Multiomic sequencing of paired primary and metastatic small bowel carcinoids.

Background: Small bowel carcinoids are insidious tumors that are often metastatic when diagnosed. Limited mutation landscape studies of carcinoids indicate that these tumors have a relatively low mutational burden. The development of targeted therapies will depend upon the identification of mutations that drive the pathogenesis and metastasis of carcinoid tumors. Methods: Whole exome and RNA sequencing of 5 matched sets of normal tissue, primary small intestine carcinoid tumors, and liver metastases were investigated. Germline and somatic variants included: single nucleotide variants (SNVs), insertions/deletions (indels), structural variants, and copy number alterations (CNAs). The functional impact of mutations was predicted using Ensembl Variant Effect Predictor. Results: Large-scale CNAs were observed including the loss of chromosome 18 in all 5 metastases and 3/5 primary tumors. Certain somatic SNVs were metastasis-specific; including mutations in ATRX, CDKN1B, MXRA5 (leading to the activation of a cryptic splice site and loss of mRNA), SMARCA2, and the loss of UBE4B. Additional mutations in ATRX, and splice site loss of PYGL, leading to intron retention observed in primary and metastatic tumors. Conclusions: We observed novel mutations in primary/metastatic carcinoid tumor pairs, and some have been observed in other types of neuroendocrine tumors. We confirmed a previously observed loss of chromosome 18 and CDKN1B. Transcriptome sequencing added relevant information that would not have been appreciated with DNA sequencing alone. The detection of several splicing mutations on the DNA level and their consequences at the RNA level suggests that RNA splicing aberrations may be an important mechanism underlying carcinoid tumors.

Transcriptome analysis provides critical answers to the "variants of uncertain significance" conundrum.

While whole-genome and exome sequencing have transformed our collective understanding of genetics' role in disease pathogenesis, there are certain conditions and populations for whom DNA-level data fails to identify the underlying genetic etiology. Specifically, patients of non-White race and non-European ancestry are disproportionately affected by "variants of unknown/uncertain significance" (VUS), limiting the scope of precision medicine for minority patients and perpetuating health disparities. VUS often include deep intronic and splicing variants which are difficult to interpret from DNA data alone. RNA analysis can illuminate the consequences of VUS, thereby allowing for their reclassification as pathogenic versus benign. Here we review the critical role transcriptome analysis plays in clarifying VUS in both neoplastic and non-neoplastic diseases.

The cost of preventing readmissions: why surgeons should lead the effort.

In accordance with the Affordable Care Act, Medicare has instituted financial penalties for hospitals with 30-day readmission rates that exceed a predetermined value. Currently, this value only considers "excess" readmissions for myocardial infarction, heart failure, and pneumonia with a maximum fine being one per cent of total Medicare reimbursements. In 2015, this penalty will increase to three per cent and encompass more surgical diagnoses. We retrospectively reviewed a database of adult patients undergoing cardiac surgery treated at our institution in 2012 to establish whether patients with readmissions within 30 days of the index operation could have been managed more cost-effectively without readmission. A calculation of cost efficiency was performed to compare the net hospital profit for two scenarios: admitting patients versus hypothetical preventative measures. Of the 576 patients during the study period, a total of 68 (11.8%) patients with unplanned 30-day readmissions were identified. Outpatient management was determined to have been feasible for 18 (26.5%) patients. Whereas the calculated net profit for readmission was $144,000, inclusion of Medicare's penalty resulted in a loss of $11,950. A readmission reduction program with an annual cost exceeding $11,950 would lead to financial loss. The financial implications of Medicare's readmission penalty alone necessitate the development of cost-effective strategies to reduce rehospitalization.

Introspection into institutional database allows for focused quality improvement plan in cardiac surgery: example for a new global healthcare system.

Reducing readmission rates is vital to improving quality of care and reducing healthcare costs. In accordance with the Patient Protection and Affordable Care Act, Medicare will cut payments to hospitals with high 30-day readmission rates. We retrospectively reviewed an institutional database to identify risk factors predisposing adult cardiac surgery patients to rehospitalization within 30 days of discharge. Of 2302 adult cardiac surgery patients within the study period from 2008 to 2011, a total of 218 patients (9.5%) were readmitted within 30 days. Factors found to be significant predictors of readmission were nonwhite race (P = 0.003), government health insurance (P = 0.02), ejection fraction less than 40 per cent (P = 0.001), chronic lung disease (P < 0.001), and hospital length of stay greater than 7 days (P = 0.02). Patients undergoing aortic and mitral valve operations had an increased risk of readmission compared with other cardiac operations (P < 0.001). The most common reasons for rehospitalization were pneumonia and other respiratory complications (n = 27 [12.4%]). Recognition of risk factors is crucial to reducing readmissions and improving patient care. Our data suggest that optimizing cardiopulmonary status in patients with comorbidities such as heart failure and chronic obstructive pulmonary disease, increasing directed pneumonia prophylaxis, patient education tailored to specific patient social needs, earlier patient follow-up, and better communication between inpatient and outpatient physicians may reduce readmission rates.