Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix.

High-grade neuroendocrine cervical cancers (NETc) are exceedingly rare, highly aggressive tumors. We analyzed 64 NETc tumor samples by whole-exome sequencing (WES). Human papillomavirus DNA was detected in 65.6% (42/64) of the tumors. Recurrent mutations were identified in PIK3CA, KMT2D/MLL2, K-RAS, ARID1A, NOTCH2, and RPL10. The top mutated genes included RB1, ARID1A, PTEN, KMT2D/MLL2, and WDFY3, a gene not yet implicated in NETc. Somatic CNV analysis identified two copy number gains (3q27.1 and 19q13.12) and five copy number losses (1p36.21/5q31.3/6p22.2/9q21.11/11p15.5). Also, gene fusions affecting the ACLY-CRHR1 and PVT1-MYC genes were identified in one of the eight samples subjected to RNA sequencing. To resolve evolutionary history, multiregion WES in NETc admixed with adenocarcinoma cells was performed (i.e., mixed-NETc). Phylogenetic analysis of mixed-NETc demonstrated that adenocarcinoma and neuroendocrine elements derive from a common precursor with mutations typical of adenocarcinomas. Over one-third (22/64) of NETc demonstrated a mutator phenotype of C > T at CpG consistent with deficiencies in MBD4, a member of the base excision repair (BER) pathway. Mutations in the PI3K/AMPK pathways were identified in 49/64 samples. We used two patient-derived-xenografts (PDX) (i.e., NET19 and NET21) to evaluate the activity of pan-HER (afatinib), PIK3CA (copanlisib), and ATR (elimusertib) inhibitors, alone and in combination. PDXs harboring alterations in the ERBB2/PI3K/AKT/mTOR/ATR pathway were sensitive to afatinib, copanlisib, and elimusertib (P < 0.001 vs. controls). However, combinations of copanlisib/afatinib and copanlisib/elimusertib were significantly more effective in controlling NETc tumor growth. These findings define the genetic landscape of NETc and suggest that a large subset of these highly lethal malignancies might benefit from existing targeted therapies.

Hospital-Wide Adherence to Postsurgical Opioid Prescribing Guidelines: A Retrospective Cohort Study.

INTRODUCTION: Lowering opioid prescription doses and quantity decreases the risk of chronic opioid usage. A tool was inserted into the brief operative note for the surgeon to assess the severity of pain associated with the procedure. We studied surgeon adherence to current opioid-prescribing recommendations. METHODS: Retrospective cohort study with 5486 patients were included in the study population. Each patient's prescription was scored yes or no for adherence on total morphine milligram equivalents (MMEs) and days prescribed with the selection in the brief operative note. The entire study population was tested for an increase from the null-hypothesis "benchmark" value of 75% using a one-sided exact binomial test of a single proportion with P < 0.05. This procedure was repeated for subgroups, with P < 0.01. RESULTS: Adherence to guidelines was higher than the 75% benchmark for "total MMEs prescribed" (79.5%; P < 0.001), but lower for "number of days prescribed" (63.5%; P > 0.999). Surgeries with severe predicted pain showed the highest adherence toward total MMEs prescribed at 87.1%, followed by moderate (80.5%) and mild (74.5%). Severe cases also showed the highest adherence in number of days prescribed (92.4%). Adherence to total MMEs prescribed was highest among attending physicians (88.1%) and lowest among residents/fellows (76.6%). CONCLUSIONS: Adherence to current guidelines was 79.5% for MMEs prescribed but only 63.5% for days prescribed. Compliance with guidelines was better for severe procedures than mild or moderate. Differences were seen across surgical departments. While an improvement from previous reports, further improvement is needed to reduce the number of days of opioids prescribed and increase compliance with recommended guidelines.

Correlation of fetal heart rate dynamics to inflammatory markers and brain-derived neurotrophic factor during pregnancy.

OBJECTIVES: This study aims to show the relation between biomarkers in maternal and cord-blood samples and fetal heart rate variability (fHRV) metrics through a non-invasive fetal magnetocardiography (fMCG) technique. METHODS: Twenty-three women were enrolled for collection of maternal serum and fMCG tracings immediately prior to their scheduled cesarean delivery. The umbilical cord blood was collected for measurement of biomarker levels. The fMCG metrics were then correlated to the biomarker levels from the maternal serum and cord blood. RESULTS: Brain-derived neurotrophic factor (BDNF) had a moderate correlation with fetal parasympathetic activity (0.416) and fetal sympathovagal ratios (-0.309; -0.356). Interleukin (IL)-6 also had moderate-sized correlations but with an inverse relationship as compared to BDNF. These correlations were primarily in cord-blood samples and not in the maternal blood. CONCLUSIONS: In this small sample-sized exploratory study, we observed a moderate correlation between fHRV and cord-blood BDNF and IL-6 immediately preceding scheduled cesarean delivery at term. These findings need to be validated in a larger population.

Using focused ethnography to inform biomedical research infrastructure enhancement at primarily undergraduate institutions.

The National Institutes of Health (NIH) supports 24 IDeA Networks of Biomedical Research Excellence (INBRE) Programs that help develop university-based biomedical research capacity in states that historically receive low levels of extramural grant support. To assess the effectiveness of the Arkansas INBRE in meeting its biomedical research capacity-building goals, we evaluated how the context (i.e., local and institutional settings) at two undergraduate institutions impacted variability in science faculty use of program resources. Data were collected by in-depth interviews with faculty and administrators (N = 9), focused observations, a review of Arkansas INBRE databases, and internet searches. Content analysis was used to code interview transcripts and field notes, and then qualitative data were integrated with data from databases and internet searches to construct two institutional case summaries. Constant comparison was used to identify similarities and differences between the institutions that helped to explain variability in how frequently faculty used Arkansas INBRE resources, including an enrollment crisis at undergraduate institutions in the United States and the presence or absence of a robust research culture at each institution. These findings were used to suggest program improvements (e.g., classroom-based research) that could further strengthen biomedical research capacity in Arkansas. As some barriers to program effectiveness are likely found in other IDeA-eligible states, improvements suggested for the Arkansas INBRE could apply to INBRE programs elsewhere.NEW & NOTEWORTHY This article describes results from an approach to program evaluation (i.e., focused ethnography) that has not been previously used to evaluate grant mechanisms. This "experience near" approach, which involved qualitative interviews and firsthand observations, lent valuable insights into how broader and institutional contexts at two primarily undergraduate institutions hindered or facilitated use of Arkansas INBRE resources. The insights gained can be used to enhance the Arkansas INBRE, which aims to strengthen the statewide biomedical infrastructure.

Do Quality Measures or Hospital Characteristics Predict Readmission Penalties for Hip and Knee Arthroplasty?

BACKGROUND: Quality rating systems exist to grade the value of care provided by hospitals, but the extent to which these rating systems correlate with patient outcomes is unclear. The association of quality rating systems and hospital characteristics with excess readmission penalties for total hip arthroplasty (THA) and total knee arthroplasty (TKA) was studied. METHODS: The fiscal year 2022 Inpatient Prospective Payment System final rule was used to identify 2,286 hospitals subject to the Hospital Readmissions Reduction Program. Overall, 6 hospital quality rating systems and 5 hospital characteristics were obtained. These factors were analyzed to determine the effect on hospital penalties for THA and TKA excess readmissions. RESULTS: Hospitals that achieved a higher Medicare Overall Hospital Quality Star Rating demonstrated a significantly lower likelihood of receiving THA and TKA readmission penalties (Cramer's V = 0.236 and Rp = -0.233; P < .001 for both). Hospitals ranked among the US News & World Report's top 50 best hospitals for orthopaedics were significantly less likely to be penalized (V = 0.042; P = .043). The remaining 4 quality rating systems were not associated with readmission penalties. Penalization was more likely for hospitals with fewer THA and TKA discharges (Rp = -0.142; P < .001), medium-sized institutions (100 to 499 beds; V = 0.075; P = .002), teaching hospitals (V = 0.049; P = .019), and safety net hospitals (V = 0.043; P = .039). Penalization was less likely for West and Midwest hospitals (V = 0.112; P < .001). CONCLUSIONS: A higher Overall Hospital Quality Star Rating and recognition among the US News & World Report's top 50 orthopaedic hospitals were associated with a reduced likelihood of THA and TKA readmission penalties. The other 4 widely accepted quality rating systems did not correlate with readmission penalties. Teaching and safety net hospitals may be biased toward higher readmission rates.

Does the type of lower extremity fracture affect long-term opioid usage? A meta-analysis.

INTRODUCTION:  Patients recovering from musculoskeletal trauma have a heightened risk of opioid dependence and misuse, as these medications are typically required for pain management. The purpose of this meta-analysis was to examine the association between fracture type and chronic opioid use following fracture fixation in patients who sustain lower extremity trauma. MATERIALS AND METHODS: A meta-analysis was performed using PubMed and Web of Science to identify articles reporting chronic opioid use in patients recovering from surgery for lower extremity fractures. 732 articles were identified using keyword and MeSH search functions, and 9 met selection criteria. Studies were included in the final analysis if they reported the number of patients who remained on opioids 6 months after surgery for a specific lower extremity fracture (chronic usage). Logistic regressions and descriptive analyses were performed to determine the rate of chronic opioid use within each fracture type and if age, year, country of origin of study, or pre-admission opioid use influenced chronic opioid use following surgery. RESULTS: Bicondylar and unicondylar tibial-plateau fractures had the largest percentage of patients that become chronic opioid users (29.7-35.2%), followed by hip (27.8%), ankle (19.7%), femoral-shaft (18.5%), pilon (17.2%), tibial-shaft (13.8%), and simple ankle fractures (2.8-4.7%).Most opioid-naive samples had significantly lower rates of chronic opioid use after surgery (2-9%, 95% CI) when compared to samples that allowed pre-admission opioid use (13-50%, 95% CI). There were no significant associations between post-operative chronic opioid use and age, year, or country of origin of study. CONCLUSIONS:  Patients with lower extremity fractures have substantial risk of becoming chronic opioid users. Even the lowest rates of chronic opioid use identified in this meta-analysis are higher than those in the general population. It is important that orthopedic surgeons tailor pain-management protocols to decrease opioid usage after lower extremity trauma.

Monitoring Treatment Response, Early Recurrence, and Survival in Uterine Serous Carcinoma and Carcinosarcoma Patients Using Personalized Circulating Tumor DNA Biomarkers.

Uterine serous carcinoma (USC) and carcinosarcomas (CSs) are rare, highly aggressive variants of endometrial cancer. No reliable tumor biomarkers are currently available to guide response to treatment or detection of early recurrence in USC/CS patients. Circulating tumor DNA (ctDNA) identified using ultrasensitive technology such as droplet digital polymerase chain reaction (ddPCR) may represent a novel platform for the identification of occult disease. We explored the use of personalized ctDNA markers for monitoring USC and CS patients. Tumor and plasma samples from USC/CS patients were collected at the time of surgery and/or during the treatment course for assessment of tumor-specific somatic structural variants (SSVs) by a clinical-grade next-generation sequencing (NGS) platform (i.e., Foundation Medicine) and a droplet digital PCR instrument (Raindance, ddPCR). The level of ctDNA was quantified by droplet digital PCR in plasma samples and correlated to clinical findings, including CA-125 serum and/or computed tomography (CT) scanning results. The genomic-profiling-based assay identified mutated "driver" target genes for ctDNA analysis in all USC/CS patients. In multiple patients, longitudinal ctDNA testing was able to detect the presence of cancer cells before the recurrent tumor was clinically detectable by either CA-125 or CT scanning. Persistent undetectable levels of ctDNA following initial treatment were associated with prolonged progression-free and overall survival. In a USC patient, CA-125 and TP53 mutations but not PIK3CA mutations become undetectable in the plasma at the time of recurrence, suggesting that more than one customized probe should be used for monitoring ctDNA. Longitudinal ctDNA testing using tumor-informed assays may identify the presence of residual tumors, predict responses to treatment, and identify early recurrences in USC/CS patients. Recognition of disease persistence and/or recurrence through ctDNA surveillance may allow earlier treatment of recurrent disease and has the potential to change clinical practice in the management of USC and CS patients. CtDNA validation studies in USC/CS patients prospectively enrolled in treatment trials are warranted.

A phase 2 evaluation of pembrolizumab for recurrent Lynch-like versus sporadic endometrial cancers with microsatellite instability.

BACKGROUND: Microsatellite instability-high (MSI-H)/mismatch repair deficiency (dMMR) is a biomarker for responses to immune checkpoint inhibitors (ICIs). Whether mechanisms underlying microsatellite instability alter responses to ICIs is unclear. This article reports data from a prospective phase 2 pilot study of pembrolizumab in patients with recurrent MSI-H endometrial cancer (EC) analyzed by whole exome sequencing (WES) and potential mechanisms of primary/secondary ICI resistance (NCT02899793). METHODS: Patients with measurable MSI-H/dMMR EC confirmed by polymerase chain reaction/immunohistochemistry were evaluated by WES and received 200 mg of pembrolizumab every 3 weeks for ≤2 years. The primary end point was the objective response rate (ORR). Secondary end points included progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty-five patients (24 evaluable) were treated. Six patients (25%) harbored Lynch/Lynch-like tumors, whereas 18 (75%) had sporadic EC. The tumor mutation burden was higher in Lynch-like tumors (median, 2939 mutations/megabase [Mut/Mb]; interquartile range [IQR], 867-5108 Mut/Mb) than sporadic tumors (median, 604 Mut/Mb; IQR, 411-798 Mut/Mb; P = .0076). The ORR was 100% in Lynch/Lynch-like patients but only 44% in sporadic patients (P = .024). The 3-year PFS and OS proportions were 100% versus 30% (P = .017) and 100% versus 43% (P = .043), respectively. CONCLUSIONS: This study suggests prognostic significance of Lynch-like cancers versus sporadic MSI-H/dMMR ECs for ORR, PFS, and OS when patients are treated with pembrolizumab. Larger confirmatory studies in ECs and other MSI-H/dMMR tumors are necessary. Defective antigen processing/presentation and deranged induction in interferon responses serve as mechanisms of resistance in sporadic MSI-H ECs. Oligoprogression in MSI-H/dMMR patients appears salvageable with surgical resection and/or local treatment and the continuation of pembrolizumab off study. Clinical studies evaluating separate MSI-H/dMMR EC subtypes treated with ICIs are warranted.

Randomised phase II trial of weekly ixabepilone ± biweekly bevacizumab for platinum-resistant or refractory ovarian/fallopian tube/primary peritoneal cancer.

BACKGROUND: This multi-center RP2 study assessed activity/safety of ixabepilone + bevacizumab compared to ixabepilone in platinum-resistant/refractory ovarian/fallopian tube/primary peritoneal cancer. Additional objectives were to examine the role of prior bevacizumab and taxanes, and explore class III-ß-tubulin (TUBB3) as a predictive biomarker. METHODS: Participants were randomised to receive ixabepilone 20 mg/m2 days 1, 8, 15 with (IXA + BEV) or without (IXA) bevacizumab 10 mg/kg days 1, 15 every 28 days. Patients were stratified by prior BEV. The primary endpoint was PFS. OS, safety, and ORR served as secondary endpoints. RESULTS: Among 76 evaluable patients who received IXA + BEV (n = 39) compared to IXA (n = 37), the ORR was 33% (n = 13) versus 8% (n = 3)(P = 0.004), durable at 6 months in 37% (n = 14) and 3% (n = 1) (P < 0.001). BEV significantly improved PFS (median:5.5 vs 2.2 months, HR = 0.33, 95%CI 0.19-0.55, P < 0.001) and OS (median:10.0 vs 6.0 months, HR = 0.52, 95%CI 0.31-0.87, P = 0.006). Both regimens were well-tolerated. TUBB3 expression did not predict response. Subgroup analyses revealed minimal effect of prior BEV or taxane resistant/refractory status on response to IXA + BEV. CONCLUSIONS: IXA + BEV is a well-tolerated, effective combination for platinum/taxane-resistant ovarian cancer that extends PFS and likely OS relative to IXA monotherapy. Prior receipt of BEV should not preclude the use of IXA + BEV. TUBB3 is not a predictive biomarker. CLINICAL TRIAL REGISTRATION: NCT3093155.

Impact of Myc in HIV-associated non-Hodgkin lymphomas treated with EPOCH and outcomes with vorinostat (AMC-075 trial).

EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) is a preferred regimen for HIV-non-Hodgkin lymphomas (HIV-NHLs), which are frequently Epstein-Barr virus (EBV) positive or human herpesvirus type-8 (HHV-8) positive. The histone deacetylase (HDAC) inhibitor vorinostat disrupts EBV/HHV-8 latency, enhances chemotherapy-induced cell death, and may clear HIV reservoirs. We performed a randomized phase 2 study in 90 patients (45 per study arm) with aggressive HIV-NHLs, using dose-adjusted EPOCH (plus rituximab if CD20+), alone or with 300 mg vorinostat, administered on days 1 to 5 of each cycle. Up to 1 prior cycle of systemic chemotherapy was allowed. The primary end point was complete response (CR). In 86 evaluable patients with diffuse large B-cell lymphoma (DLBCL; n = 61), plasmablastic lymphoma (n = 15), primary effusion lymphoma (n = 7), unclassifiable B-cell NHL (n = 2), and Burkitt lymphoma (n = 1), CR rates were 74% vs 68% for EPOCH vs EPOCH-vorinostat (P = .72). Patients with a CD4+ count <200 cells/mm3 had a lower CR rate. EPOCH-vorinostat did not eliminate HIV reservoirs, resulted in more frequent grade 4 neutropenia and thrombocytopenia, and did not affect survival. Overall, patients with Myc+ DLBCL had a significantly lower EFS. A low diagnosis-to-treatment interval (DTI) was also associated with inferior outcomes, whereas preprotocol therapy had no negative impact. In summary, EPOCH had broad efficacy against highly aggressive HIV-NHLs, whereas vorinostat had no benefit; patients with Myc-driven DLBCL, low CD4, and low DTI had less favorable outcomes. Permitting preprotocol therapy facilitated accruals without compromising outcomes. This trial was registered at www.clinicaltrials.gov as #NCT0119384.

Social Needs of Patients Undergoing Total Joint Arthroplasty.

BACKGROUND: Many patients have unmet social needs that may affect their health care utilization and outcomes. We sought to examine a program to determine the types of social needs facing arthroplasty patients and methods used to address these needs. METHODS: We conducted a pilot, retrospective review of our integrated social needs program for total joint arthroplasty (TJA) patients. A 16-question needs assessment was instituted as part of our perioperative protocol between February 1, 2020, to October 1, 2020. We examined the types of social needs in 250 primary TJA patients and a resolution method. We evaluated associations between social needs and demographics and Area Deprivation Index (ADI). Outcome measures were also evaluated, including readmissions, discharge date, and outcome score changes. RESULTS: Forty-four (17.6%) patients had a social need. Social needs frequency increased in non-White patients (P ≤ .0001), non-English speakers (P = .0304), younger patients (P = .001), nonmarried patients (P = .0006), unemployed patients (P = .0189), and patients with less health literacy (P = .0215). ADI scores were positively associated with social needs at the national (P = .0006) and state levels (P = .0004). Overall, 75.9% of needs centered around utility payments, employment, prescription costs, education, and transportation. In addition, 64% of the identified needs were resolved through outside referrals. Ninety-day readmissions were significantly higher in patients with social needs (P = .0087). DISCUSSION: Overall, 17.6% of patients in our state have social needs before TJA. Factors increasing the risk of social needs include younger age, minority race, single or divorced marital status, unemployment, low health literacy, and higher ADI. The 90-day readmission rate was significantly higher in patients with social needs.

Does In-Hospital Opioid Use Affect Opioid Consumption After Total Joint Arthroplasty?

BACKGROUND: Preoperative opioid use strongly correlates with greater postoperative opioid use and complications following total joint arthroplasty (TJA). However, there is a lack of information regarding the effect of opioid consumption during the hospital stay and within the operating room on postoperative opioid use. METHODS: We retrospectively reviewed 369 consecutive patients undergoing primary TJA at an academic center over a 9-month period. Ninety-day preoperative and postoperative opioid prescriptions were obtained from the state's drug monitoring database. In-hospital opioid consumption data was obtained from the preoperative unit, operating room, postanesthesia care unit (PACU), and hospital floor. Multivariate analysis was utilized to compare patients' total in-hospital opioid consumption with their preoperative and postoperative use, along with opioid use throughout the hospitalization. RESULTS: Total in-hospital opioid consumption was independently associated with postoperative opioid use (rs = 0.17, P = .0010). Opioids consumed on the hospital floor correlated with opioid use in the preoperative unit (rs = 0.11, P = .0338) and PACU (rs = 0.15, P = .0032). Increased preoperative opioid consumption was the greatest risk factor for excessive postoperative use (rs = 0.44, P < .0001). A greater proportion of patients <65 years of age were high posthospital opioid consumers (P = .0146) and significantly more TKA patients were in the higher use groups (P = .0006). CONCLUSION: In-hospital opioid use is independently associated with preoperative and postoperative consumption. Preoperative opioid use remains the greatest risk factor for increased opioid consumption after TJA. Multimodal approaches to decrease reliance on opioids for pain control during hospitalization may offer hope to further decrease postoperative usage. LEVEL OF EVIDENCE: III.

The Hip and Femur Fracture Bundle: Preliminary Findings From a Tertiary Hospital.

BACKGROUND: The voluntary hip and femur fracture Bundled Payments for Care Improvement Advanced (BCPI-A) includes Diagnosis Related Groups (DRG) 480, 481, and 482, which include diverse and medically complex patients undergoing urgent inpatient surgery without optimization. Concern exists that this bundle is financially unfavorable for hospitals, and this study aimed to identify the costliest services. METHODS: We retrospectively reviewed a 12-month cohort of 32 consecutive patients in the DRG 480-482 bundle at our academic tertiary referral center. Cost of discharge disposition, readmission, and other variables were analyzed for all patients in the 90-day bundle. RESULTS: Overall, a net financial gain averaging $2,028 per patient (range -$52,128 to +$30,199) was seen. Discharge to facilities (n = 19) resulted in higher costs than discharge to home (n = 11, P < .0001). Use of inpatient rehabilitation (n = 6) averaged a loss of $11,028 per patient and use of skilled nursing facilities (n = 15) averaged a loss of $7,250 per patient, compared to a gain of $15,011 for patients discharged home (n = 11). Episodes with readmission (n = 6) averaged a loss of only $1,390. Total index admission costs averaged $12,489 ± $2,235 per patient (range $9,329-$18,884) while post-inpatient cost averaged $30,150 per patient (range $4,803 - $77,768). CONCLUSION: The BPCI-A hip and femur fracture bundle has a wide variability in costs, with the largest component in the post-acute care phase. Discharge home is favorable in the bundle while discharge to post-acute facilities leads to net losses. Institutions in this bundle need to develop multi-disciplinary teams to promote safe discharge home.

Transfers of pediatric patients with isolated injuries to a rural Level 1 Orthopedic Trauma Center in the United States: are they all necessary?

BACKGROUND: Pediatric fractures are difficult to manage and often result in expensive urgent transfers to a pediatric trauma center. Our study seeks to identify patients transferred with isolated acute orthopedic injuries to a Level 1 center in which no procedure occurred and the patient was discharged home. We sought to examine all patients who are transferred to a Level 1 pediatric trauma center for care of isolated orthopedic injuries, and to determine how often no procedure is performed after transfer. Identification of this group ahead of time could potentially lead to less avoidable transfers. METHODS AND METHODS: A retrospective chart review of all patients with isolated orthopaedic injuries who were transferred to a Level 1 pediatric trauma center in a rural state within the United States over a 5-year period beginning January, 2011 and ending December, 2015. Demographic factors were collected for each patient as well as diagnosis and treatment at the trauma center. Patients were divided into two groups, those who underwent an operation or fracture reduction after admission and those that had no procedure performed. Patient demographics, fracture types and presentation characteristics were examined to attempt to determine factors related to the potentially avoidable transfers. RESULTS: 1303 patients were identified who were transferred with isolated orthopedic fractures. Of these, 1113 (85.6%) patients underwent a procedure for their injuries, including 821 treated with surgical intervention and 292 treated with closed reduction of their fracture. 190 of 1303 (14.6%) of the patients transferred with isolated injuries had neither surgery nor a reduction performed. Identifying characteristics of the non-operative group were that they contained a substantially higher percentage of females, transfers by ambulance, fractures involving only the tibia, fracture types classified as other, and fractures from motor-vehicle accidents. DISCUSSION: Approximately 14.6% of patients transferred to a pediatric Level 1 trauma center for isolated orthopedic injury underwent no surgery or fracture reductions and were discharged directly home. In particular, isolated tibia fractures were more frequently treated without reduction or surgery. In the future, telemedicine consultation for these specific injury types may limit unnecessary and costly transfers to a Level 1 pediatric trauma hospital.

Lymph Liquid Biopsy for Detection of Cancer Stem Cells.

Collection of a blood sample defined by the term "blood liquid biopsy" is commonly used to detect diagnostic, prognostic, and therapeutic decision-making markers of metastatic tumors including circulating tumor cells (CTCs). Many tumors also release CTCs and other markers into lymph fluid, but the utility of lymphatic markers largely remains unexplored. Here, we introduce lymph liquid biopsy through collection of peripheral (afferent) and central (thoracic duct [TD]) lymph samples and demonstrates its feasibility for detection of stem-like CTCs potentially responsible for metastasis development and tumor relapse. Stemness of lymphatic CTCs (L-CTCs) was determined by spheroid-forming assay in vitro. Simultaneously, we tested blood CTCs by conventional blood liquid biopsy, and monitored the primary tumor size, early metastasis in a sentinel lymph node (SLN) and distant metastasis in lungs. Using a mouse model at early melanoma stage with no distant metastasis, we identified stem-like L-CTCs in lymph samples from afferent lymphatic vessels. Since these vessels transport cells from the primary tumor to SLN, our finding emphasizes the significance of the lymphatic pathway in development of SLN metastasis. Surprisingly, in pre-metastatic disease, stem-like L-CTCs were detected in lymph samples from the TD, which directly empties lymph into blood circulation. This suggests a new contribution of the lymphatic system to initiation of distant metastasis. Integration of lymph and blood liquid biopsies demonstrated that all mice with early melanoma had stem-like CTCs in at least one of three samples (afferent lymph, TD lymph, and blood). At the stage of distant metastasis, spheroid-forming L-CTCs were detected in TD lymph, but not in afferent lymph. Altogether, our results demonstrated that lymph liquid biopsy and testing L-CTCs holds promise for diagnosis and prognosis of early metastasis. © 2020 International Society for Advancement of Cytometry.

Trastuzumab tolerability in the treatment of advanced (stage III-IV) or recurrent uterine serous carcinomas that overexpress HER2/neu.

OBJECTIVE: Due to previously reported trastuzumab safety concerns and the scant data available in endometrial cancer patients, we sought to assess the safety, tolerability and toxicity profile of trastuzumab in patients with advanced/recurrent uterine serous carcinoma (USC) that overexpress HER2/neu in our multicenter randomized phase II trial. METHODS: Patients were randomized 1:1 to receive carboplatin/paclitaxel (C/P) for 6 cycles ± trastuzumab (T) with the experimental arm continuing to receive single agent trastuzumab maintenance treatment until disease progression/toxicity. Progression-free-survival was the primary endpoint; overall-survival and toxicity were secondary endpoints. Adverse events (AEs) were compared between treatment arms. RESULTS: There were 28 patients in the C/P arm and 32 patients in the experimental (C/P + T) arm. Fifty-eight patients (97%) experienced 977 treatment-related AEs of which 875 (89.6%) were low-grade (grade 1-2) and 102 (10.4%) were high-grade (grade 3-5). The mean ± standard deviation of AEs per patient was 15.5 ± 16.3 in the C/P arm and 17.0 ± 16.0 in the C/P + T arm. Gastrointestinal AEs were the most common in both arms (n = 155, 15.7%) of which 94.2% were low-grade (n = 146). Importantly, no significant difference between treatment arms was detected in any system-organ class of AE including cardiac AE. Five (17%) of 29 patients who received prolonged trastuzumab maintenance therapy had no sign of cumulative toxicity after an average (range) of 5.1 (4.2-6.3) years. CONCLUSIONS: Trastuzumab appears to be safe and has a manageable toxicity profile both when used in combination with chemotherapy and when used for single agent maintenance in patients with HER2/neu positive USC. This safety profile is reassuring given the proven efficacy of trastuzumab in advanced/recurrent HER2/neu positive USC.

Tracking evoked responses to auditory and visual stimuli in fetuses exposed to maternal high-risk conditions.

Magnetoencephalography (MEG) has been successfully applied to record fetal auditory (auditory evoked response [AER]) and visual evoked responses (VER). In this study, we report the AER and VER development trajectory by tracking the evoked response detectability and latency from recordings starting at 27 weeks of gestation in pregnancies classified as high risk. Fetal MEG and ultrasound recordings were performed on 158 pregnant women, and the total number of fetal auditory and visual tests conducted was 321 and 237, respectively. The overall evoked response analysis showed 237 AER (73.8%) and 164 VER detections (69.2%). The mean AER latency was 290.7 (SD 125.5) ms and the mean VER latency was 293.7 (SD 114.5) ms. The rate of decrease (95% confidence limits) in average AER and VER first-peak latency between 100-350 ms was 1.97 (-1.86, +5.81) ms/week and 1.35 (-3.83, +6.53) ms/week, respectively. This trend in high-risk fetuses conforms to the general trajectory of decrease in latency with gestational age progression, even though this decrease was non-significant, as reported in the case of normal growing fetuses. Although there was a significant difference in detection rates between male and female fetuses, this was not reflected in either latency values or the sensory modality applied. Furthermore, the main factors that had the most significant effect on response detectability included the presence of intervening layers of adipose tissue between the fetal head and stimulus source and an increase in the maternal body mass index.

The Alpha-Defensin Prosthetic Joint Infection Test Has Poor Validity for Native Knee Joint Infection.

BACKGROUND: The alpha-defensin test known as Synovaure has been very effective in diagnosis of prosthetic joint infections (PJIs). Being able to easily and accurately differentiate septic and inflammatory arthropathies in native joints would improve diagnostic workup and management. We tested the ability of an alpha-defensin test to distinguish septic from inflammatory or crystalline arthropathy in the native knee. METHODS: 40 native knee joint fluid specimens were tested with cell count, fluid analysis, and culture and alpha-defensin testing. We determined the sensitivity and specificity of the alpha-defensin test using culture-positive fluid as the gold standard for septic arthropathy and positive crystals as the gold standard for crystalline arthropathy. RESULTS: The Synovasure PJI test had 100% specificity for septic arthritis coupled with a 28% false-positive rate when applied to native knee aspirations. False-positive rate was 5.3 times higher in patients with crystals found in the joint fluid. CONCLUSION: Alpha-defensin testing, in the form of the Synovasure PJI test, has a high-false-positive rate when used to distinguish septic and inflammatory arthritis in the native knee joint. Future work will need to determine the sensitivity and specificity of the newer native joint panel. Clinicians should be cognizant of the specific alpha-defensin test used when sampling native knee synovial fluid.

Narcotic Refills and Patient Satisfaction With Pain Control After Total Joint Arthroplasty.

BACKGROUND: Patient satisfaction has become an important metric for total joint arthroplasty (TJA) used to reimburse hospitals. Despite ubiquitous narcotic use for post-TJA pain control, there is little understanding regarding patient factors associated with obtaining opioid refills and associations with patient satisfaction. METHODS: Using our state's mandatory opioid prescription monitoring program, we reviewed preoperative and postoperative narcotic prescriptions filled for 438 consecutive TJA patients. Subjects were divided into 3 groups based on the number of post-TJA narcotic refills obtained (0, 1, or >1), and logistic regression analysis was conducted comparing demographics, surgical factors, and satisfaction with pain control. RESULTS: One hundred twenty-five patients (25.8%) did not consume preoperative opioids and received no postoperative refills. Total hip arthroplasty (THA) patients (P = .0004), subjects ≥65 years (P = .0057), and Medicare patients (P = .0058) had significantly higher rates of 0 postdischarge refills. THA recipients had 268% increased odds of not receiving a refill narcotic (adjusted odds ratio = 0.373; 95% confidence interval, 0.224- 0.622). Every 100-morphine milligram equivalent (MME) increase in presurgery use led to a 16% increase in odds of needing >1 opioid refill (adjusted odds ratio = 1.161; 95% confidence interval, 1.085-1.242). Subjects who noted higher satisfaction consumed less overall opioids when receiving a refill (436 vs 1119 MMEs, P = .021). CONCLUSION: Subjects who received fewer narcotic prescriptions and overall MMEs demonstrated higher rates of satisfaction with early pain control. Our results are consistent with other studies in showing that increased preoperative narcotic use portends higher rates of postoperative refills. There appears to be a subset of THA patients >65 years of age who may be candidates for opioid-sparing analgesia.

Dual antivascular function of human fibulin-3 variant, a potential new drug discovery strategy for glioblastoma.

The ECM protein EFEMP1 (fibulin-3) is associated with all types of solid tumor through its cell context-dependent dual function. A variant of fibulin-3 was engineered by truncation and mutation to alleviate its oncogenic function, specifically the proinvasive role in glioblastoma multiforme (GBM) cells at stem-like state. ZR30 is an in vitro synthesized 39-kDa protein of human fibulin-3 variant. It has a therapeutic effect in intracranial xenograft models of human GBM, through suppression of epidermal growth factor receptor/AKT and NOTCH1/AKT signaling in GBM cells and extracellular MMP2 activation. Glioblastoma multiforme is highly vascular, with leaky blood vessels formed by tumor cells expressing endothelial cell markers, including CD31. Here we studied GBM intracranial xenografts, 2 weeks after intratumoral injection of ZR30 or PBS, by CD31 immunohistochemistry. We found a 70% reduction of blood vessel density in ZR30-treated xenografts compared with that of PBS-treated ones. Matrigel plug assays showed the effect of ZR30 on suppressing angiogenesis. We further studied the effect of ZR30 on genes involved in endothelial transdifferentiation (ETD), in 7 primary cultures derived from 3 GBMs under different culture conditions. Two GBM cultures formed mesh structures with upregulation of ETD genes shortly after culture in Matrigel Matrix, and ZR30 suppressed both. ZR30 also downregulated ETD genes in two GBM cultures with high expression of these genes. In conclusion, multifaceted tumor suppression effects of human fibulin-3 variant include both suppression of angiogenesis and vasculogenic mimicry in GBM.