Fewer adverse effects associated with a modified two-bag intravenous acetylcysteine protocol compared to traditional three-bag regimen in paracetamol overdose.

Context: The intravenous (IV) N-acetylcysteine (NAC) regimen used worldwide in paracetamol overdose is complex with three separate weight-based doses and is associated with a high incidence of adverse events including non-allergic anaphylactoid reactions (NAARs). In 2012, Denmark adopted the two-bag IV NAC regimen which combined the first two infusions of the three-bag regimen and kept the third infusion unchanged. We compared the safety and efficacy of the two-bag IV NAC regimen with the traditional Danish three-bag regimen. Methods: A medical chart review was conducted in three Danish medical centers from January 2012 through December 2014. Safety and efficacy data were compared for patients who received the traditional infusion protocol in Denmark or the 20-h two-bag IV regimen. Results: Four hundred and ninety-three cases received the two-bag regimen and 274 received the three-bag regimen. The overall incidence of NAARs was 9% with all being mild to moderate in intensity. Fewer subjects in the two-bag group (4%) developed NAARs compared to 17% in the three-bag group (p < .001). Overall, 31 patients (4%) developed hepatotoxicity. There was no apparent difference in hepatotoxicity rates between the groups and no deaths or liver transplants. Patients receiving the two-bag regimen had fewer interruptions or delays (5%) compared to the three-bag regimen cohort (12%). Overall, there were very few medication errors reported (1%). Conclusions: The incidence of NAARs was lower in patients receiving acetylcysteine in a two-bag regimen compared to the traditional Danish three-bag regimen without an apparent reduction in efficacy.

GS-1101: a delta-specific PI3K inhibitor in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) remains an incurable B-cell malignancy with many unanswered questions. While the cell of origin and etiology are still unknown, significant scientific progress has revealed numerous molecular targets for novel therapeutic interventions. Phosphatidylinositol 3-kinases (PI3K) regulate key cellular functions, including growth, survival and migration, by integrating and transmitting signals from diverse surface molecules including the B-cell receptor (BCR). In lymphocytes, the PI3Kδ isoform plays a critical role in B-cell homeostasis and function. In CLL, the PI3K pathway is constitutively active and dependent on PI3Kδ. GS-1101 is a highly selective PI3Kδ inhibitor that in CLL patients causes a rapid and sustained reduction in lymphadenopathy, accompanied by transient lymphocytosis. This article will review new insights into the pathophysiology of CLL, the preclinical rationale of a PI3Kδ inhibitor in CLL, and the clinical evidence supporting this first-in-class therapeutic target for CLL patients.

B-cell receptor pathobiology and targeting in NHL.

B-cell receptor signaling plays varied and critical roles in B-cell development, homeostasis and disease. The key players of the pathway and its many signaling modulators have been identified as well as some of the mechanisms by which the pathway is regulated. With the increased incidence of non-Hodgkin's lymphoma in recent years, there is a clear clinical need for novel agents to offer new options in resistant disease to potentially improve outcomes in curative settings. With the tremendous insight gained in the last 2 decades from basic science research, our understanding of the pathobiology of the B-cell receptor is leading to the discovery and clinical development of many new therapeutic targets such as Syk, Bruton's tyrosine kinase, and phosphatidylinositol 3-kinase. This review will emphasize contemporary and salient findings on novel agents targeting the B-cell receptor signaling pathway for the treatment of non-Hodgkin's lymphoma.

Oxaliplatin and capecitabine in the treatment of patients with recurrent or refractory carcinoma of unknown primary site: a phase 2 trial of the Sarah Cannon Oncology Research Consortium.

BACKGROUND: Despite the widespread use of oxaliplatin-based regimens for colorectal and other gastrointestinal cancers, there is surprisingly little information regarding their empiric use for the treatment of carcinoma of unknown primary site (CUP). In the current study, the combination of oxaliplatin and capecitabine in patients with recurrent and refractory CUP was examined. METHODS: Patients with CUP who had received at least 1 previous chemotherapy regimen were treated with oxaliplatin (130 mg/m(2) intravenously on Day 1) and capecitabine (1000 mg/m(2) orally twice daily on Days 1-14). Treatment cycles were repeated every 21 days. Patients with objective response or stable disease after 2 cycles continued treatment for 6 cycles or until disease progression. RESULTS: Nine of 48 patients (19%) had objective responses to treatment; an additional 22 patients had stable disease at the time of first re-evaluation. After a median follow-up of 17 months, the median progression-free and overall survivals were 3.7 months and 9.7 months, respectively. This regimen was reasonably well tolerated by most patients. CONCLUSIONS: The combination of oxaliplatin and capecitabine was found to have activity as a salvage treatment for patients with CUP. This regimen should be considered in patients with clinical and pathologic features suggesting a primary site in the gastrointestinal tract. Further development of the regimen as a first-line therapy, or with bevacizumab added, is indicated.

Mouse EP3 alpha, beta, and gamma receptor variants reduce tumor cell proliferation and tumorigenesis in vivo.

Prostaglandin E(2), which exerts its functions by binding to four G protein-coupled receptors (EP1-4), is implicated in tumorigenesis. Among the four E-prostanoid (EP) receptors, EP3 is unique in that it exists as alternatively spliced variants, characterized by differences in the cytoplasmic C-terminal tail. Although three EP3 variants, alpha, beta, and gamma, have been described in mice, their functional significance in regulating tumorigenesis is unknown. In this study we provide evidence that expressing murine EP3 alpha, beta, and gamma receptor variants in tumor cells reduces to the same degree their tumorigenic potential in vivo. In addition, activation of each of the three mEP3 variants induces enhanced cell-cell contact and reduces cell proliferation in vitro in a Rho-dependent manner. Finally, we demonstrate that EP3-mediated RhoA activation requires the engagement of the heterotrimeric G protein G(12). Thus, our study provides strong evidence that selective activation of each of the three variants of the EP3 receptor suppresses tumor cell function by activating a G(12)-RhoA pathway.