ABSTRACT
PURPOSE: Geriatric Assessments (GAs) in older adults with cancer have informed treatment decision-making and refined survival prediction. However, little is known about the needs of older inpatients with cancer. Our objectives were to test the feasibility of a bedside GA, assess the prevalence of impairments in geriatric domains, determine how many were unknown to the medical team, and assess the impact of GA on patient care. METHODS: We conducted a cross-sectional observational single-centre pilot study. Structured GAs were performed on patients age 65+ admitted to the medical or radiation oncology inpatient wards at a tertiary care cancer centre. GA findings were shared with the patient's most responsible physician (MRP). RESULTS: 356 patients were screened, 39 were eligible and approached, and 37 were enrolled (recruitment rate 95%). Completion of the GA was possible in 92% of patients (34/37) and required a mean of 35â¯min. The mean number of geriatric domains impaired per patient was five (of seven assessed domains). The most common abnormal domains not known to the medical team were medication optimization (91%), cognition (90%), mood (69%), and social vulnerability (69%). MRPs responded to our survey for fifteen of thirty-three participants (45% response rate), and indicated that the GA results provided helpful information for patient management in 10 of 15 cases. CONCLUSION: Abnormal geriatric domains are common in older inpatients with cancer. Domains such as medication optimization, cognition, mood, and social vulnerability often go undetected and unaddressed. Identifying abnormal domains may improve the care of older inpatients with cancer.
Subject(s)
Affect , Cognition , Geriatric Assessment , Medication Adherence , Needs Assessment , Neoplasms/physiopathology , Neoplasms/psychology , Social Support , Academic Medical Centers , Activities of Daily Living , Aged , Aged, 80 and over , Cancer Care Facilities , Comorbidity , Cross-Sectional Studies , Fatigue/physiopathology , Female , Hospitalization , Humans , Inpatients , Male , Neoplasms/therapy , Oncology Service, Hospital , Pain/physiopathology , Patient Health Questionnaire , Physical Functional Performance , Pilot ProjectsABSTRACT
Aneuploidy is a characteristic feature of established cancers and can promote tumor development. Aneuploidy may arise directly, through unequal distribution of chromosomes into daughter cells, or indirectly, through a tetraploid intermediate. The polo family kinase Plk4/Sak is required for late mitotic progression and is haploinsufficient for tumor suppression in mice. Here we show that loss of heterozygosity (LOH) occurs at the Plk4 locus in 50% of human hepatocellular carcinomas (HCC) and is present even in preneoplastic cirrhotic liver nodules. LOH at Plk4 is associated with reduced Plk4 expression in HCC tumors but not with mutations in the remaining allele. Plk4(+/-) murine embryonic fibroblasts (MEFs) at early passage show a high incidence of multinucleation, supernumerary centrosomes, and a near-tetraploid karyotype. Underlying these phenotypes is a high rate of primary cytokinesis failure, associated with aberrant actomyosin ring formation, reduced RhoA activation, and failure to localize the RhoA guanine nucleotide exchange factor Ect2 to the spindle midbody. We further show that Plk4 normally localizes to the midbody and binds to and phosphorylates Ect2 in vitro. With serial passaging Plk4(+/-) MEFs rapidly immortalize, acquiring an increasing burden of nonclonal and clonal gross chromosomal irregularities, and form tumors in vivo. Our results indicate that haploid levels of Plk4 disrupt RhoGTPase function during cytokinesis, resulting in aneuploidy and tumorigenesis, thus implicating early LOH at Plk4 as one of the drivers of human hepatocellular carcinogenesis. These findings represent an advance in our understanding of genetic predisposition to HCC, which continues to increase in incidence globally and particularly in North America.
Subject(s)
Chromosomal Instability , Gene Expression Regulation , Protein Serine-Threonine Kinases/metabolism , Alleles , Animals , Cell Line, Tumor , Cytokinesis , Fibroblasts/metabolism , Humans , Mice , Mice, SCID , Mitosis , Models, Biological , Phosphorylation , Protein Serine-Threonine Kinases/physiologyABSTRACT
The bHLH transcription factor Hand1 is essential for placentation and cardiac morphogenesis in the developing embryo. Here we implicate Hand1 as a molecular switch that determines whether a trophoblast stem cell continues to proliferate or commits to differentiation. We identify a novel interaction of Hand1 with a protein that contains an I-mfa (inhibitor of myogenic factor) domain that anchors Hand1 in the nucleolus where it negatively regulates Hand1 activity. In the trophoblast stem-cell line Rcho-1, nucleolar sequestration of Hand1 accompanies sustained cell proliferation and renewal, whereas release of Hand1 into the nucleus leads to its activation, thus committing cells to a differentiated giant-cell fate. Site-specific phosphorylation is required for nucleolar release of Hand1, for its dimerization and biological function, and this is mediated by the non-canonical polo-like kinase Plk4 (Sak). Sak is co-expressed in Rcho-1 cells, localizes to the nucleolus during G2 and phosphorylates Hand1 as a requirement for trophoblast stem-cell commitment to a giant-cell fate. This study defines a novel cellular mechanism for regulating Hand1 that is a crucial step in the stem-cell differentiation pathway.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Cell Differentiation , Cell Nucleolus/metabolism , Stem Cells/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/physiology , Blotting, Northern , Blotting, Western , Cell Proliferation , Gene Expression Regulation, Developmental , Giant Cells/cytology , Giant Cells/metabolism , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Immunoprecipitation , Mice , Myogenic Regulatory Factors/metabolism , NIH 3T3 Cells , Phosphorylation , Protein Binding , Protein Phosphatase 2 , Protein Serine-Threonine Kinases/metabolism , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Stem Cells/cytology , Trophoblasts/cytology , Trophoblasts/metabolism , Two-Hybrid System TechniquesABSTRACT
The polo-like kinase Plk4 (also called Sak) is required for late mitotic progression, cell survival and postgastrulation embryonic development. Here we identified a phenotype resulting from Plk4 haploinsufficiency in Plk4 heterozygous cells and mice. Plk4+/- embryonic fibroblasts had increased centrosomal amplification, multipolar spindle formation and aneuploidy compared with wild-type cells. The incidence of spontaneous liver and lung cancers was approximately 15 times high in elderly Plk4+/- mice than in Plk4+/+ littermates. Using the in vivo model of partial hepatectomy to induce synchronous cell cycle entry, we determined that the precise regulation of cyclins D1, E and B1 and of Cdk1 was impaired in Plk4+/- regenerating liver, and p53 activation and p21 and BubR1 expression were suppressed. These defects were associated with progressive cell cycle delays, increased spindle irregularities and accelerated hepatocellular carcinogenesis in Plk4+/- mice. Loss of heterozygosity occurs frequently (approximately 60%) at polymorphic markers adjacent to the PLK4 locus in human hepatoma. Reduced Plk4 gene dosage increases the probability of mitotic errors and cancer development.
