Long-term data on the proposed adalimumab biosimilar BCD-057 in patients with moderate to severe psoriasis: A randomized controlled trial.

INTRODUCTION: The objective of this study was to demonstrate that BCD-057 is similar to innovator adalimumab (iADA) in terms of efficacy, safety, and pharmacokinetics in steady state in the target population of patients with moderate to severe plaque psoriasis (NCT02762955). METHODS: Patients were randomized in 1:1 ratio to receive 80 mg of BCD-057 or iADA at week 0 and 40 mg thereafter every other week from week 1. At week 24 patients from iADA group were re-randomized (1:1) to continue iADA or to be switched to BCD-057. The primary efficacy endpoint was 75% improvement in Psoriasis Area and Severity Index from baseline (PASI 75), secondary endpoints included PASI percent improvement and relative change in affected Body Surface Area (BSA) from baseline at weeks 16, 24, 33, and 55. Safety was assessed through monitoring of adverse events (AEs) and antidrug antibodies. Pharmacokinetics was evaluated at steady state. RESULTS: Overall, 346 adult patients were included in the study (174/172 patients in BCD-057/iADA arms, respectively). At week 16 PASI 75 was achieved by 60.34% and 63.37% of patients in BCD-057 and iADA arms, respectively (p = 0.5622). Bounds of the calculated 95% confidence interval (CI) for the difference between PASI 75 responses in arms [-13.26%; 7.2%] fall within the equivalence margin [-15% to 15%] demonstrating equivalent efficacy of BCD-057 and iADA. At week 55 81.61%, 85.56%, and 80.49% of patients in BCD-057, iADA and iADA/BCD-057 arms achieved PASI 75. Comparison of the secondary endpoints did not show significant differences between arms. A comparable pharmacokinetics was shown at steady state. Safety profiles and proportions of patients with antidrug antibodies were similar between arms. The switch from the iADA to BCD-057 did not affect the immunogenicity profile. CONCLUSION: Obtained data demonstrate that BCD-057 and iADA are highly similar in clinical efficacy, pharmacokinetics, safety, and immunogenicity in patients with moderate to severe plaque psoriasis.

Efficacy and safety of carfilzomib regimens in multiple myeloma patients relapsing after autologous stem cell transplant: ASPIRE and ENDEAVOR outcomes.

Autologous stem cell transplantation (ASCT) is a standard treatment for eligible multiple myeloma (MM) patients, but many patients will relapse after ASCT and require subsequent therapy. The proteasome inhibitor carfilzomib is approved for relapsed or refractory MM (RRMM). In phase 3 trials, carfilzomib-based regimens (ASPIRE, carfilzomib-lenalidomide-dexamethasone; ENDEAVOR, carfilzomib-dexamethasone) demonstrated superior progression-free survival (PFS) compared with standard therapies for RRMM (ASPIRE: lenalidomide-dexamethasone; ENDEAVOR, bortezomib-dexamethasone). This subgroup analysis of ASPIRE and ENDEAVOR evaluated outcomes according to prior ASCT status. In total, 446 patients in ASPIRE and 538 in ENDEAVOR had prior ASCT. Median PFS was longer for carfilzomib-based regimens vs non-carfilzomib-based regimens for patients with prior ASCT (ASPIRE: 26.3 vs 17.8 months (hazard ratio (HR)=0.68); ENDEAVOR: not estimable vs 10.2 months (HR=0.61)), those with one prior line of therapy that included ASCT (ASPIRE: 29.7 vs 17.8 months (HR=0.70); ENDEAVOR: not estimable vs 11.2 months (HR=0.46)), and those without prior ASCT (ASPIRE: 26.4 vs 16.6 months (HR=0.76); ENDEAVOR: 17.7 vs 8.5 months (HR=0.43)). Overall response rates also favored the carfilzomib-based regimens. No new safety signals were detected. This analysis suggests that carfilzomib-based treatment may lead to improvement in PFS and response rates regardless of prior transplant status. Further evaluation is warranted.

Modern multiple myeloma therapy: deep, sustained treatment response and good clinical outcomes.

In the USA at the beginning of this century, the average overall survival in patients with multiple myeloma was about 3 years. Around that time, three drugs (bortezomib, lenalidomide and thalidomide) were introduced for the treatment of multiple myeloma and, in 2012, carfilzomib received accelerated approval by the US Food and Drug Administration (FDA). Driven by access to better drugs, median overall survival in younger patients (aged <50 years) was >10 years by 2014. The FDA approved 14 new drugs for the treatment of cancer in 2015; four of these were approved for the treatment of myeloma (panobinostat, daratumumab, elotuzumab and ixazomib). In 2015 and 2016, expanded label indications were approved by the FDA for lenalidomide and carfilzomib, respectively. The recent increase in approved, highly effective combination therapies for patients with multiple myeloma has led the way to redefining the goals of therapy. Here, we review and provide a clinical perspective on the treatment goals and management of multiple myeloma in the era of modern therapy. Recent meta-analyses show that minimal residual disease (MRD) negativity is associated with longer progression-free and overall survival in patients with multiple myeloma. With the use of modern combination therapy, large proportions (>60-70%) of newly diagnosed multiple myeloma patients achieve complete responses and MRD negativity. Modern combination therapies induce rapid, deep and sustainable responses (including MRD negativity), supporting a treatment paradigm shift away from palliative two-drug combinations towards the use of modern, potent, three- or four-drug combination regimens in early lines of therapy. Data support the use of modern therapy upfront rather than reserving it for later stages of the disease. As survival time increases with modern combination therapies, development of early reliable surrogate end-points for survival, such as MRD negativity, are needed for expedited read-out of future randomized clinical trials.

Obesity-related complications: few biochemical phenomena with reference to tumorigenesis.

Overweight or obesity is currently a common health problem in westernized societies globally. Obesity is linked with a sizeable number of disease aetiologies, notably type-2 diabetes, cardiovascular disorders and certain cancers, perhaps through some common mechanisms that favor persistent low-grade inflammation. Both epidemiological and laboratory studies have demonstrated that the pathogenesis of certain cancers and the related prognosis are influenced by obesity. Clinically, a complex situation is present in obesity, which usually shows higher blood levels of various biomolecules, e.g., lipids like triglycerides, hormones like insulin, and fat cell-secreted adipokines like leptin. On the contrary, obesity is associated with lower concentrations of substances like sex hormone-binding globulin and adiponectin. Many of these biochemical compounds are used routinely for clinical diagnosis and assessment during the follow-up period. Nonetheless, approximately one-fifth of the total cancer burden is associated with obesity. Excess adipose tissue and different hormonal substances possibly play a significant role in this complex obesity-related carcinogenesis. A precise understanding of the pertinent pathological processes is definitely useful in early diagnosis, clinical management, and designing of novel pharmaceutical agents.

Iatrogenic pulpal reactions to orthodontic extrusion.

A careful review of the literature reveals an absence of studies about the reactions of dental pulp to orthodontic extrusion. The purpose of the present research investigation is to study the pulpal reactions and the sequence of histologic events in human dental pulp after orthodontic extrusion. The sample consisted of 36 intact maxillary first premolars of young adult orthodontic subjects. The mean age of the subjects was 18 years. Eighteen maxillary first premolars were extruded, under controlled conditions with the aid of fixed edgewise orthodontic appliances, for either 1, 2, or 4 weeks. The contralateral maxillary first premolars were not extruded and were used as controls. Immediately after removal of the appliances, all the maxillary first premolars were extracted. The pulps were histologically examined in a double-blind experiment. The results obtained from this study indicate that certain characteristic pulpal reactions arise from orthodontic extrusion. These reactions involve circulatory disturbances with congested and dilated blood vessels, odontoblastic degeneration, vacuolization and edema of the pulp tissues, and (by the fourth week) manifestation of fibrotic changes. It is speculated that the vacuolization of the pulp tissues (which occurred after the application of extrusive orthodontic forces in young adult subjects) resulted from a prolapse of the pulp, made possible by the relatively wide apical foramina. However, the odontoblastic degeneration is most probably the result of a compromised blood supply. The authors believe that this study constitutes a building block for establishing a more complete biologic foundation for orthodontic tooth movement. Further studies are suggested to reach more definitive conclusions.

Oxyphilic granular cell adenoma (oncocytoma)--a histochemical and ultrastructural study.

Oxyphilic granular cell adenoma (oncocytoma) is extremely rare usually benign neoplasm. Specimens from four oncocytomas of the parotid gland were studied by light microscopy using different histochemical stains, and by electron microscopy. The haematoxylin and eosin stained sections revealed large cells with eosinophilic granular cytoplasm. These granules appear blue with phosphotungstic acid haematoxylin stain, purplish blue with mallory aniline blue stain and are moderately reactive to alcian blue and PAS. No elastic fibers could be seen in the intercellular substance using Verhoeff's stain. At the ultrastructural level, the tumour cells were characterized by great numbers of mitochondria. Many of the mitochondria contained glycogen granules. Dividing mitochondria were also observed.