Alternative Treatment Regimens Research Articles

The methodical approaches to health technology assessment in Ukraine according to the european model

The aim of the study was to analyze and present the methodical approaches of health technology assessment(HTA) in Ukraine based on the European experience of HTA Agencies and the opportunities and prospects of adaptation of international data. The methods of HTA have been analyzed and substantiated on the example of treatment of endometriosis in Ukraine. The analysis of the national and international scientific publications, articles, systematic reviews, guidelines on HTA using PubMed,EMBASE and internet resources has been conducted. The HTA methods with the HTA Core Model have been substantiated and tested; directions for the use of the main methodical approaches to HTA taking into account the peculiarities of the national pharmaceutical and medical care have been suggested. As a result of our systematic analysis of the use of the HTA Core Model® by European HTA Agencies the algorithm of the HTA Core model in Ukraine on the national and regional levels according to the European requirements taking into account all the priorities and key trends has been determined. On the example of endometriosis management the method of the HTA Core Model® has been adapted, the alternative treatment regimens have been assessed and the adaptation stages for the assessment of methods and data have been proposed.

The sialyl-glycolipid stage-specific embryonic antigen 4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal features

IntroductionChemotherapy resistance resulting in incomplete pathologic response is associated with high risk of metastasis and early relapse in breast cancer. The aim of this study was to identify and evaluate biomarkers of treatment-resistant tumor cells.MethodsWe performed a cell surface marker screen in triple-negative breast cancer patient-derived xenograft models treated with standard care genotoxic chemotherapy. Global expression profiling was used to further characterize the identified treatment-resistant subpopulations.ResultsHigh expression of sialyl-glycolipid stage-specific embryonic antigen 4 (SSEA4) was found in residual tumor cells surviving chemotherapy and in samples from metastatic patients who relapsed after neoadjuvant chemotherapy. Gene and microRNA (miRNA) expression profiling linked SSEA4 positivity with a mesenchymal phenotype and a deregulation of drug resistance pathways. Functional assays demonstrated a direct link between epithelial–mesenchymal transition (EMT) and SSEA4 expression. Interestingly, SSEA4 expression, EMT, and drug resistance seemed to be regulated posttranscriptionally. Finally, high expression of CMP-N-acetylneuraminate-β-galactosamide-α-2,3-sialyltransferase 2 (ST3GAL2), the rate-limiting enzyme of SSEA4 synthesis, was found to be associated with poor clinical outcome in breast and ovarian cancer patients treated with chemotherapy.ConclusionsIn this study, we identified SSEA4 as highly expressed in a subpopulation of tumor cells resistant to multiple commonly used chemotherapy drugs, as well as ST3GAL2, the rate-limiting enzyme of SSEA4 synthesis, as a predictive marker of poor outcome for breast and ovarian cancer patients undergoing chemotherapy. Both biomarkers and additionally identified regulatory miRNAs may be used to further understand chemoresistance, to stratify patient groups in order to avoid ineffective and painful therapies, and to develop alternative treatment regimens for breast cancer patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0652-6) contains supplementary material, which is available to authorized users.

Management of Gonorrhea in Adolescents and Adults in the United States.

Gonorrhea is the second most commonly reported notifiable disease in the United States and is associated with serious health sequelae, including pelvic inflammatory disease, infertility, and ectopic pregnancy. Treatment for gonorrhea has been complicated by antimicrobial resistance. Neisseria gonorrhoeae has developed resistance to each of the antimicrobials that were previously recommended as first-line treatment regimens, and current treatment options are severely limited. This article summarizes the key questions and data that were discussed at the Sexually Transmitted Diseases (STD) Treatment Guidelines Expert Consultation meeting in April 2013, and the rationale for the 2015 Centers for Disease Control and Prevention STD treatment guidelines for gonococcal infections in adolescents and adults. Key issues addressed include whether to change the dosage of ceftriaxone and azithromycin used in the recommended dual treatment regimen, whether to continue to list dual treatment with cefixime and azithromycin as an alternative treatment regimen, and management of gonococcal infections in persons with severe cephalosporin allergy or suspected treatment failure.

Combination with vorinostat overcomes ABT-263 (navitoclax) resistance of small cell lung cancer

ABSTRACTSmall cell lung cancer (SCLC) is an aggressive tumor type with high mortality. One promising approach for SCLC treatment would be to utilize agents targeting molecular abnormalities regulating resistance to apoptosis. BH3 mimetic antagonists, such as ABT-737 and its orally available derivative ABT-263 (navitoclax) have been developed to block the function of pro-survival BCL-2 family members. The sensitivity of SCLC to these drugs varies over a broad range in vitro and in clinical trials. We have previously shown that the expression of Noxa, a BH3-only pro-apoptotic BCL-2 family protein, is a critical determinant of sensitivity to ABT-737. Thus, pharmacological up-regulation of Noxa could enhance cell death induced by the BH3 mimetics. We find that the combination of ABT-263 and a HDAC inhibitor, vorinostat, efficiently induces apoptosis in a variety of SCLC cell lines, including ABT-263 resistant cell lines. Cell death induced by combined treatment is Noxa- and/or BIM-dependent in some cell lines but in others appears to be mediated by down-regulation of BCL-XL and release of BAK from BCL-XL and MCL-1. These results suggest that combination of HDAC inhibitors and BCL-2 inhibitors could be an alternative and effective regimen for SCLC treatment.

Compliance with the guidelines of the European Society of Cardiology and morbidity and mortality from infectious endocarditis

ObjectiveThe antibiotic treatment recommended for infectious endocarditis (IE) has a low level of evidence. Our objective was to determine whether compliance with the recommendations of the European Society of Cardiology (ESC) was related to lower in hospital morbidity and mortality for this disease. MethodsA retrospective study was conducted on 162 cases of IE diagnosed between 2005 and 2014. A propensity score-matching analysis was performed to determine the effect of treatment on hospital mortality. ResultsThere were no differences in terms of disease complications between the treatment groups. Hospital mortality was 29.2% when the treatment was adjusted to the guidelines and 28.2% when the treatment was not adjusted (OR=1.048; 95% CI: 0.442–2.484; p=.916). ConclusionThe use of the ESC guidelines does not appear to translate into a reduction in hospital morbidity and mortality due to IE when compared with alternative antibiotic treatment regimens.

Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system.

Inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway by the FDA-approved drug rapamycin has been shown to promote lifespan and delay age-related diseases in model organisms including mice. Unfortunately, rapamycin has potentially serious side effects in humans, including glucose intolerance and immunosuppression, which may preclude the long-term prophylactic use of rapamycin as a therapy for age-related diseases. While the beneficial effects of rapamycin are largely mediated by the inhibition of mTOR complex 1 (mTORC1), which is acutely sensitive to rapamycin, many of the negative side effects are mediated by the inhibition of a second mTOR-containing complex, mTORC2, which is much less sensitive to rapamycin. We hypothesized that different rapamycin dosing schedules or the use of FDA-approved rapamycin analogs with different pharmacokinetics might expand the therapeutic window of rapamycin by more specifically targeting mTORC1. Here, we identified an intermittent rapamycin dosing schedule with minimal effects on glucose tolerance, and we find that this schedule has a reduced impact on pyruvate tolerance, fasting glucose and insulin levels, beta cell function, and the immune system compared to daily rapamycin treatment. Further, we find that the FDA-approved rapamycin analogs everolimus and temsirolimus efficiently inhibit mTORC1 while having a reduced impact on glucose and pyruvate tolerance. Our results suggest that many of the negative side effects of rapamycin treatment can be mitigated through intermittent dosing or the use of rapamycin analogs.

Glaucoma patient satisfaction regarding tolerance to their prostaglandin treatment: results from the GOAL (Glaucoma patients treated with prOstaglandins; sAtisfaction evaLuation) survey in Europe

PurposeThe high prevalence of ocular surface diseases (OSD) in patients treated for OHT/glaucoma is expected to displease them. To evaluate this, a survey was conducted in three European countries: the Netherlands, Belgium and United Kingdom.MethodsIn this multicentre epidemiological survey, the following data were recorded during a visit to the ophthalmologist: glaucoma history, previous treatments and reasons for any change, tolerance, patient satisfaction, ocular signs and the presence of OSD.ResultsThe data of 793 patients treated with prostaglandins were analysed (168 from the Netherlands, 253 from Belgium and 372 from England). Only 9% of the treatments were preservative‐free.A very large number (93.7%) of patients declared to be satisfied or very satisfied with their current glaucoma treatment. The mean score of tolerance evaluated on a Visual Analog Scale (VAS) was 82.7 ± 16.1 mm (range from 0 mm: very bad tolerance to 100 mm: very good tolerance).At the same time, the survey revealed (displayed in percentage of all patients): OSD was diagnosed in 42.5% symptoms upon instillation in 31.4% symptoms between instillations in 57.3% a conjunctival hyperaemia in 32% frequent use of artificial tears in 25.1% The presence of hyperaemia, ocular signs, and symptoms upon or between instillations, positive conjunctival staining and frequent use of tear substitutes was statistically significantly linked to patient satisfaction (p ≤ 0.006).ConclusionsA high percentage of satisfied patients (94%) was found in this survey, despite OSD signs and symptoms. Tear film substitutes are commonly prescribed to treat these side effects. Alternative treatment regimes such as preservative free treatments may reduce local side effects and encourage ophthalmologists to convince their patients that local intolerance is no longer inevitable.

Cumplimiento de las guías de la Sociedad Europea de Cardiología y morbimortalidad por endocarditis infecciosa

ObjectiveThe antibiotic treatment recommended for infectious endocarditis (IE) has a low level of evidence. Our objective was to determine whether compliance with the recommendations of the European Society of Cardiology (ESC) was related to lower inhospital morbidity and mortality for this disease. MethodsA retrospective study was conducted on 162 cases of IE diagnosed between 2005 and 2014. A propensity score-matching analysis was performed to determine the effect of treatment on hospital mortality. ResultsThere were no differences in terms of disease complications between the treatment groups. Hospital mortality was 29.2% when the treatment was adjusted to the guidelines and 28.2% when the treatment was not adjusted (OR=1.048; 95%CI: 0.442-2.484; P=.916). ConclusionThe use of the ESC guidelines does not appear to translate into a reduction in hospital morbidity and mortality due to IE when compared with alternative antibiotic treatment regimens.

Costs and cost-effectiveness analysis of 2015 GESIDA/Spanish AIDS National Plan recommended guidelines for initial antiretroviral therapy in HIV-infected adults

IntroductionGESIDA and the AIDS National Plan panel of experts suggest a preferred (PR), alternative (AR) and other regimens (OR) for antiretroviral treatment (ART) as initial therapy in HIV-infected patients for 2015. The objective of this study is to evaluate the costs and the effectiveness of initiating treatment with these regimens. MethodsEconomic assessment of costs and effectiveness (cost/effectiveness) based on decision tree analyses. Effectiveness was defined as the probability of reporting a viral load <50 copies/mL at week 48, in an intention-to-treat analysis. Cost of initiating treatment with an ART regimen was defined as the costs of ART and its consequences (adverse effects, changes of ART regimen, and drug resistance studies) during the first 48 weeks. The payer perspective (National Health System) was applied, only taking into account differential direct costs: ART (official prices), management of adverse effects, studies of resistance, and HLA B*5701 testing. The setting is Spain and the costs correspond to those of 2015. A deterministic sensitivity analysis was conducted, building three scenarios for each regimen: base case, most favourable and least favourable. ResultsIn the base case scenario, the cost of initiating treatment ranges from 4663 Euros for 3TC+LPV/r (OR) to 10,902 Euros for TDF/FTC+RAL (PR). The effectiveness varies from 0.66 for ABC/3TC+ATV/r (AR) and ABC/3TC+LPV/r (OR), to 0.89 for TDF/FTC+DTG (PR) and TDF/FTC/EVG/COBI (AR). The efficiency, in terms of cost/effectiveness, ranges from 5280 to 12,836 Euros per responder at 48 weeks, for 3TC+LPV/r (OR) and RAL+DRV/r (OR), respectively. ConclusionThe most efficient regimen was 3TC+LPV/r (OR). Among the PR and AR, the most efficient regimen was TDF/FTC/RPV (AR). Among the PR regimes, the most efficient was ABC/3TC+DTG.

Predictive Bayesian inference and dynamic treatment regimes.

While optimal dynamic treatment regimes (DTRs) can be estimated without specification of a predictive model, a model-based approach, combined with dynamic programming and Monte Carlo integration, enables direct probabilistic comparisons between the outcomes under the optimal DTR and alternative (dynamic or static) treatment regimes. The Bayesian predictive approach also circumvents problems related to frequentist estimators under the nonregular estimation problem. However, the model-based approach is susceptible to misspecification, in particular of the "null-paradox" type, which is due to the model parameters not having a direct causal interpretation in the presence of latent individual-level characteristics. Because it is reasonable to insist on correct inferences under the null of no difference between the alternative treatment regimes, we discuss how to achieve this through a "null-robust" reparametrization of the problem in a longitudinal setting. Since we argue that causal inference can be entirely understood as posterior predictive inference in a hypothetical population without covariate imbalances, we also discuss how controlling for confounding through inverse probability of treatment weighting can be justified and incorporated in the Bayesian setting.

Abstract 2524: Combination with vorinostat overcomes ABT-263 resistance of small cell lung cancer

Abstract Lung cancer is the most common cause of cancer related mortality worldwide, with small cell lung cancer (SCLC) representing 15% of cases, accounting for 30,000 new cases in the US each year. While SCLC is initially a highly chemotherapy-responsive disease, relapse and progressive development of chemotherapy resistance is the rule. One promising approach to overcome the therapeutic resistance would be to utilize agents targeting molecular abnormalities regulating resistance to apoptosis. Tumor cell death induced by chemotherapy or lack of appropriate cellular survival signals is mediated by the BCL-2 family-dependent mitochondrial apoptotic pathway. We and others have shown that the pro-survival member BCL-2, as well as BCL-XL and MCL-1, is overexpressed in SCLC. BH3 mimetic antagonists have been developed to block the function of pro-survival BCL-2 family members. ABT-737 and its orally available derivative ABT-263 bind to and block BCL-2 and BCL-XL, but not MCL-1 function. Although SCLC is the only non-hematologic malignancy against which ABT-737/ABT-263 are effective as single agents, the sensitivity of SCLC to these drugs varies over a broad range in vitro and in clinical trials. We have shown in a model SCLC system that expression of Noxa, a BH3-only pro-apoptotic BCL-2 family protein, is a critical determinant of ABT-737 sensitivity, demonstrating that Noxa specifically binds to and recruits MCL-1 from the cytosol to the mitochondria. Recent integrative genome analysis in SCLC implicates histone modification as a major feature of SCLC. It has also been demonstrated that Noxa is transcriptionally activated by HDAC inhibitors. Thus, we hypothesized that alteration of histone modification by a HDAC inhibitor, vorinostat could induce Noxa to enhance cell death by ABT-737/263 treatment. We have found that combination of ABT-263 and vorinostat efficiently induces apoptosis in a variety of SCLC cell lines, even in the ABT-263 resistant cells. Cell death induced by combined treatment is Noxa- and/or BIM-dependent in some cell lines but in others appears to be mediated by an alternative mechanism. These results suggest that combination of HDAC inhibitors and BCL-2 inhibitors could be an alternative effective regimen for SCLC treatment. Citation Format: Wataru Nakajima, Mark A. Hicks, Kanika Sharma, Ngoc Le, Geoffrey W. Krystal, Hisashi Harada. Combination with vorinostat overcomes ABT-263 resistance of small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2524. doi:10.1158/1538-7445.AM2015-2524

Abstract 2944: 5-azacytidine nucleosides and their derivatives: Molecular hallmarks of drug resistance &amp; alternative therapeutic regimen

Abstract Background: Aberrant DNA methylation turning ‘off’ the gene expression remains the consistent hallmark due to its involvement in all types of cancer. The prototypal DNA methylation inhibitors, 5-azacytidine and 2′-deoxy-5-azacytidine, are currently one of the most effective epigenetic drugs, for the treatment of blood malignancies. However, the chemotherapeutic resistance to these medicines is the major obstacle, preventing the successful epigenetic therapy. Objective: (i) To investigate the mechanism of resistance to 2′-deoxy-5-azacytidine and (ii) Design alternative therapeutic regimen. Materials and Methods: We developed several HCT116 p53 wild-type cell clones, resistant towards 2′-deoxy-5-azacytidine. Principal methods used to study the molecular alterations during the development of resistance included, flow cytometry based analyses, high throughput RNA sequencing based transcriptomics, and mass spectrometry based proteomics utilizing stable isotope labelling of amino acids in cell culture (SILAC). Further, we used MTT assays to determine the cross-resistance or sensitivity of the resistant clones towards the inhibitors of epigenetic “Readers-Writers-Erasers”. Results: Flow cytometry based studies revealed significant up-regulation of DNA and RNA synthesis. Molecular profiling of resistant clones unveiled 8010 genes and 3352 proteins, which were differentially expressed (ANOVA p&amp;lt;0.05) compared to parental cell line. The major affected cellular pathways were (i) Cell cycle: role of 14-3-3 proteins in cell cycle regulation, G1/S transition and initiation of mitosis (ii) Apoptosis and survival: granzyme A signaling, BAD phosphorylation, p53 dependent apoptosis (iii) Transcription: role of heterochromatin protein I family in transcriptional silencing, role of AP1 in regulation of cellular metabolism (iv) DNA damage: role of SUMO in p53 regulation. During MTT cytotoxicity assays, resistant clones exhibited cross-resistance towards all the tested epigenetic inhibitors, however, significant sensitivity was exceptionally observed for bromodomain inhibitors, which was further validated by significant down-regulation of BET bromodomains. Validation of relevant genes and/or proteins as biomarkers of drug resistance, and bromodomains as alternative therapeutic target, for re-sensitizing the cancer patients, resistant to DNA methylation inhibitors is currently ongoing. Conclusion: The present study will aid to the understanding of the molecular basis of acquired tumor resistance to 2′-deoxy-5-azacytidine and help in predicting its clinical response, as well as in designing alternative treatment regimens for overcoming resistance, hence furthering clinical development. Acknowledgement: Internal Grant Agency of Palacky University (LF-2013/016), BIOMEDREG (CZ.l.05/2.1 .00/ 01.0030) and Ministry of Industry and Trade of the Czech Republic (FR-TI4/625). Citation Format: Khushboo Agrawal, Petr Vojta, Dušan Holub, Ivo Frydrych, Petr Džubák, Miroslav Otmar, Marcela Krečmerová, Marián Hajdúch. 5-azacytidine nucleosides and their derivatives: Molecular hallmarks of drug resistance &amp; alternative therapeutic regimen. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2944. doi:10.1158/1538-7445.AM2015-2944

Abstract 4317: The sialyl-glycolipid SSEA4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal features

Abstract Currently, the main option for systemic therapy of high-risk breast cancer is chemotherapy, with an overall poor efficacy and severe side effects. Chemotherapy-resistance and incomplete pathologic response associate with risk of metastasis and early relapse in breast cancer. In order to characterize treatment-resistant tumor cells, we performed a cell surface marker screen in 4 triple-negative breast cancer patient-derived xenograft (PDX) models that respond well to adriamycin/cyclophosphamide-based chemotherapy but fail to reach complete pathological response. We used multi-parameter flow cytometry to screen for the expression of a set of 45 cell surface markers during the course of chemotherapy. This set of markers represented both proteins involved in stem cell function and proteins known to be over-expressed in stem cells or cancer stem cell sub-populations. We identified the sialyl-glycolipid SSEA4 as a constant marker of chemotherapy-resistant cancer cells in all four models. In addition, SSEA4 expression was found higher in 3 out of 4 TNBC PDXs that are de novo resistant to neo-adjuvant chemotherapy compared to sensitive TNBC PDXs. Two cell populations with different percentage of SSEA4-positive (SSEA4+) cells and with different growth characteristics were identified in a PDX model. When treated with genotoxic compounds, the cell population with higher SSEA4+ expression showed increased resistance to chemotherapy, indicating this post-translational modification as potential marker of tumor resistance. Comparison of SSEA4+ and SSEA4-negative (SSEA4-) tumor cells from TNBC PDX models by global gene expression profiling showed overexpression of mesenchymal-associated genes in SSEA4+ tumor cells and a deregulation of drug resistance pathway-associated genes and miRNAs. In addition, high expression of ST3 beta-galactoside alpha-2,3-sialyltransferase 2 (ST3GAL2), the enzyme catalyzing the last step of SSEA4 synthesis, was found associated with poor outcome in breast and ovarian cancer patients treated with chemotherapy. Thus, we propose SSEA4 as a novel marker of epithelial-mesenchymal transition associated with chemoresistance, and ST3GAL2 expression as a predictive marker for tumor chemoresistance associated with poor outcome in breast and ovarian cancer patients. Both biomarkers and additionally identified regulatory miRNAs may be used to further understand chemoresistance and to develop alternative treatment regimens for breast and ovarian cancer patients. Citation Format: Andrea Aloia, Evgeniya Petrova, Stefan Tomiuk, Ute Bissels, Sophie Banis, Olivier Deas, Silvia Rüberg, Bernhard Gerstmayer, David Agorku, Jean-Gabriel Judde, Andreas Bosio, Stefano Cairo, Olaf T. Hardt. The sialyl-glycolipid SSEA4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal features. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4317. doi:10.1158/1538-7445.AM2015-4317

Diagnostic struggles in congenital myasthenic syndromes in children

Congenital myasthenic syndromes (CMS) cover a group of heterogeneous disorders in which the neuromuscular transmission is affected. We diagnosed CMS in nine unrelated patients in the Netherlands. Six mutations were discovered in the acetylcholine receptor epsilon subunit gene, two in the receptor-associated protein of the synapse gene and one mutation in dolichyl-phosphate (UDP-N-acetylglucosamine) N-acetylglucosaminephosphotransferase 1. We describe the diagnostic work up in these children and common diagnostic pitfalls that caused delay in diagnosis and treatment, such as the lack of specificity of clinical features, technical drawbacks of invasive testing in young children, non-specific changes in muscle histology and false negative results of electromyography. Early initiation of treatment and alternative treatment regimens can considerably improve the quality of life of patients with CMS.

Fluoroquinolone Sequential Therapy for Helicobacter pylori: A Meta‐analysis

As resistance of Helicobacter pylori to standard first-line therapy is increasing globally, alternative treatment regimens, such as a fluoroquinolone-based sequential regimen, have been explored. The objective of this meta-analysis was to compare the efficacy of fluoroquinolone-based sequential therapy with standard first-line treatment for H.pylori infection. Meta-analysis of six randomized controlled trials. A total of 738 H.pylori-infected, treatment-naive adults who received fluoroquinolone-based sequential therapy (5-7days of a proton pump inhibitor [PPI] and amoxicillin therapy followed by 5-7days of a PPI, a fluoroquinolone, and metronidazole or tinidazole or furazolidone therapy) and 733 H.pylori-infected, treatment-naive adults who received guideline-recommended, first-line therapy with standard triple therapy (7-14days of a PPI plus amoxicillin and clarithromycin) or standard sequential therapy (5days of a PPI plus amoxicillin, followed by an additional 5days of triple therapy consisting of a PPI, clarithromycin, and metronidazole or tinidazole). A systematic literature search of the MEDLINE, PubMed, and Cochrane Central Register of Controlled Trials databases (from inception through January 2015) was conducted to identify randomized controlled trials that compared fluoroquinolone-based sequential therapy with guideline-recommended, first-line treatment regimens in H.pylori-infected, treatment-naive adults. All selected trials confirmed H.pylori infection prior to treatment as well as post-treatment eradication. A meta-analysis was performed by using Review Manager 5.2. Treatment effect was determined with a random-effects model by using the Mantel-Haenszel method and was reported as a risk ratio (RR) with 95% confidence interval (CI). In the six randomized controlled trials that met the inclusion criteria, 648 (87.8%) of 738 patients receiving fluoroquinolone-based sequential therapy and 521 (71.1%) of 733 patients receiving standard regimens achieved eradication (RR 1.21, 95% CI 1.09-1.35). The frequencies of adverse effects that were reported in three of the trials were comparable for all treatments (RR 0.99, 95% CI 0.76-1.29). In addition, no statistically significant difference was noted in the number of patients who experienced adverse effects that prompted discontinuation of therapy (RR 1.03, 95% CI 0.34-3.09). The H.pylori eradication rate appeared similar among the six trials with respect to duration of therapy and daily dose of the fluoroquinolone. Fluoroquinolone-based sequential therapy is a reasonable treatment alternative to first-line eradication therapy for treatment of H.pylori.

Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial

The international standard of care for women with suspected advanced ovarian cancer is surgical debulking followed by platinum-based chemotherapy. We aimed to establish whether use of platinum-based primary chemotherapy followed by delayed surgery was an effective and safe alternative treatment regimen. In this phase 3, non-inferiority, randomised, controlled trial (CHORUS) undertaken in 87 hospitals in the UK and New Zealand, we enrolled women with suspected stage III or IV ovarian cancer. We randomly assigned women (1:1) either to undergo primary surgery followed by six cycles of chemotherapy, or to three cycles of primary chemotherapy, then surgery, followed by three more cycles of completion chemotherapy. Each 3-week cycle consisted of carboplatin AUC5 or AUC6 plus paclitaxel 175 mg/m(2), or an alternative carboplatin combination regimen, or carboplatin monotherapy. We did the random assignment by use of a minimisation method with a random element, and stratified participants according to the randomising centre, largest radiological tumour size, clinical stage, and prespecified chemotherapy regimen. Patients and investigators were not masked to group assignment. The primary outcome measure was overall survival. Primary analyses were done in the intention-to-treat population. To establish non-inferiority, the upper bound of a one-sided 90% CI for the hazard ratio (HR) had to be less than 1.18. This trial is registered, number ISRCTN74802813, and is closed to new participants. Between March 1, 2004, and Aug 30, 2010, we randomly assigned 552 women to treatment. Of the 550 women who were eligible, 276 were assigned to primary surgery and 274 to primary chemotherapy. All were included in the intention-to-treat analysis; 251 assigned to primary surgery and 253 to primary chemotherapy were included in the per-protocol analysis. As of May 31, 2014, 451 deaths had occurred: 231 in the primary-surgery group versus 220 in the primary-chemotherapy group. Median overall survival was 22.6 months in the primary-surgery group versus 24.1 months in primary chemotherapy. The HR for death was 0.87 in favour of primary chemotherapy, with the upper bound of the one-sided 90% CI 0.98 (95% CI 0.72-1.05). Grade 3 or 4 postoperative adverse events and deaths within 28 days after surgery were more common in the primary-surgery group than in the primary-chemotherapy group (60 [24%] of 252 women vs 30 [14%] of 209, p=0.0007, and 14 women [6%] vs 1 woman [<1%], p=0.001). The most common grade 3 or 4 postoperative adverse event was haemorrhage in both groups (8 women [3%] in the primary-surgery group vs 14 [6%] in the primary-chemotherapy group). 110 (49%) of 225 women receiving primary surgery and 102 (40%) of 253 receiving primary chemotherapy had a grade 3 or 4 chemotherapy related toxic effect (p=0.0654), mostly uncomplicated neutropenia (20% and 16%, respectively). One fatal toxic effect, neutropenic sepsis, occurred in the primary-chemotherapy group. In women with stage III or IV ovarian cancer, survival with primary chemotherapy is non-inferior to primary surgery. In this study population, giving primary chemotherapy before surgery is an acceptable standard of care for women with advanced ovarian cancer. Cancer Research UK and the Royal College of Obstetricians and Gynaecologists.

Management of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) is usually diagnosed in asymptomatic patients with early-stage disease. The standard management approach is careful observation, irrespective of risk factors unless patients meet the International Workshop on CLL (IWCLL) criteria for "active disease," which requires treatment. The initial standard therapy for most patients combines an anti-CD20 antibody (such as rituximab, ofatumumab, or obinutuzumab) with chemotherapy (fludarabine/cyclophosphamide [FC], bendamustine, or chlorambucil) depending on multiple factors including the physical fitness of the patient. However, patients with very high-risk CLL because of a 17p13 deletion (17p-) with or without mutation of TP53 (17p-/TP53mut) have poor responses to chemoimmunotherapy and require alternative treatment regimens containing B-cell receptor (BCR) signaling pathway inhibitors. The BCR signaling pathway inhibitors (ibrutinib targeting Bruton's tyrosine kinase [BTK] and idelalisib targeting phosphatidyl-inositol 3-kinase delta [PI3K-delta], respectively) are currently approved for the treatment of relapsed/refractory CLL and all patients with 17p- (ibrutinib), and in combination with rituximab for relapsed/refractory patients (idelalisib). These agents offer great efficacy, even in chemotherapy refractory CLL, with increased tolerability, safety, and survival. Ongoing studies aim to determine the best therapy combinations with the goal of achieving long-term disease control and the possibility of developing a curative regimen for some patients. CLL is associated with a wide range of infectious, autoimmune, and malignant complications. These complications result in considerable morbidity and mortality that can be minimized by early detection and aggressive management. This active monitoring requires ongoing patient education, provider vigilance, and a team approach to patient care.

RNA Disruption and Drug Response in Breast Cancer Primary Systemic Therapy.

As there is now evidence that switching clinical nonresponders early in primary systemic therapy to alternate treatment regimens can enhance survival in some breast cancer patients, the need for a robust intermediate endpoint that can guide treatment response across all tumor subtypes is urgent. Recently, chemotherapy drugs have been shown to induce a decrease in RNA quality in tumor cells from breast cancer biopsies in some patients at midtherapy, and that this has been associated with subsequent achievement of pathological complete response (pCR). The decrease in RNA quality has been shown to be associated with RNA disruption; aberrant RNA bands visualized by RNA electrophoresis have been associated with subsequent tumor cell death. The objectives of these studies are to show that a new assay based on induction of RNA disruption in tumor cells by chemotherapy can stratify at midtherapy, pCR responders from non-pCR responders irrespective of clinical response and to present early evidence that clinically useful RNA disruption can be detected as early as 14 days after initiation of treatment. RNA disruption in tumor cells was quantified by analysis of the RNA electrophoresis banding pattern and expressed as an RNA disruption index (RDI). To develop the RNA disruption assay (RDA), RDI was correlated with clinical outcome (pCR) from the NCIC-CTG MA.22 breast cancer clinical trial (ClinicalTrials.gov NCT00066443). RDA Zones were established by stratifying patients using RDI values into Zone 1, Zone 2, and Zone 3. Zone 3 included seven out of eight pCR responders, whereas Zone 1 contained no pCR responders. An intermediate zone (Zone 2) was established which contained one pCR. Subsequently, to determine early drug response, RNA disruption was examined by RDI after 14 days exposure to trastuzumab, zoledronic acid, or letrozole + cyclophosphamide ± sorafenib therapy. In MA.22, RDA stratified 23 of 85 patients in Zone 1 as pCR nonresponders, 24 patients in Zone 2, an intermediate zone, and 38 patients in Zone 3, pCR responders and non-pCR patients who share RDI comparable to those achieving pCR. In the early response studies, after 14 days exposure to chemotherapy, some RNA disruption as measured by RDI elevation could be detected in 3/12 trastuzumab, 7/15 zoledronic acid, 5/29 letrozole + cyclophosphamide, and 5/23 letrozole + cyclophosphamide + sorafenib patients. RDA is a novel intermediate endpoint that has promise for clinical utility for breast cancers early in response-guided primary systemic therapy.

Safety and efficacy of alternative antibiotic regimens compared with 7 day injectable procaine benzylpenicillin and gentamicin for outpatient treatment of neonates and young infants with clinical signs of severe infection when referral is not possible: a randomised, open-label, equivalence trial.

Severe infections remain one of the main causes of neonatal deaths worldwide. Possible severe infection is diagnosed in young infants (aged 0-59 days) according to the presence of one or more clinical signs. The recommended treatment is hospital admission with 7-10 days of injectable antibiotic therapy. In low-income and middle-income countries, barriers to hospital care lead to delayed, inadequate, or no treatment for many young infants. We aimed to identify effective alternative antibiotic regimens to expand treatment options for situations where hospital admission is not possible. We did this randomised, open-label, equivalence trial in four urban hospitals and one rural field site in Bangladesh to determine whether two alternative antibiotic regimens with reduced numbers of injectable antibiotics combined with oral antibiotics had similar efficacy and safety to the standard regimen, which was also used as outpatient treatment. We randomly assigned infants who showed at least one clinical sign of severe, but not critical, infection (except fast breathing alone), whose parents refused hospital admission, to one of the three treatment regimens. We stratified randomisation by study site and age (<7 days or 7-59 days) using computer-generated randomisation sequences. The standard treatment was intramuscular procaine benzylpenicillin and gentamicin once per day for 7 days (group A). The alternative regimens were intramuscular gentamicin once per day and oral amoxicillin twice per day for 7 days (group B) or intramuscular procaine benzylpenicillin and gentamicin once per day for 2 days, then oral amoxicillin twice per day for 5 days (group C). The primary outcome was treatment failure within 7 days after enrolment. Assessors of treatment failure were masked to treatment allocation. Primary analysis was per protocol. We used a prespecified similarity margin of 5% to assess equivalence between regimens. This study is registered with ClinicalTrials.gov, number NCT00844337. Between July 1, 2009, and June 30, 2013, we recruited 2490 young infants into the trial. We assigned 830 infants to group A, 831 infants to group B, and 829 infants to group C. 2367 (95%) infants fulfilled per-protocol criteria. 78 (10%) of 795 per-protocol infants had treatment failure in group A compared with 65 (8%) of 782 infants in group B (risk difference -1.5%, 95% CI -4.3 to 1.3) and 64 (8%) of 790 infants in group C (-1.7%, -4.5 to 1.1). In group A, 14 (2%) infants died before day 15, compared with 12 (2%) infants in group B and 12 (2%) infants in group C. Non-fatal relapse rates were similar in all three groups (12 [2%] infants in group A vs 13 [2%] infants in group B and 10 [1%] infants in group C). Our results suggest that the two alternative antibiotic regimens for outpatient treatment of clinical signs of severe infection in young infants whose parents refused hospital admission are as efficacious as the standard regimen. This finding could increase treatment options in resource-poor settings when referral care is not available or acceptable.

Clinical outcomes of adult inpatients treated with continuous subcutaneous insulin infusion for diabetes mellitus: a systematic review.

To provide a systematic review of the current evidence concerning the diabetes-related outcomes of patients provided with continuous subcutaneous insulin infusion for treating diabetes mellitus while a hospital inpatient. Relevant publications were obtained from MEDLINE and EMBASE databases concerning hospital inpatients with diabetes being treated with continuous subcutaneous insulin infusion. Studies were assessed independently by two reviewers, and data on the following outcomes were extracted: inpatient mortality; clinical complications, e.g. diabetic ketoacidosis; hyperglycaemia; hypoglycaemia; length of hospital stay; mean bedside glucose level; and glucose level on discharge. Obstetric cases were examined separately to look at maternal and neonatal glycaemic outcomes. A total of 11 studies met the required criteria and were analysed in detail, 5 of which were predominantly obstetric. No significant complications were reported, with no incidences of death, ketoacidosis or severe hypoglycaemia. Length of hospital stay appeared to be shorter in those patients who remained on continuous subcutaneous insulin infusion, while data on mild hyperglycaemia and hypoglycaemia were inconclusive. There are limited data available to form a significant conclusion about the safety of continuous subcutaneous insulin infusion continuation in hospital; however, its use can be justified with the presence of a specialized inpatient diabetes team for advice and support and an alternative treatment regime (e.g. subcutaneous basal bolus) should be accessible if the need were to arise.