ALK inhibitors in cancer: mechanisms of resistance and therapeutic management strategies.

Anaplastic lymphoma kinase (ALK) gene rearrangements have been identified as potent oncogenic drivers in several malignancies, including non-small cell lung cancer (NSCLC). The discovery of ALK inhibition using a tyrosine kinase inhibitor (TKI) has dramatically improved the outcomes of patients with ALK-mutated NSCLC. However, the emergence of intrinsic and acquired resistance inevitably occurs with ALK TKI use. This review describes the molecular mechanisms of ALK TKI resistance and discusses management strategies to overcome therapeutic resistance.

Pretreatment With P2Y12 Inhibitors in ST-Segment Elevation Myocardial Infarction: Insights From the Bern-PCI Registry.

BACKGROUND: Evidence to support immediate P2Y12 inhibitor loading in ST-segment elevation myocardial infarction (STEMI) is limited. OBJECTIVES: This study sought to compare outcomes of STEMI patients receiving immediate or delayed P2Y12 inhibitor treatment. METHODS: Using data from the prospective Bern-PCI registry between 2016 and 2020, we stratified STEMI patients undergoing percutaneous coronary intervention according to time periods with different institutional recommendations regarding P2Y12 inhibitor pretreatment. In cohort 1 (October 2016-September 2018), immediate P2Y12 inhibitor treatment was recommended. In cohort 2 (October 2018-September 2020), P2Y12 inhibitor treatment was recommended after coronary anatomy was confirmed. The primary endpoint was a composite of major adverse cardiac or cerebrovascular events (MACCEs) defined as all-cause death, recurrent myocardial infarction, stroke, or definite stent thrombosis at 30 days. Sensitivity analysis included only patients in whom these recommendations were followed. RESULTS: Cohort 1 included 1,116 patients; pretreatment was actually given in 708 (63.4%). Cohort 2 included 847 patients; pretreatment was withheld in 798 (94.2%). The mean age was 65 ± 13 years, and 24% were female. Baseline characteristics were well-balanced between groups. The median difference for P2Y12 loading to angiography was 52 minutes between cohort 1 and 2 and 100 minutes between patients receiving vs not receiving pretreatment. Rates of MACCEs were similar between cohort 1 and cohort 2 (10.1% vs 8.1%; adjusted HR: 0.91; 95% CI: 0.65-1.28; P = 0.59) and between patients receiving vs not receiving pretreatment (7.1% vs 8.4%; adjusted HR: 1.17; 95% CI: 0.78-1.74; P = 0.45). CONCLUSIONS: In this cohort study of patients with STEMI undergoing primary percutaneous coronary intervention, P2Y12 inhibitor pretreatment was not associated with improved MACCEs.

Evidence-based strategies for interdental cleaning: a practical decision tree and review of the literature.

Objectives: Although several studies have investigated the effectiveness of various interdental cleaning devices, there is a need for an evidence-based synopsis for clinicians to customize interdental hygiene instructions and provide specific devices for each patient. This literature review aims to establish an evidence-based decision-making tree recommending individualized approaches to interdental cleaning based on embrasure size and patient-specific conditions.
Data sources: Specific keywords related to interdental cleaning were used to search and identify the existing literature in PubMed and the Cochrane Library. Through a series of review processes, qualifying studies were identified and assessed with respect to the inclusion criteria to establish the decision tree.
Results: A total of 27 studies were included to support a decision tree. Traditional dental floss continues to remain the first choice for individuals of high motivation and good ?manual dexterity with type I closed embrasures. For individuals with closed embrasures, but lack of motivation and/or dexterity, the use of easy flossers, soft picks, oral irrigation, and small (0.6 to 0.7 mm) interdental brushes are alternatives. For individuals with type II and type III open embrasure spaces, an interdental brush has the highest evidence for its effectiveness to remove interdental plaque. However, two studies showed that residual plaque could be found over lingual embrasur?es and thus lingual approach of the interdental brush is sometimes needed. The use of gum stimulators and/or woodsticks continues to be supported when significant gingival inflammation is present.
Conclusion: Each patient should be individually assessed and given tailored oral hygiene home care instructions for the most effective outcomes. The proposed decision tree provides clinicians with an evidence-based guideline to help customize the use of interdental cleaning devices for each patient.

Transcutaneous Electrical Spinal Cord Neuromodulator (TESCoN) Improves Symptoms of Overactive Bladder.

Neuromodulation is a therapeutic technique that is well-established in the treatment of idiopathic Lower urinary tract (LUT) dysfunction such as overactive bladder (OAB). We have recently developed a novel neuromodulation approach, Transcutaneous Electrical Spinal Cord Neuromodulation (TESCoN) and demonstrated its acute effects on LUT dysfunction after spinal cord injury (SCI) during urodynamic studies. We found that TESCoN can promote urinary storage and induce urinary voiding when delivered during urodynamic studies. The objective of this study was to determine whether TESCoN can retrain the spinal neural networks to induce chronic improvement in the LUT, such that positive changes can persist even in the absence of stimulation. In addition, we wished to examine the effect of TESCoN on LUT dysfunction due to multiple pathologies. To achieve this objective, 14 patients [SCI = 5, stroke = 5, multiple sclerosis (MS) = 3, and idiopathic OAB (iOAB) = 1] completed 24 sessions of TESCoN over the course of 8 weeks. Patients completed urodynamic studies before and after undergoing TESCoN therapy. Additionally, each subject completed a voiding diary and the Neurogenic Bladder Symptom Score questionnaire before and after receiving TESCoN therapy. We found that TESCoN led to decreased detrusor overactivity, improved continence, and enhanced LUT sensation across the different pathologies underlying LUT dysfunction. This study serves as a pilot in preparation for a rigorous randomized placebo-controlled trial designed to demonstrate the effect of TESCoN on LUT function in neurogenic and non-neurogenic conditions. NEW AND NOTEWORTHY: Non-Surgical modality to reduce incidence of urinary incontinence and improve neurogenic bladder symptom scores (NBSS) in individuals with neurogenic bladder due to spinal cord injury or stroke.