Adjuvant chemotherapy after D2 gastrectomy is standard for resectable locally advanced gastric cancer (LAGC) in Asia. Based on positive findings for perioperative chemotherapy in European phase III studies, the phase III PRODIGY study (ClinicalTrials.gov identifier NCT01515748) investigated whether neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 could improve outcomes versus standard treatment in Korean patients with resectable LAGC.
 
  Patients 20-75 years of age, with Eastern Cooperative Oncology Group performance status 0-1, and with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma (clinical TNM staging T2-3N+ or T4Nany) were randomly assigned to D2 surgery followed by adjuvant S-1 (40-60 mg orally twice a day, days 1-28 q6w for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m
  , oxaliplatin 100 mg/m
  intravenously day 1, S-1 40 mg/m
  orally twice a day, days 1-14 q3w for three cycles) before D2 surgery, followed by perioperative chemotherapy, is effective and tolerable in Korean patients with LAGC.Divisions of the genetic material and cytoplasm are coordinated spatially and temporally to ensure genome integrity. This coordination is mediated in part by the major cell cycle regulator cyclin-dependent kinase (Cdk1). Cdk1 activity peaks during mitosis, but during mitotic exit/cytokinesis Cdk1 activity is reduced, and phosphorylation of its substrates is reversed by various phosphatases including Cdc14, PP1, PP2A, and PP2B. Cdk1 is known to phosphorylate several components of the actin- and myosin-based cytokinetic ring (CR) that mediates division of yeast and animal cells. Here we show that Cdk1 also phosphorylates the Schizosaccharomyces pombe CR component paxillin Pxl1. We determined that both the Cdc14 phosphatase Clp1 and the PP1 phosphatase Dis2 contribute to Pxl1 dephosphorylation at mitotic exit, but PP2B/calcineurin does not. Preventing Pxl1 phosphorylation by Cdk1 results in increased Pxl1 levels, precocious Pxl1 recruitment to the division site, and increased duration of CR constriction. In vitro Cdk1-mediated phosphorylation of Pxl1 inhibits its interaction with the F-BAR domain of the cytokinetic scaffold Cdc15, thereby disrupting a major mechanism of Pxl1 recruitment.  https://www.selleckchem.com/products/bicuculline.html  Thus, Pxl1 is a novel substrate through which S. pombe Cdk1 and opposing phosphatases coordinate mitosis and cytokinesis.
  Tumor mutational profiling is increasingly performed in patients with advanced cancer. We determined the extent to which germline mutation profiling guides therapy selection in patients with advanced cancer.
 
  Patients with cancer undergoing tumor genomic profiling were prospectively consented for germline cancer predisposition gene analysis (2015-2019). In patients harboring germline likely pathogenic or pathogenic (LP/P) alterations, therapeutic actionability was classified using a precision oncology knowledge base. Patients with metastatic or recurrent cancer receiving germline genotype-directed therapy were determined.
 
  Among 11,947 patients across > 50 malignancies, 17% (n = 2,037) harbored a germline LP/P variant. By oncology knowledge base classification, 9% (n = 1042) had an LP/P variant in a gene with therapeutic implications (4% level 1; 4% level 3B; < 1% level 4). 
  variants accounted for 42% of therapeutically actionable findings, followed by 
  (13%), 
  (12%), mismatch repair genes (11cer analysis, 8% of patients with advanced cancer harbored a germline variant with therapeutic actionability with 40% of these patients receiving germline genotype-directed treatment. Germline sequence analysis is additive to tumor sequence analysis for therapy selection and should be considered for all patients with advanced cancer.This article highlights five knee injuries that, in the author's experience, are commonly overlooked by readers inexperienced in knee MRI ramp lesions, meniscocapsular tears, meniscal root ligament tears, posterior capsular ligament tears, and partial anterior cruciate ligament tear. While these injuries are readily apparent when the images are assessed for the given abnormality, the author's belief is that these may be overlooked because either the injury is not considered, or the affected area is not closely inspected. While these injuries may not alter immediate clinical management or require surgical intervention, they may, nevertheless, result in patient symptoms and may potentially increase the risk of further knee injury. Further, these injuries are difficult to recognize clinically and arthroscopically. In this review, we present these five injuries, emphasising relevant anatomy, normal MRI appearances, common injury patterns, and tips to avoid their being overlooked. Routine review of these areas when interpreting knee MRI, with additional imaging as necessary, will allow these injuries to be recognized more regularly.Background Gadobutrol and gadoterate are widely used macrocyclic gadolinium-based contrast agents. Given gadobutrol's higher T1 relaxivity, reduced gadobutrol dose should achieve essentially equivalent diagnostic efficacy as standard gadoterate dose. Objective To demonstrate that efficacy of 25%-reduced dose of gadobutrol (rd-gadobutrol) is non-inferior to 100%-standard-dose of gadoterate (sd-gadoterate) for contrast-enhanced MRI of the CNS. Methods In this international, prospective, multicenter, open-label, cross-over trial (LEADER-75), adult patients with known or suspected CNS pathology underwent contrast-enhanced brain MRI with sd-gadoterate (0.1 mmol/kg); if an enhancing lesion was identified, a second MRI with rd-gadobutrol (0.075 mmol/kg) was performed within 15 days. Three radiologists independently reviewed images to score three primary efficacy measures (subjective lesion enhancement, lesion border delineation, lesion internal morphology); primary non-inferiority analysis used readers' mean scores. using a narrow ±5% margin (p≤.025). Total lesions detected by mean reading was 301 for rd-gadobutrol versus 291 for sd-gadoterate. Mean confidence was 3.3±0.6 for rd-gadobutrol versus 3.3±0.6 for sd-gadoterate. Sensitivity (58.7%), specificity (91.8%), and accuracy (70.2%) for malignancy from majority reading were identical for rd-gadobutrol and sd-gadoterate. Reader preference was not different (95% CI [-0.10, 0.11]). Conclusion A 25%-reduced dose of gadobutrol is non-inferior to sd-gadoterate for contrast-enhanced brain MRI. Clinical Impact Use of rd-gadobutrol should be considered for brain MRI, particularly in patients undergoing multiple contrast-enhanced examinations.