; N: 1269) compared to BSC (T: 2; N: 234) only (P= 0.013). The combination of gemcitabine and platinum (T: 5; N: 154) was the only regimen that showed a trend toward superior outcomes compared to the other regimens (T: 28; N: 1115) in terms of RR and PFS (P= 0.006 and 0.059, respectively). However, there was no difference in overall survival (P= 0.10). When compared to 5FU+platinum (T: 12; N: 450) the regimen of gemcitabine+platinum (T: 5; N: 154) showed only a trend toward significance in terms of improved RR (P= 0.030) with no difference in PFS or OS (P= 0.60 and 0.22, respectively). Overall, there was a trend toward a worse RR and PFS with no change in OS over the past 13 years. Conclusions: The combination of gemcitabine and platinum may provide a valid second line option in patients with locally advanced or metastatic pancreatic cancer who progress on gemcitabine.

Second-line treatment for renal cell cancer

Second-line treatment for renal cell cancer

Is cabazitaxel a therapeutic second-line option for patients with castrate-resistant prostate cancer?

Is cabazitaxel a therapeutic second-line option for patients with castrate-resistant prostate cancer?

Analysis of Factors Associated with Outcome in Patients Undergoing Isolated Hepatic Perfusion for Unresectable Liver Metastases from Colorectal Center

To define the indications for hyperthermic isolated hepatic perfusion (IHP) in patients with unresectable liver metastases (LM) from colorectal cancer (CRC) with particular focus on IHP's utility as a second-line option for patients whose tumors have progressed following combination systemic chemotherapy treatment. From June 1994 through July 2005, 120 patients with unresectable CRC LM underwent IHP with melphalan (n = 69), tumor necrosis factor (TNF) (n = 10) or both (n = 41). Hepatic arterial infusion (HAI) with floxuridine started 6-8 weeks post IHP in 46 (38%). Patients were followed for toxicity, radiographic response, and overall survival (OS). Wilcoxon rank-sum and Fisher's exact tests were used to compare parameters by response category; survival and hepatic progression-free survival were calculated by the Kaplan-Meier method. Of 79 males and 41 females, 96 (80%) received prior chemotherapy. There were five (4%) operative/treatment mortalities. There were 69 responses in 114 evaluable patients (61%). Total melphalan dose and combination melphalan/TNF were each associated with response; age, preoperative carcinoembryonic antigen (CEA), prior chemotherapy for established LM, tumor burden, and post-IHP HAI therapy were not. Median overall survival was 17.4 months and 2-year survival was 34%. Factors found to be independently related to survival were preoperative CEA <30 ng/mL and use of post-IHP HAI (P < 0.015). IHP results in marked tumor regression and prolonged survival in patients with CRC LM. Continued development of IHP in this clinical setting is warranted.

Treatment Options in Imatinib-Resistant Chronic Myelogenous Leukemia

To discuss new therapeutic options available in the treatment of chronic myelogenous leukemia (CML) in patients who failed or were intolerant to imatinib therapy. Literature was accessed via MEDLINE (1966-May 2007), EMBASE (1991-3rd quarter 2007), the Proceedings of the American Society of Hematology (2000-2006), and the Proceedings of the American Society of Clinical Oncology (2000-2007). Search terms included imatinib, dasatinib, nilotinib, and chronic myelogenous leukemia. Meeting abstracts and studies that reported preclinical and Phase 1, 2, and 3 trials published in English are included. Imatinib is the standard of care for CML; however, some patients develop resistance or are intolerant to the drug. Phase 1 and 2 clinical data for the more potent tyrosine kinase inhibitors, dasatinib and nilotinib, are promising. Hematologic and cytogenetic responses are reported with both. There does not appear to be cross-resistance between the drugs, although neither is effective against all mutations of the hallmark molecular marker, the Philadelphia chromosome. Novel agents are also being examined for the treatment of patients with CML, including aurora kinase and farnesyl transferase inhibitors, as well as combination therapies. Dasatinib and nilotinib are second-line options for patients who have CML and are resistant or intolerant to imatinib. Toxicity profiles between agents may differ. Clinical trials with these drugs and others are ongoing.

Ablation vs. drug use for atrial fibrillation

The relative merits of rate and rhythm control in the treatment of patients with atrial fibrillation (AF) have been compared in several major clinical trials, none of which demonstrated a significant difference in all-cause mortality. Yet, there is clear evidence that restoration and maintenance of sinus rhythm is associated with beneficial reverse atrial and ventricular remodelling. In addition, patients may feel better if AF is resolved, and data from some post hoc analyses suggest a possible mortality benefit. These apparently contradictory findings may reflect the high risk of serious adverse events associated with currently available antiarrhythmic drugs (AAD), counterbalancing their beneficial effect in restoring sinus rhythm. Catheter ablation offers an alternative means of restoring sinus rhythm in patients with AF and several clinical trials have indicated superior outcomes in certain subgroups after ablation with or without AAD vs. antiarrhythmic therapy alone. This study reviews the relative advantages and actual use of catheter ablation and other therapeutic options in the treatment of AF, with or without concomitant heart failure or structural heart disease. Catheter ablation is recognized in the latest ACC/AHA/ESC guidelines as a valid second-line option in patients who have failed or were intolerant of first-line antiarrhythmic therapy. In the absence of new antiarrhythmics with an improved benefit/risk profile, it could become a first-line strategy for certain patient populations. The ongoing CABANA trial should confirm its impact on overall survival relative to that of pharmacological rate or rhythm control.

Diuretics: A modern day treatment option? (Review Article)

The choice of drugs to initiate therapy for the management of hypertension remains contentious and diuretics are central to this controversy. Because most of the major trials involve complex treatment algorithms and allow diverse background treatments, one of the greatest challenges lies in separating out true class-specific effects - for example, separating true class-specific effects of diuretics from those of beta blockers. Despite these difficulties, the evidence confirms that diuretics are at least as effective as the newer first line groups in preventing cardiovascular events. The main area of doubt lies in relation to the risk of renal outcomes and of metabolic outcomes, such as new onset diabetes - where the evidence suggests that drugs that inhibit the renin-angiotensin system may be more protective than all other drug classes. These issues are reflected in the most recent international guidelines, all of which include diuretics among the first-line drugs for the treatment of hypertension, although they do differ on the role of diuretics in the initiation of therapy. Diuretics remain important for treating hypertension, especially in combination with other drug classes. The particular place of diuretics in the rank order of drugs must be tailored to suit the clinical situation in the individual patient. This will vary from a preferred option, as in black patients or elderly patients with systolic hypertension, to a second-line option in patients at high risk of developing new onset diabetes.