Ibrutinib combinations in CLL therapy: scientific rationale and clinical results

Ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia (CLL). This drug irreversibly inhibits Bruton tyrosine kinase (BTK) by covalently binding to the C481 residue in the BTK kinase domain. BTK is a pivotal protein for B cell receptor signaling and tissue homing of CLL cells. Preclinical investigations have established the importance of the B cell receptor pathway in the maintenance and survival of normal and malignant B cells, underscoring the importance of targeting this axis for CLL. Clinical trials demonstrated overall and progression-free survival benefit with ibrutinib in multiple CLL subgroups, including patients with relapsed or refractory disease, patients with 17p deletion, elderly patients, and treatment-naïve patients. Consequently, ibrutinib was approved by the US Food and Drug Administration for newly diagnosed and relapsed disease. Ibrutinib has transformed the treatment of CLL; however, several limitations have been identified, including low complete remission rates, development of resistance, and uncommon substantial toxicities. Further, ibrutinib must be used until disease progression, which imposes a financial burden on patients and society. These limitations were the impetus for the development of ibrutinib combinations. Four strategies have been tested in recent years: combinations of ibrutinib with immunotherapy, chemoimmunotherapy, cell therapy, and other targeted therapy. Here, we review the scientific rationale for and clinical outcome of each strategy. Among these strategies, ibrutinib with targeted agent venetoclax results in high complete response rates and, importantly, high rates of undetectable minimal residual disease. Although we concentrate here on ibrutinib, similar combinations are expected or ongoing with acalabrutinib, tirabrutinib, and zanubrutinib, second-generation BTK inhibitors. Future investigations will focus on the feasibility of discontinuing ibrutinib combinations after a defined time; the therapeutic benefit of adding a third agent to ibrutinib-containing combinations; and profiling of resistant clones that develop after combination treatment. A new standard of care for CLL is expected to emerge from these investigations.Subject terms: Combination drug therapy, Medical research     

Carotid webs and ischemic stroke: Experiences in a comprehensive stroke center

Background and purpose

Carotid webs are intraluminal filling defects at the carotid bulb which are considered rare, though possibly underappreciated entities with recent studies demonstrating a likely casual association with ischemic stroke. The purpose of the study is to describe our recent experience with clinical and imaging manifestations of carotid webs.

Role of leukotrienes in NSAID induced gastric ulceration and inflammation in wistar rats

ObjectiveTo evaluate the effects of Montelukast and Curcumin against indomethacin induced gastric damage in rats in order to assess the role of leukotriene (LTs) if any, in non steroidal anti-inflammatory drug (NSAID) induced gastroinflammation.MethodsThe effects of Montelukast (10 mg/kg) and Curcumin (100 mg/kg) were observed on gastric lesion induced by Indomethacin. The blood samples were analyzed for neutrophil adhesion and lipid peroxide levels in gastric tissue measured spectrophotometrically. The skin vascular permeability study was performed by using compound 48/80 induced vascular permeability model.ResultsMontelukast and Curcumin significantly reduced Indomethacin induced gastric lesion score. Pretreatment with Montelukast and Curcumin significantly counteracted Indomethacin induced gastropathy by a combination of its effect on inhibition of neutrophil adherence, through decrease in related production of free radicals that disrupts integrity of stomach mucosa and decrease in vascular permeability as compared to Indomethacin group. The results of the present study further indicates the role of 5-LOX metabolites in NSAIDs induced gastro inflammation and suggests that Montelukast and Curcumin counteracted the Indomethacin induced gastropathy by a combination of its effect on inhibition of neutrophil adherence and through decrease in related production of free radicals that disrupts integrity of stomach mucosa.ConclusionsExperimental data clearly demonstrated the role of LTs was indomethacin induced gastric ulcers. However, inhibition of ulcerogenic events by Montelukast and Curcumin is suggestive of an important balance between COX and 5-LOX products.     

Autism as a disorder of prediction

A rich collection of empirical findings accumulated over the past three decades attests to the diversity of traits that constitute the autism phenotypes. It is unclear whether subsets of these traits share any underlying causality. This lack of a cohesive conceptualization of the disorder has complicated the search for broadly effective therapies, diagnostic markers, and neural/genetic correlates. In this paper, we describe how theoretical considerations and a review of empirical data lead to the hypothesis that some salient aspects of the autism phenotype may be manifestations of an underlying impairment in predictive abilities. With compromised prediction skills, an individual with autism inhabits a seemingly “magical” world wherein events occur unexpectedly and without cause. Immersion in such a capricious environment can prove overwhelming and compromise one’s ability to effectively interact with it. If validated, this hypothesis has the potential of providing unifying insights into multiple aspects of autism, with attendant benefits for improving diagnosis and therapy.     

Treatment of lepromatous ulcers using citric acid as a sole antimicrobial agent

A prospective study was carried out to assess the role of citric acid as a sole antimicrobial agent in the management of lepromatous ulcers. Thirty-four known cases of lepromatous ulcers not responding to conventional antibiotic therapies for long duration were investigated for culture and susceptibility studies. Staphylococcus aureus (25·00%) and Klebsiella spp. (23·43%) were found to be the most common isolates. Amikacin (68·75%) and ciprofloxacin (67·18%) were found to be the most effective antimicrobial agents. Topical application of citric acid ointment resulted in complete healing in 25 (73·52%) cases. In eight cases (26·48%), there was elimination of infective agent from ulcer site and formation of healthy granulation, but no complete healing of ulcer was seen. Results indicate that citric acid is the best alternative for the effective management of lepromatous ulcers when other therapies are exhausted.