Denosumab was noninferior (trending to superiority) to ZA in preventing or delaying first on-study SRE in patients with advanced cancer metastatic to bone or myeloma. Denosumab represents a potential novel treatment option with the convenience of subcutaneous administration and no requirement for renal monitoring or dose adjustment.

No abstract

No abstract

Anemia of chronic inflammation (ACI) is the most frequent anemia in hospitalized patients and is associated with significant morbidity. A major underlying mechanism of ACI is the retention of iron within cells of the reticuloendothelial system (RES), thus making the metal unavailable for efficient erythropoiesis. This reticuloendothelial iron sequestration is primarily mediated by excess levels of the iron regulatory peptide hepcidin downregulating the functional expression of the only known cellular iron export protein ferroportin resulting in blockade of iron egress from these cells. Using a well-established rat model of ACI, we herein provide novel evidence for effective treatment of ACI by blocking endogenous hepcidin production using the small molecule dorsomorphin derivative LDN-193189 IntroductionAnemia of chronic inflammation (ACI), also termed anemia of chronic disease, is the most frequent anemia in hospitalized patients and develops in subjects suffering from diseases with associated immune activation, such as infections, autoimmune disorders, cancer and end stage renal disease. 1,2 A major cornerstone in the pathophysiology of ACI is iron limited erythropoiesis, caused by iron retention within macrophages. 1,[3][4][5][6] Cytokines and most importantly the acute phase protein hepcidin promote macrophage iron retention by increasing erythrophagocytosis and cellular iron uptake and by blocking iron egress from these cells. 5,[7][8][9][10] The primarily liver derived peptide, hepcidin, exerts regulatory effects on iron homeostasis by binding to ferroportin, the only known iron export protein, thereby leading to ferroportin degradation and subsequently to inhibition of duodenal iron absorption and macrophage iron release. 5,6,11,12 The crucial role of hepcidin for the development of macrophage iron retention, hypoferremia and ACI is underscored by the observations that mice overexpressing hepcidin develop severe anemia, 7,13 that macrophage iron retention and hyperferritinemia are positively associated with hepcidin formation 5,14 and that injection of LPS into healthy volunteers results in hepcidin production and hypoferremia. 15 The expression of hepcidin in hepatocytes is regulated by multiple signals. 16 Iron overload induces the formation of bone morphogenetic proteins (BMPs) 17 and activates phosphorylation of Smad1/5/8 phosphorylation, 17-20 which forms a transcriptional activator complex with Smad4 to stimulate hepcidin transcription. [21][22][23] In mice, BMP6 appears to play a major role in hepcidin regulation, as BMP6 knock out mice have hepcidin deficiency resulting in systemic iron overload. 24,25 Hemojuvelin (HJV) or HFE2, a membrane bound GPI-anchored protein 26,27 acts as a BMP coreceptor and promotes hepcidin transcription. 21 In contrast, a soluble form of HJV (sHJV) blocks BMP6 and inhibits hepcidin expression. 28 The inflammation mediated activation of hepcidin is mainly transmitted via the IL6-inducible transcription factor Stat3. [29][30][31] In addition, Stat3 signaling is influe...

PURPOSE Nivolumab, an anti–programmed death-1 monoclonal antibody, has demonstrated frequent and durable responses in relapsed/refractory classic Hodgkin lymphoma (cHL). We report results from Cohort D of the CheckMate 205 trial, which assessed nivolumab monotherapy followed by nivolumab plus doxorubicin, vinblastine, and dacarbazine (N-AVD) for newly diagnosed cHL. METHODS Patients 18 years of age or older with untreated, advanced-stage (defined as III to IV and IIB with unfavorable risk factors) cHL were eligible for Cohort D of this multicenter, noncomparative, phase II trial. Patients received nivolumab monotherapy for four doses, followed by 12 doses of N-AVD; all doses were every 2 weeks, and nivolumab was administered at 240 mg intravenously. The primary end point was safety. Efficacy end points included objective response rate and modified progression-free survival, defined as time to disease progression/relapse, death, or next therapy. Chromosome 9p24.1 alterations and programmed death-ligand 1 expression were assessed in Hodgkin Reed-Sternberg cells in evaluable patients. RESULTS A total of 51 patients were enrolled and treated. At diagnosis, 49% of patients had an International Prognostic Score of 3 or greater. Overall, 59% experienced a grade 3 to 4 treatment-related adverse event. Treatment-related febrile neutropenia was reported in 10% of patients. Endocrine immune-mediated adverse events were all grade 1 to 2 and did not require high-dose corticosteroids; all nonendocrine immune-mediated adverse events resolved (most commonly, rash; 5.9%). At the end of therapy, the objective response rate (95% CI) per independent radiology review committee was 84% (71% to 93%), with 67% (52% to 79%), achieving complete remission (five patients [10%] were nonevaluable and counted as nonresponders). With a minimum follow-up of 9.4 months, 9-month modified progression-free survival was 92%. Patients with higher-level Hodgkin Reed-Sternberg programmed death-ligand 1 expression had more favorable responses to N-AVD ( P = .041). CONCLUSION Nivolumab followed by N-AVD was associated with promising efficacy and safety profiles for newly diagnosed, advanced-stage cHL.