Real-world evidence in the reassessment of oncology therapies: payer perceptions from five countries.

Aim: This study explored the perceived value of real-world evidence (RWE) in the reassessment of oncology therapies by collecting the perspectives of health technology assessment/payer decision-makers. Materials & methods: A web-based survey was conducted using the Market Access Transformation Rapid Payer Response online portal. 30 participants from France, Germany, Spain, the UK and the USA were recruited based on their expertise. Results: Participants agreed that the most common uses of RWE are to confirm efficacy and safety results from randomized controlled trials and to reevaluate the projected utilization of an oncology therapy. We found variability in other reported uses of RWE. Conclusion: The organizations developing RWE should ensure that their plans recognize the heterogeneity in payer perceptions.

A survey from the Market Access Transformation RPR portal queried decision-makers from five countries about the value of real-world evidence in oncology therapy reassessment. Participants agreed that RWE can confirm efficacy/safety and reevaluate utilization, but other uses varied.

Management and treatment of relapsed or refractory Ph(-) B-precursor ALL: a web-based, double-blind survey of EU clinicians.

BACKGROUND: The prognosis for adult patients with Ph(-) B-precursor acute lymphoblastic leukaemia (ALL) who are refractory to treatment or experience relapse (R/R), is poor; over 90% of these patients die from the disease, typically within a few months. While there are some national guidelines published for the treatment of adult patients with ALL, and local working group recommendations do exist, there is very little detail and no preferred treatment regimens for adult patients with R/R Ph(-) B-precursor ALL. The aim of this study was to describe current real-world clinical practice in Europe for the management and treatment of adult R/R Ph(-) B-precursor ALL. METHODS: A web-based, double-blind survey was conducted in November/December 2013 in France, Germany, Italy, Spain, and the UK. The survey was developed following consultation with specialist clinicians and a critical review of published literature. Eligible clinicians (15 per country) were board-certified in haemato-oncology or haematology; had at least 4 years of experience in their current role and had treated at least five patients with adult ALL in the 36 months before the survey, including at least one with R/R Ph(-) B-precursor ALL. RESULTS: Clinicians across the five countries consulted 16 guidelines and local working group recommendations for the diagnosis and treatment of R/R Ph(-) B-precursor ALL. Thirty three regimens for salvage therapy were reported; the most frequently cited was augmented hyper-CVAD (15%), with vincristine the most commonly used agent. Salvage therapy regimens involved a range of agents, and most respondents reported using at least one cytotoxic agent; across respondents 10 different cytotoxic agents were cited. All respondents reported that toxicity was common for the regimens they used to treat R/R Ph(-) B-precursor ALL. CONCLUSIONS: This study provides evidence of current management and treatment patterns of R/R Ph(-) B-precursor ALL in the real-world clinical practice in Europe. The approach to the treatment of R/R Ph(-) B-precursor ALL is heterogeneous, reflecting the lack of any clearly superior chemotherapeutic option, thus it appears that clinicians are trying a wide variety of therapies. These findings show a clear need for effective, tolerable treatments for R/R Ph(-) B-precursor ALL.

Dutasteride plus tamsulosin fixed-dose combination first-line therapy versus tamsulosin monotherapy in the treatment of benign prostatic hyperplasia: a budget impact analysis in the Greek healthcare setting.

BACKGROUND: The purpose of this study was to explore the budget impact of dutasteride plus tamsulosin fixed-dose combination (DUT + TAM FDC) versus tamsulosin monotherapy, in the treatment of patients with benign prostatic hyperplasia (BPH) from the perspective of the Greek healthcare insurance system. METHODS: A Microsoft Excel-based model was developed to estimate the financial consequences of adopting DUT + TAM FDC within the Greek healthcare setting. The model, compared six mutually exclusive health states in two alternative treatment options: current standard of care and the introduction of DUT + TAM FDC in the market. The model used clinical inputs from the CombAT study; data on resource use associated with the management of BPH in Greece were derived from expert panel, and unit cost data were derived from official reimbursement tariffs. A payer perspective was taken into account. As patient distribution data between public and private sectors are not available in Greece two scenarios were investigated, considering the whole eligible population in each scenario. A 4 year time horizon was taken into account and included treatment costs, number of transurethral resections of the prostate (TURPs) and acute urinary retention (AUR) episodes avoided. RESULTS: The clinical benefit from the market adoption of DUT + TAM FDC in Greece was 1,758 TURPs and 972 episodes of AUR avoided cumulatively in a four year period. The increase in total costs from the gradual introduction of DUT + TAM FDC to the Greek healthcare system ranges from €1.3 million in the first year to €5.8 million in the fourth year, for the public sector, and €1.2 million to €4.0 million, for the private sector. This represents an increase of 1.91% to 7.94% for the public sector and 1.10% 3.29% in the private sector, during the 4-year time horizon. CONCLUSIONS: Budget impact analysis (BIA) results indicated that the gradual introduction of DUT + TAM FDC, would increase the overall budget of the disease, however providing better clinical outcomes. DUT + TAM FDC drug acquisition cost is partly offset by the reduction in the costs associated with the treatment of the disease.

Rationally designed less toxic SPD-304 analogs and preliminary evaluation of their TNF inhibitory effects.

SPD-304 was discovered as a promising tumor necrosis factor alpha (TNF) antagonist that promotes dissociation of TNF trimers and therefore blocks the interaction of TNF and its receptor. However, SPD-304 contains a potentially toxic 3-alkylindole moiety, which can be bioactivated to a reactive electrophilic intermediate. A series of SPD-304 analogs was synthesized with the aim to diminish its toxicophore groups while maintaining the binding affinity for TNF. Incorporation of electron-withdrawing substituents at the indole moiety, in conjunction with elimination of the 6'-methyl group of the 4-chromone moiety, led to a significantly less toxic and equally potent TNF inhibitor.

Designed spiro-bicyclic analogues targeting the ribosomal decoding center.

The bacterial ribosome represents the confirmed biological target for many known antibiotics that interfere with bacterial protein synthesis. Aminoglycosides represent a lead paradigm in RNA molecular recognition and constitute ideal starting points for the design and synthesis of novel RNA binders. Previous rational design approaches of RNA-targeting small molecules have been mainly concentrated on direct functionalization of aminoglycosidic substructures. Herein, we successfully designed and synthesized rigid spirocyclic scaffolds locked in a predicted ribosome-bound "bioactive" conformation. These analogues are able to mimic many of the interactions of the natural products for the A-site, as proven by their obtained binding affinities. The development of an optimized approach for their synthesis and their potential to inhibit protein production in vitro are presented. Our results could be further utilized for the development of analogues with improved antibiotic profiles.

A bidirectional approach to the synthesis of polypropionates: synthesis of C1-C13 fragment of zincophorin and related isomers.

The structure-activity study of a bioactive natural product containing polypropionate subunits requires that its stereoisomers also be evaluated. Therefore, a general approach to synthesize these motifs is necessary. We describe herein the synthesis of the C1-C13 polypropionate subunit of zincophorin and isomers thereof using a two-reaction sequence: an aldol reaction using a mixture of tetrasubstituted enoxysilanes and a hydrogen-transfer reaction, both under Lewis acid control. Selection of the appropriate Lewis acid dictates the stereochemical outcome of these reactions. From a tactical standpoint, this study shows how a polypropionate sequence can be read and constructed in two directions, either the east-west or the west-east approaches. The choice of the optimal route is influenced by the number of complexation sites that can interfere in the aldol step under bidentate Lewis acid control.

Second generation analogs of rigid 6,7-spiro scaffolds targeting the bacterial ribosome.

Previous work from our group described the synthesis and biological evaluation of new rigid, 6,6- and 6,7-spiro aminoglycosidic scaffolds targeting the bacterial ribosome. Herein we describe an improved synthetic protocol for their construction, and extend our study by further amino-functionalization of their 6,7-spiro analogs. The synthetic strategy, preparation and evaluation of some representative examples are reported.

Hereditary long QT syndrome in pregnancy: antenatal and intrapartum management options.

Long QT syndrome is a rare but severe cardiac arrhythmia. We report the antenatal and intrapartum management of a primigravida carrying the hereditary form of the disease and specifically the Romano-Ward syndrome. A multidisciplinary approach and close obstetric surveillance are mandatory for a good maternal and perinatal outcome. Follow-up of the neonate is equally important.

Takayasu arteritis in pregnancy: safe management options in antenatal care. Case report.

Takayasu arteritis is a nonspecific chronic inflammatory vascular disease of unknown etiology with a higher incidence during the child-bearing years. It usually involves the branches of the aortic arch. Most of the patients enter the pregnancy being already diagnosed as having the disease and being on medication. The state of the disease in early pregnancy is a definitive factor for determining its management. Although it seems that pregnancy is a state favorable to this disease, nevertheless, complications should be anticipated, and close multidisciplinary maternal and fetal surveillance is mandatory. Early-onset hypertension is the commonest complication, and its magnitude during the late gestational period is the second definitive factor for the management of these pregnancies. A vaginal delivery should be aimed at term with continuous electronic fetal monitoring. The immediate postpartum period is usually uncomplicated despite the circulatory alterations that take place.

A strategy for exploiting the pseudosymmetry of the C1-C13 stretch of discodermolide.

[reaction: see text] The pseudo-C(2)() symmetry of the C1 to C13 stretch of the discodermolide structure offers a potential strategic advantage for synthetic design. Two approaches based on this recognition were devised, and one was shown to be effective in a model series.

Retrorectal endometrioid cyst: a case report.

INTRODUCTION: Developmental cysts are the most common retrorectal cystic lesions in adults, whereas reports of endometrioid cysts in this anatomic location are extremely rare. CASE PRESENTATION: A 21-year-old nulliparous Greek woman presented with chronic noncyclic pelvic pain, and a retrorectal cyst was diagnosed. The lesion was resected through a laparotomy and, on histologic examination, was found to be an endometrioid cyst. The treatment was completed with a six-month course of a gonadotropin-releasing hormone analogue. One year after surgery, the woman remained free of symptoms, and pelvic imaging showed no recurrence of the lesion. Reviewing the literature, we found only three previous reports of an endometrioid cyst in this anatomic location. CONCLUSION: In women of reproductive age, endometriosis must be included in the differential diagnosis of retrorectal cysts.