Assessing the Complex General Surgical Oncology Pipeline: Trends in Race and Ethnicity Among US Medical Students, General Surgery Residents, and Complex General Surgical Oncology Trainees.

BACKGROUND: Cancer incidence is expected to increase in coming decades, disproportionately so among minoritized communities. Racially and ethnically concordant care is essential to addressing disparities in cancer outcomes within at-risk groups. Here, we assess trends in racial and ethnic representation of medical students (MS), general surgery (GS) residents, and complex general surgical oncology (CGSO) fellows. METHODS: This is a retrospective review of data from the American Association of Medical Colleges and the Accreditation Council of Medical Education (ACGME) from 2015 to 2020. Self-reported race and ethnicity was obtained for MS, GS, and CGSO trainees. Race and ethnicity proportions were compared with respective representation in the 2020 US Census. Mann-Kendall, Wilcoxon rank sum, and linear regression were used to assess trends, as appropriate. RESULTS: A total of 316,448 MS applicants, 128,729 MS matriculants, 27,574 GS applicants, 46,927 active GS residents, 710 CGSO applicants, and 659 active CGSO fellows were included. With every progressive stage in training, there was a smaller proportion of URM active trainees than applicants. Further, URM, Hispanic/Latino, and Black/African American trainees were significantly underrepresented compared with 2020 Census data. While the proportion of White CGSO fellows increased over time (54.5-69.2%, p = 0.009), the proportion of Black/African American and Hispanic/Latino (URM) CGSO fellows did not significantly change over the study period, though URM representation was lower in 2020 as compared with 2015. DISCUSSION: From 2015 to 2020, minority representation decreased at every advancing stage in surgical oncology training. Efforts to address barriers for URM applicants to CGSO fellowships are needed.

A cost-effectiveness analysis of surgical care delivery in Eastern Uganda-a societal perspective.

BACKGROUND: The mismatch between the global burden of surgical disease and global health funding for surgical illness exacerbates disparities in surgical care access worldwide. Amidst competing priorities, governments need to rationally allocate scarce resources to address local needs. To build an investment case for surgery, economic data on surgical care delivery is needed. This study focuses on femur fractures. METHODS: This prospective cohort study at Soroti Regional Referral Hospital (SRRH), captured demographic, clinical, and cost data from all surgical inpatients and their caregivers at SRRH from February 2018 through July 2019. We performed descriptive and inferential analyses. We estimated the cost effectiveness of intramedullary nailing relative to traction for femur fractures by using primary data and making extrapolations using regional data. RESULTS: Among the 546 patients, 111 (20.3%) had femur fractures and their median [IQR] length of hospitalization was 27 days [14, 36 days]. The total societal cost and Quality Adjusted Life Year (QALY) gained was USD 61,748.10 and 78.81 for femur traction and USD 23,809 and 85.47 for intramedullary nailing. Intramedullary nailing was dominant over traction of femur fractures with an Incremental Cost Effectiveness Ratio of USD 5,681.75 per QALY gained. CONCLUSION: Femur fractures are the most prevalent and most expensive surgical condition at SRRH. Relative to intramedullary nailing, the use of femur traction at SRRH is not cost effective. There is a need to explore and adopt more cost-effective approaches like internal fixation.

The societal cost and economic impact of surgical care on patients' households in rural Uganda; a mixed method study.

BACKGROUND: The epidemiology and cost of surgical care delivery in low-and middle-income countries (LMICs) is poorly understood. This study characterizes the cost of surgical care, rate of catastrophic medical expenditure and medical impoverishment, and impact of surgical hospitalization on patients' households at Soroti Regional Referral Hospital (SRRH), Uganda. METHODS: We prospectively collected demographic, clinical, and cost data from all surgical inpatients and caregivers at SRRH between February 2018 and January 2019. We conducted and thematically analyzed qualitative interviews to discern the impact of hospitalization on patients' households. We employed the chi-square, t-test, ANOVA, and Bonferroni tests and built regression models to identify predictors of societal cost of surgical care. Out of pocket spending (OOPS) and catastrophic expenses were determined. RESULTS: We encountered 546 patients, mostly male (62%) peasant farmers (42%), at a median age of 22 years; and 615 caregivers, typically married (87%), female (69%), at a median age of 35 years. Femur fractures (20.4%), soft tissue infections (12.3%), and non-femur fractures (11.9%) were commonest. The total societal cost of surgical care was USD 147,378 with femur fractures (USD 47,879), intestinal obstruction (USD 18,737) and non-femur fractures (USD 10,212) as the leading contributors. Procedures (40%) and supplies (12%) were the largest components of societal cost. About 29% of patients suffered catastrophic expenses and 31% were medically impoverished. CONCLUSION: Despite free care, surgical conditions cause catastrophic expenses and impoverishment in Uganda. Femur fracture is the most expensive surgical condition due to prolonged hospitalization associated with traction immobilization and lack of treatment modalities with shorter hospitalization.

Co-evolution of tumor and immune cells during progression of multiple myeloma.

Multiple myeloma (MM) is characterized by the uncontrolled proliferation of plasma cells. Despite recent treatment advances, it is still incurable as disease progression is not fully understood. To investigate MM and its immune environment, we apply single cell RNA and linked-read whole genome sequencing to profile 29 longitudinal samples at different disease stages from 14 patients. Here, we collect 17,267 plasma cells and 57,719 immune cells, discovering patient-specific plasma cell profiles and immune cell expression changes. Patients with the same genetic alterations tend to have both plasma cells and immune cells clustered together. By integrating bulk genomics and single cell mapping, we track plasma cell subpopulations across disease stages and find three patterns: stability (from precancer to diagnosis), and gain or loss (from diagnosis to relapse). In multiple patients, we detect "B cell-featured" plasma cell subpopulations that cluster closely with B cells, implicating their cell of origin. We validate AP-1 complex differential expression (JUN and FOS) in plasma cell subpopulations using CyTOF-based protein assays, and integrated analysis of single-cell RNA and CyTOF data reveals AP-1 downstream targets (IL6 and IL1B) potentially leading to inflammation regulation. Our work represents a longitudinal investigation for tumor and microenvironment during MM progression and paves the way for expanding treatment options.

Discovery of driver non-coding splice-site-creating mutations in cancer.

Non-coding mutations can create splice sites, however the true extent of how such somatic non-coding mutations affect RNA splicing are largely unexplored. Here we use the MiSplice pipeline to analyze 783 cancer cases with WGS data and 9494 cases with WES data, discovering 562 non-coding mutations that lead to splicing alterations. Notably, most of these mutations create new exons. Introns associated with new exon creation are significantly larger than the genome-wide average intron size. We find that some mutation-induced splicing alterations are located in genes important in tumorigenesis (ATRX, BCOR, CDKN2B, MAP3K1, MAP3K4, MDM2, SMAD4, STK11, TP53 etc.), often leading to truncated proteins and affecting gene expression. The pattern emerging from these exon-creating mutations suggests that splice sites created by non-coding mutations interact with pre-existing potential splice sites that originally lacked a suitable splicing pair to induce new exon formation. Our study suggests the importance of investigating biological and clinical consequences of noncoding splice-inducing mutations that were previously neglected by conventional annotation pipelines. MiSplice will be useful for automatically annotating the splicing impact of coding and non-coding mutations in future large-scale analyses.

Evolution and structure of clinically relevant gene fusions in multiple myeloma.

Multiple myeloma is a plasma cell blood cancer with frequent chromosomal translocations leading to gene fusions. To determine the clinical relevance of fusion events, we detect gene fusions from a cohort of 742 patients from the Multiple Myeloma Research Foundation CoMMpass Study. Patients with multiple clinic visits enable us to track tumor and fusion evolution, and cases with matching peripheral blood and bone marrow samples allow us to evaluate the concordance of fusion calls in patients with high tumor burden. We examine the joint upregulation of WHSC1 and FGFR3 in samples with t(4;14)-related fusions, and we illustrate a method for detecting fusions from single cell RNA-seq. We report fusions at MYC and a neighboring gene, PVT1, which are related to MYC translocations and associated with divergent progression-free survival patterns. Finally, we find that 4% of patients may be eligible for targeted fusion therapies, including three with an NTRK1 fusion.

Comprehensive molecular characterization of mitochondrial genomes in human cancers.

Mitochondria are essential cellular organelles that play critical roles in cancer. Here, as part of the International Cancer Genome Consortium/The Cancer Genome Atlas Pan-Cancer Analysis of Whole Genomes Consortium, which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we performed a multidimensional, integrated characterization of mitochondrial genomes and related RNA sequencing data. Our analysis presents the most definitive mutational landscape of mitochondrial genomes and identifies several hypermutated cases. Truncating mutations are markedly enriched in kidney, colorectal and thyroid cancers, suggesting oncogenic effects with the activation of signaling pathways. We find frequent somatic nuclear transfers of mitochondrial DNA, some of which disrupt therapeutic target genes. Mitochondrial copy number varies greatly within and across cancers and correlates with clinical variables. Co-expression analysis highlights the function of mitochondrial genes in oxidative phosphorylation, DNA repair and the cell cycle, and shows their connections with clinically actionable genes. Our study lays a foundation for translating mitochondrial biology into clinical applications.

Mass Spectrometry-Based Proteomics Reveals Potential Roles of NEK9 and MAP2K4 in Resistance to PI3K Inhibition in Triple-Negative Breast Cancers.

Activation of PI3K signaling is frequently observed in triple-negative breast cancer (TNBC), yet PI3K inhibitors have shown limited clinical activity. To investigate intrinsic and adaptive mechanisms of resistance, we analyzed a panel of patient-derived xenograft models of TNBC with varying responsiveness to buparlisib, a pan-PI3K inhibitor. In a subset of patient-derived xenografts, resistance was associated with incomplete inhibition of PI3K signaling and upregulated MAPK/MEK signaling in response to buparlisib. Outlier phosphoproteome and kinome analyses identified novel candidates functionally important to buparlisib resistance, including NEK9 and MAP2K4. Knockdown of NEK9 or MAP2K4 reduced both baseline and feedback MAPK/MEK signaling and showed synthetic lethality with buparlisib in vitro A complex in/del frameshift in PIK3CA decreased sensitivity to buparlisib via NEK9/MAP2K4-dependent mechanisms. In summary, our study supports a role for NEK9 and MAP2K4 in mediating buparlisib resistance and demonstrates the value of unbiased omic analyses in uncovering resistance mechanisms to targeted therapy.Significance: Integrative phosphoproteogenomic analysis is used to determine intrinsic resistance mechanisms of triple-negative breast tumors to PI3K inhibition. Cancer Res; 78(10); 2732-46. ©2018 AACR.

GenomeVIP: a cloud platform for genomic variant discovery and interpretation.

Identifying genomic variants is a fundamental first step toward the understanding of the role of inherited and acquired variation in disease. The accelerating growth in the corpus of sequencing data that underpins such analysis is making the data-download bottleneck more evident, placing substantial burdens on the research community to keep pace. As a result, the search for alternative approaches to the traditional "download and analyze" paradigm on local computing resources has led to a rapidly growing demand for cloud-computing solutions for genomics analysis. Here, we introduce the Genome Variant Investigation Platform (GenomeVIP), an open-source framework for performing genomics variant discovery and annotation using cloud- or local high-performance computing infrastructure. GenomeVIP orchestrates the analysis of whole-genome and exome sequence data using a set of robust and popular task-specific tools, including VarScan, GATK, Pindel, BreakDancer, Strelka, and Genome STRiP, through a web interface. GenomeVIP has been used for genomic analysis in large-data projects such as the TCGA PanCanAtlas and in other projects, such as the ICGC Pilots, CPTAC, ICGC-TCGA DREAM Challenges, and the 1000 Genomes SV Project. Here, we demonstrate GenomeVIP's ability to provide high-confidence annotated somatic, germline, and de novo variants of potential biological significance using publicly available data sets.

Proteogenomic integration reveals therapeutic targets in breast cancer xenografts.

Recent advances in mass spectrometry (MS) have enabled extensive analysis of cancer proteomes. Here, we employed quantitative proteomics to profile protein expression across 24 breast cancer patient-derived xenograft (PDX) models. Integrated proteogenomic analysis shows positive correlation between expression measurements from transcriptomic and proteomic analyses; further, gene expression-based intrinsic subtypes are largely re-capitulated using non-stromal protein markers. Proteogenomic analysis also validates a number of predicted genomic targets in multiple receptor tyrosine kinases. However, several protein/phosphoprotein events such as overexpression of AKT proteins and ARAF, BRAF, HSP90AB1 phosphosites are not readily explainable by genomic analysis, suggesting that druggable translational and/or post-translational regulatory events may be uniquely diagnosed by MS. Drug treatment experiments targeting HER2 and components of the PI3K pathway supported proteogenomic response predictions in seven xenograft models. Our study demonstrates that MS-based proteomics can identify therapeutic targets and highlights the potential of PDX drug response evaluation to annotate MS-based pathway activities.