Impact of cancer therapy on clonal hematopoiesis mutations and subsequent clinical outcomes.

ABSTRACT: Exposure to cancer therapies is associated with an increased risk of clonal hematopoiesis (CH). The objective of our study was to investigate the genesis and evolution of CH after cancer therapy. In this prospective study, we undertook error-corrected duplex DNA sequencing in blood samples collected before and at 2 time points after chemoradiation in patients with esophageal or lung cancer recruited from 2013 to 2018. We applied a customized workflow to identify the earliest changes in CH mutation count and clone size and determine their association with clinical outcomes. Our study included 29 patients (87 samples). Their median age was 67 years, and 76% (n = 22) were male; the median follow-up period was 3.9 years. The most mutated genes were DNMT3A, TET2, TP53, and ASXL1. We observed a twofold increase in the number of mutations from before to after treatment in TP53, which differed from all other genes examined (P < .001). Among mutations detected before and after treatment, we observed an increased clone size in 38% and a decreased clone size in 5% of TP53 mutations (odds ratio, 3.7; 95% confidence interval [CI], 1.75-7.84; P < .001). Changes in mutation count and clone size were not observed in other genes. Individuals with an increase in the number of TP53 mutations after chemoradiation experienced shorter overall survival (hazard ratio, 7.07; 95% CI, 1.50-33.46; P = .014). In summary, we found an increase in the number and size of TP53 CH clones after chemoradiation that were associated with adverse clinical outcomes.

Causes of Clonal Hematopoiesis: a Review.

PURPOSE OF REVIEW: Clonal hematopoiesis (CH) is an age-dependent process detectable using advanced sequencing technologies and is associated with multiple adverse health outcomes including cardiovascular disease and cancer. The purpose of this review is to summarize known causes of CH mutations and to identify key areas and considerations for future research on CH. RECENT FINDINGS: Studies have identified multiple potential causes of CH mutations including smoking, cancer therapies, cardiometabolic disease, inflammation, and germline risk factors. Additionally, large-scale studies have facilitated the identification of gene-specific effects of CH mutation risk factors that may have unique downstream health implications. For example, cancer therapies and sources of environmental radiation appear to cause CH through their impact on DNA damage repair genes. There is a growing body of evidence defining risk factors for CH mutations. Standardization in the identification of CH mutations may have important implications for future research. Additional studies in underrepresented populations and their diverse environmental exposures are needed to facilitate broad public health impact of the study of CH mutations.

Comparison of somatic mutation landscapes in Chinese versus European breast cancer patients.

Recent genomic studies suggest that Asian breast cancer (BC) may have distinct somatic features; however, most comparisons of BC genomic features across populations did not account for differences in age, subtype, and sequencing methods. In this study, we analyzed whole-exome sequencing (WES) data to characterize somatic copy number alterations (SCNAs) and mutation profiles in 98 Hong Kong BC (HKBC) patients and compared with those from The Cancer Genome Atlas of European ancestry (TCGA-EA, N = 686), which had similar distributions of age at diagnosis and PAM50 subtypes as in HKBC. We developed a two-sample Poisson model to compare driver gene selection pressure, which reflects the effect sizes of cancer driver genes, while accounting for differences in sample size, sequencing platforms, depths, and mutation calling methods. We found that somatic mutation and SCNA profiles were overall very similar between HKBC and TCGA-EA. The selection pressure for small insertions and deletions (indels) in GATA3 (false discovery rate (FDR) corrected p < 0.01) and single-nucleotide variants (SNVs) in TP53 (nominal p = 0.02, FDR corrected p = 0.28) was lower in HKBC than in TCGA-EA. Among the 13 signatures of single-base substitutions (SBS) that are common in BC, we found a suggestively higher contribution of SBS18 and a lower contribution of SBS1 in HKBC than in TCGA-EA, while the two APOBEC-induced signatures showed similar prevalence. Our results suggest that the genomic landscape of BC was largely very similar between HKBC and TCGA-EA, despite suggestive differences in some driver genes and mutational signatures that warrant future investigations in large and diverse Asian populations.

Safety of robotic-assisted gynecologic surgery and early hospital discharge in elderly patients.

BACKGROUND: A minimally invasive surgical approach has proven to decrease peri- and postoperative complications and shorten duration of hospital stay; however, there are limited data evaluating the safety of robotic-assisted surgery and early hospital discharge in the elderly population. Because age is a well-known, independent risk factor for perioperative morbidity and gynecologists treat many elderly patients, this is an important area of study. OBJECTIVE: The objective of the study was to evaluate discharge timing and surgical outcomes in elderly compared with younger patients undergoing robotic-assisted gynecologic surgery. STUDY DESIGN: This was a retrospective cohort study of all patients who underwent robotic-assisted gynecologic surgery at a high-volume, single institution from January 2013 through May 2016. Demographic information, discharge timing, and peri- and postoperative outcomes were compared for patients <65 years with those ≥65 years using univariate and multivariate analyses. RESULTS: There were 2757 patients included, with 2521 <65 years and 236 ≥65 years. Median age of the younger group was 42 years, while the median age of the elderly group was 69 years. Elderly patients had a higher body mass index (kilograms per square meter) (28 vs 26, P < .001) and higher American Society of Anesthesia classification (P < .001). Elderly were more likely to have malignancy as the indication for surgery (68% vs 11%, P < .001) and to undergo hysterectomy (81% vs 38%, P < .001) or surgery with lymph node dissection (44.5% vs 7.1%, P < .001). Elderly patients had a higher incidence of intraoperative complications (9% vs 4.6%, P = .002) and longer median hospital stay (17 vs 7 hours, P < .001) compared with younger patients. Same-day discharge was more common in younger patients (76% vs 45%, P < .001), and elderly patients were more likely to have admissions lasting >23 hours (13% vs 3%, P < .001) on univariate and multivariate analysis. Analysis of postoperative outcomes included 2023 patients with available postoperative data (80% of total population) (1794 <65 years, 229 ≥ 65 years). There were no differences between elderly and younger patients in overall postoperative complications, reoperations, intensive care unit admissions, emergency room visits, or hospital readmission within 6 weeks of surgery. CONCLUSION: Despite having more preoperative risk factors and more surgically complex procedures, elderly patients undergoing robotic-assisted gynecologic surgery had similar postoperative complication rates, and almost half of elderly patients were safely discharged the day of surgery. Our data suggest that robotic-assisted gynecologic surgery and early hospital discharge are safe in elderly patients.

Plate Fixation versus Percutaneous Pinning for Unstable Metacarpal Fractures: A Meta-analysis.

BACKGROUND: Whether percutaneous pinning or plate fixation is more appropriate for metacarpal fractures is still open to debate. Our study purpose was to review the current literature in an attempt to determine the optimal treatment modality for metacarpal fractures on the basis of functional outcomes, radiographic outcome and rates of complications. METHODS: We selected Pubmed, Cochrane library, EMBASE and the relevant English orthopedic journals and pooled data from eligible trials including four comparative studies and one retrospective review. Overall, the studies contained 222 patients with 231 fractures, 143 treated with pinning and 88 treated with plates and screws. Mean follow up was 7.5 months (4-12 months). Data were analyzed and the fixed effects are assumed for meta-analysis. RESULTS: Patients undergoing pinning for metacarpal fractures have higher motion scores when compared to open reduction and internal fixation with plate and screws. Functional scores, grip strength, radiographic parameters, time to union and complications were found not to be significantly different between the two groups. CONCLUSIONS: There is evidence to support the use of pins over ORIF with plates and screws in the treatment of metacarpal fractures. This may have practical advantages, including minimal dissection, easier insertion and availability of the pins. The limitations of this study include the small number of eligible studies, lack of reporting of standard deviation value, and the lack of DASH score assessments at follow up. Further randomized controlled trials that include a larger patient numbers with longer follow up are needed to substantiate the superiority of one fixation method over another.

Association of Depression With 90-Day Hospital Readmission After Total Joint Arthroplasty.

BACKGROUND: Hospital readmission after total joint arthroplasty accounts for substantial resource consumption. Depression has been shown to impact postsurgical outcomes. We therefore aimed to study the association of depression with risk of readmission after total joint arthroplasty. METHODS: Retrospective cohort data from the population-based California Healthcare Cost and Utilization Project database from 2007 to 2010 were analyzed using multivariable logistic regression to predict odds of 90-day readmission after hospital discharge for primary total knee arthroplasty (TKA, n = 132,422) or total hip arthroplasty (THA, n = 65,071) arthroplasty in adults ages 50+ years. We included the primary exposure of depression and controlled for age, sex, race/ethnicity, Medicaid insurance, comorbidities, and admission year. RESULTS: Overall 90-day readmission rates were approximately 8% for TKA and THA. Even after controlling for other chronic conditions and nonmodifiable covariates, we found depression predicted higher likelihood of readmission. The odds of readmission for subjects with depression were 21%-24% higher overall (odds ratio for TKA: 1.21, 95% confidence interval: 1.13-1.29; odds ratio for THR: 1.24, 95% confidence interval: 1.13-1.35; P < .001). Subjects with surgery in earlier years were also more likely to be readmitted (P < .01). CONCLUSION: Depression is associated with a significantly higher risk of readmission after THA and TKA. Hospital readmissions must be minimized to improve care quality, while making these procedures fiscally feasible. Promoting care coordination across disciplines for management of nonorthopedic comorbidities before surgery, particularly in higher risk patients with depression, could optimize orthopedic surgery outcomes, patient well-being, and costs of care. Therefore, every effort to address depression before surgery is warranted.

Management of Modifiable Risk Factors Prior to Primary Hip and Knee Arthroplasty: A Readmission Risk Assessment Tool.

BACKGROUND: Preoperative risk stratification and optimization of preoperative care may be helpful in reducing readmission rates after primary total joint arthroplasty. Assessment of the predictive value of individual modifiable risk factors without a tool to assess cumulative risk may not provide proper risk stratification of patients with regard to potential readmissions. As part of a Perioperative Orthopaedic Surgical Home model, we developed a scoring system, the Readmission Risk Assessment Tool (RRAT), which allows for risk stratification in patients undergoing elective primary total joint arthroplasty at our institution. The purpose of this study was to analyze the relationship between the RRAT score and readmission after primary hip or knee arthroplasty. METHODS: The RRAT, which is scored incrementally on the basis of the number and severity of modifiable comorbidities, was used to generate readmission scores for a cohort of 207 readmitted patients and two cohorts (one random and one age-matched) of 234 non-readmitted patients each. Regression analysis was performed to assess the strength of association of individual risk factors and the RRAT score with readmissions. We also calculated the odds and odds ratio (OR) at each RRAT score level to identify patients with relatively higher risk of readmission. RESULTS: There were 207 (2.08%) readmissions among 9930 patients over a six-year period (2008 through 2013). Surgical site infection was the most common cause of readmission (ninety-three cases, 45%). The median RRAT scores were 3 (IQR [interquartile range], 1 to 4) and 1 (IQR, 0 to 2) for readmitted and non-readmitted groups, respectively. An RRAT score of ≥3 was significantly associated with higher odds of readmission. CONCLUSIONS: Population health management, cost-effective care, and optimization of outcomes to maximize value are the new maxims for health-care delivery in the United States. We found that the RRAT score had a significant association with readmission after joint arthroplasty and could potentially be a clinically useful tool for risk mitigation.

Comparative analysis of patients with cauda equina syndrome versus an unaffected population undergoing spinal surgery.

STUDY DESIGN: Retrospective analysis. OBJECTIVE: To determine patient demographics, incidence of comorbidities, and procedure-related complications and identify risk factors associated with morbidity and mortality after spinal surgery for cauda equina syndrome (CES). SUMMARY OF BACKGROUND DATA: To our knowledge, no study has provided nationwide estimates of patient characteristics and procedure-related complication rates after spinal surgery for CES relative to an unaffected population. METHODS: Nationwide Inpatient Sample data collected between 2001 and 2010 were analyzed. Discharges with procedural codes for lumbar spinal fusion, decompression, or discectomy were included. The CES cohort included diagnoses of CES, and the unaffected cohort included lumbar spinal pathology diagnoses. Patient demographics, incidence of comorbidities and procedure-related complications, and risk factors associated with morbidity and mortality were compared. RESULTS: Discharges for 11,207 CES and 689,799 unaffected patients were identified. Differences between cohorts were found for demographic and hospital data. Average comorbidity indices for the CES cohort were found to be increased (0.23 vs. 0.13, P < 0.0001), as well as the incidence of total procedure-related complications (18.63% vs. 13.12%, P < 0.0001). In-hospital mortality rate was significantly increased for the CES cohort (0.30% vs. 0.08%, P < 0.0001). A number of comorbidities associated with additional risk for morbidity and mortality among the CES cohort were identified. CONCLUSION: Relative to an unaffected population undergoing similar treatment, patients with CES were more likely to have increased associated comorbidities on presentation, as well as increased complication rates with a prolonged hospital course postoperatively. CES was found to carry an increased incidence of procedure-related complications as well as in-hospital mortality. A number of comorbidities associated with additional risk for morbidity and mortality among the CES cohort were identified. This study provides clinically useful data for surgeons to educate patients at risk for morbidity and mortality as well as direct future research to improve patient outcomes. LEVEL OF EVIDENCE: 3.