Screening for hepatocellular carcinoma in patients with hepatitis C virus infection

There is no evidence that it is beneficial to screen for hepatocellular carcinoma in symptomatic patients with HCV. (Strength of Recommendation [SOR]: C, based on a systematic review and case series studies.) Neither serum AFP measurement nor imaging is an ideal screening test. Patients can be screened for hepatocellular carcinoma using AFP measurement or ultrasonography; these tests have similar sensitivity and specificity. Computed tomography and magnetic resonance imaging offer increased screening sensitivity, but may be limited by cost and availability. (SOR: C, based on retrospective case series.) Combined testing with AFP measurement and ultrasonography improves sensitivity but decreases specificity

Genomic Imprinting and Epigenetic Control of Development

Epigenetic mechanisms are extensively utilized during mammalian development. Specific patterns of gene expression are established during cell fate decisions, maintained as differentiation progresses, and often augmented as more specialized cell types are required. Much of what is known about these mechanisms comes from the study of two distinct epigenetic phenomena: genomic imprinting and X-chromosome inactivation. In the case of genomic imprinting, alleles are expressed in a parent-of-origin-dependent manner, whereas X-chromosome inactivation in females requires that only one X chromosome is active in each somatic nucleus. As model systems for epigenetic regulation, genomic imprinting and X-chromosome inactivation have identified and elucidated the numerous regulatory mechanisms that function throughout the genome during development

An essential role for a mammalian SWI/SNF chromatin-remodeling complex during male meiosis

Germ cell development and gametogenesis require genome-wide transitions in epigenetic modifications and chromatin structure. These changes include covalent modifications to the DNA and histones as well as remodeling activities. Here, we explore the role of the mammalian SWI/SNF chromatin-remodeling complex during spermatogenesis using a conditional allele of the ATPase subunit, brahma-related gene 1 (Brg1, or Smarca4). Not only do BRG1 levels peak during the early stages of meiosis, genetic ablation of Brg1 in murine embryonic gonocytes results in arrest during prophase of meiosis I. Coincident with the timing of meiotic arrest, mutant spermatocytes accumulate unrepaired DNA and fail to complete synapsis. Furthermore, mutant spermatocytes show global alterations to histone modifications and chromatin structure indicative of a more heterochromatic genome. Together, these data demonstrate a requirement for BRG1 activity in spermatogenesis, and suggest a role for the mammalian SWI/SNF complex in programmed recombination and repair events that take place during meiosis

Genetic Tests To Evaluate Prognosis and Predict Therapeutic Response in Acute Myeloid Leukemia

Management of patients with acute myeloid leukemia relies on genetic tests that inform diagnosis and prognosis, predict response to therapy, and measure minimal residual disease. The value of genetics is reinforced in the revised 2008 World Health Organization acute myeloid leukemia classification scheme. The various analytic procedures—karyotype, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, DNA sequencing, and microarray technology—each have advantages in certain clinical settings, and understanding their relative merits assists in specimen allocation and in effective utilization of health care resources. Karyotype and array technology represent genome-wide screens, whereas the other methods target specific prognostic features such as t(15;17) PML-RARA, t(8;21) RUNX1-RUNX1T1, inv(16) CBFB-MYH11, 11q23 MLL rearrangement, FLT3 internal tandem duplication, or NPM1 mutation. New biomarkers and pharmacogenetic tests are emerging. The pathologist's expertise is critical in 1) consulting with clinicians about test selection as well as specimen collection and handling; 2) allocating tissue for immediate testing and preserving the remaining specimen for any downstream testing that is indicated once morphology and other pertinent test results are known; 3) performing tests that maximize outcome based on the strengths and limitations of each assay in each available specimen type; and 4) interpreting and conveying results to the rest of the health care team in a format that facilitates clinical management. Acute myeloid leukemia leads the way for modern molecular medicine

Aligning Medical Student Curriculum with Practice Quality Goals: Impacts on Quality Metrics and Practice Capacity for Students

The practice of medicine occurs primarily in the ambulatory environment where providers have many competing demands, including health record documentation and patient volume expectations. Subsequently, medical student education has not been a priority for providers, health systems, or community practices. Yet, accrediting and professional organizations, such as the Association of American Medical Colleges, American Academy of Family Physicians, Ambulatory Pediatric Association, Society of General Internal Medicine, and the Liaison Committee on Medical Education, recommend education in ambulatory settings

The role of telepathology in improving cancer diagnostic and research capacity in sub-Saharan Africa

Non-communicable disease (NCD), including cancer, disproportionately affect Low- and Middle-Income Countries (LMICs). This inequity is in part due to limitations of pathology services, both human and infrastructural. While significant improvements have been made to address these gaps, creative approaches that are mindful of regional priorities, cultural differences, and unique local challenges are needed. In this perspective, we will describe the implementation of telepathology services in sub-Saharan Africa (SSA) that serve as cornerstones for direct patient care, multi-disciplinary care coordination, research programs, and building human capacity through training. Models and challenges of system implementation, sustainability, and pathologist engagement will be discussed. Using disease and site-specific examples, we will suggest metrics for quality control and improvement initiatives that are critical for providing high-quality cancer registry data and necessary for future implementation of therapeutic and interventional clinical trials

Students Adding Value: Improving Patient Care Measures While Learning Valuable Population Health Skills

Medical students are potential resources for ambulatory primary care practices if learning goals can align with clinical needs. The authors introduced a quality improvement (QI) curriculum in the ambulatory clinical rotation that matched student learning expectations with practice needs. In 2016-2017, 128 students were assigned to academic, university affiliated, community health, and private practices. Student project measures were matched with appropriate outcome measures on monthly practice dashboards. Binomial mixed effects models were used to model QI measures. For university collaborative practices with student involvement, the estimated odds of a patient being screened for breast cancer in March 2017 was approximately 2 times greater than in 2016. This odds ratio was 36.2% greater than the comparable odds ratio for collaborative practices without student involvement (95% confidence interval = 22.7% to 51.2% greater). When student curriculum and assignments align with practice needs, practice metrics improve and students contribute to improvements in real-world settings

Repression of the soma-specific transcriptome by Polycomb-repressive complex 2 promotes male germ cell development

Polycomb-repressive complex 2 (PRC2) catalyzes the methylation of histone H3 Lys27 (H3K27) and functions as a critical epigenetic regulator of both stem cell pluripotency and somatic differentiation, but its role in male germ cell development is unknown. Using conditional mutagenesis to remove the core PRC2 subunits EED and SUZ12 during male germ cell development, we identified a requirement for PRC2 in both mitotic and meiotic germ cells. We observed a paucity of mutant spermatogonial stem cells (SSCs), which appears independent of repression of the known cell cycle inhibitors Ink4a/Ink4b/Arf. Moreover, mutant spermatocytes exhibited ectopic expression of somatic lamins and an abnormal distribution of SUN1 proteins on the nuclear envelope. These defects were coincident with abnormal chromosome dynamics, affecting homologous chromosome pairing and synapsis. We observed acquisition of H3K27me3 on stage-specific genes during meiotic progression, indicating a requirement for PRC2 in regulating the meiotic transcriptional program. Together, these data demonstrate that transcriptional repression of soma-specific genes by PRC2 facilitates homeostasis and differentiation during mammalian spermatogenesis

Identifying transcriptional profiles and evaluating prognostic biomarkers of HIV-associated diffuse large B-cell lymphoma from Malawi

Lymphoma incidence in sub-Saharan Africa (SSA) is increasing due to HIV and population aging. Diffuse Large B-cell lymphoma (DLBCL), the most common lymphoma in SSA and worldwide, is highly associated with HIV, but molecular studies of HIV-associated DLBCL are scarce globally. We describe profiling of DLBCL from Malawi, aiming to elucidate tumor biology and identify clinically meaningful biomarkers specifically for SSA. Between June 1, 2013 and June 1, 2016, 59 cases of DLBCL (32 HIV+/27 HIV−) enrolled in the Kamuzu Central Hospital Lymphoma Study were characterized, of which 54 (92%) were negative for Epstein–Barr virus. Gene expression profiling (GEP) by whole transcriptome sequencing was performed on the first 36 cases (22 HIV+/14 HIV−). Immunohistochemistry (IHC) and GEP results were compared with published data and correlated to clinical outcome and pathologic features. Unsupervised clustering strongly segregated DLBCL by HIV status (p = 0.0003, Chi-squared test), indicating a marked contribution of HIV to expression phenotype. Pathway analysis identified that HIV-associated tumors were enriched in hypoxia, oxidative stress, and metabolism related gene expression patterns. Cell-of-origin subtype, determined by sequencing and IHC, did not associate with differences in overall survival (OS), while Ki-67 proliferation index ≥80% was associated with inferior OS in HIV+ DLBCL only (p = 0.03) and cMYC/BCL2 co-expression by IHC was negatively prognostic across the entire cohort (p = 0.01). This study provides among the first molecular characterizations of DLBCL from SSA, demonstrates marked gene expression differences by HIV status, and identifies genomic and immunophenotypic characteristics that can inform future basic and clinical investigations

Differentiation-Driven Nucleolar Association of the Mouse Imprinted Kcnq1 Locus

The organization of the genome within the mammalian nucleus is nonrandom, with physiologic processes often concentrated in specific three-dimensional domains. This organization may be functionally related to gene regulation and, as such, may play a role in normal development and human disease processes. However, the mechanisms that participate in nuclear organization are poorly understood. Here, we present data characterizing localization of the imprinted Kcnq1 alleles. We show that nucleolar association of the paternal allele (1) is stimulated during the differentiation of trophoblast stem cells, (ii) is dependent upon the Kcnq1ot1 noncoding RNA, (3) does not require polycomb repressive complex 2, and (4) is not sufficient to preclude transcription of imprinted genes. Although nucleolar positioning has been proposed as a mechanism to related to gene silencing, we find that silencing and perinucleolar localization through the Kcnq1ot1 noncoding RNA are separable events