Search

Textbook oncologic outcome (TOO) and its association with regionalization of care for intrahepatic cholangiocarcinoma (ICC) have not been evaluated.We identified patients who underwent hepatic resection for ICC between 2004 and 2018 from the National Cancer Database. Facilities were categorized by annual hepatectomy volume for ICC. TOO was defined as no 90-day mortality, margin-negative resection, no prolonged hospitalization, no 30-day readmission, receipt of appropriate adjuvant therapy, and adequate lymphadenectomy. Multivariable regression was used to evaluate the association between annual hepatectomy volume and TOO.A total of 5359 patients underwent liver resection for ICC. TOO was achieved in 11.2% (n = 599) of patients. Inadequate lymphadenectomy was the largest impediment to achieving TOO. After adjusting for patient, pathologic, and facility characteristics, high volume facilities had 67% increased odds of achieving TOO (Ref.: low volume; high volume: odds ratio 1.67, 95% confidence interval: 1.24-2.25; p 0.001). Patients treated at high-volume centers who achieved a TOO had better overall survival (OS) versus patients treated at low-volume facilities (low volume vs. high volume; median OS, 47.3 vs. 71.1 months, p 0.05).A composite oncologic measure, TOO, provides a comprehensive insight into the performance of liver resection and regionalization of surgical care for ICC.

Family history (FH) of ovarian cancer and breast cancer are well-established risk factors for ovarian cancer, but few studies have examined this association in African American (AA) and white women by histotype. We assessed first- and second-degree FH of ovarian and breast cancer and risk of epithelial ovarian cancer in the Ovarian Cancer in Women of African Ancestry Consortium. Analyses included 1052 AA cases, 2328 AA controls, 2380 white cases and 3982 white controls. Race-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multilevel logistic regression with adjustment for covariates. Analyses were stratified by histotype (high-grade serous vs others). First-degree FH of ovarian cancer was associated with high-grade serous carcinoma in AA (OR = 2.32, 95% CI: 1.50, 3.59) and white women (OR = 2.48, 95% CI: 1.82, 3.38). First-degree FH of breast cancer increased risk irrespective of histotype in AAs, but with high-grade serous carcinoma only in white women. Associations with second-degree FH of ovarian cancer were observed for overall ovarian cancer in white women and with high-grade serous carcinoma in both groups. First-degree FH of ovarian cancer and of breast cancer, and second-degree FH of ovarian cancer is strongly associated with high-grade serous ovarian carcinoma in AA and white women. The association of FH of breast cancer with high-grade serous ovarian carcinoma is similar in white women and AA women, but may differ for other histotypes.

The role of neoadjuvant therapy (NT) for ampullary carcinoma (AC) has not been clearly established.Patients who underwent pancreatoduodenectomy for AC between 2004 and 2016 were identified in the National Cancer Database. Overall survival (OS) was compared between those who received NT before resection and those who underwent surgery first (SF). Propensity score matching (PSM) was performed using age, pathologic T and N stage, and tumor differentiation.Among 8688 patients with AC, 175 (2.0%) received NT before surgery. While patients who received NT were younger (p = .022) and more likely to have nodal metastasis (43.3% vs. 35.1%, p .001), there was no difference in OS on univariate (43 vs. 33 months; hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 0.88-1.37, p = .401) or multivariate (HR: 1.09, 95% CI: 0.88-1.36, p = .416) analysis between groups. After PSM, there remained no difference in OS between NT or SF groups on univariate (37 vs. 32 months; HR: 1.20, 95% CI: 0.87-1.64, p = .350) or multivariate (HR: 0.99, 95% CI: 0.71-1.38, p = .943) analysis.NT followed by surgery was not associated with improved survival outcomes compared with SF among patients with localized AC. While NT is an acceptable alternative for patients with advanced disease, SF should remain the standard of care.

Fosphenytoin (FOS) and its active form, phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA) are commonly used second-line treatments of status epilepticus. However, limited information is available regarding LEV and VPA concentrations following high intravenous doses particularly in young children. The Established Status Epilepticus Treatment Trial (ESETT), a blinded, comparative effectiveness study of FOS, LEV, and VPA for benzodiazepine-refractory status epilepticus provided an opportunity to investigate early drug concentrations. Patients ≥ 2 years who continued to seizure despite receiving adequate doses of benzodiazepines were randomized to FOS, LEV or VPA infused over 10 minutes. A sparse blood sampling approach was used, with up to two samples collected per patient within two hours following drug administration. The objective of this work was to report early drug exposure of PHT, LEV and VPA and plasma protein binding of PHT and VPA. Twenty-seven children with median (interquartile range) age of 4 (2.5, 6.5) years were enrolled. The total plasma concentrations ranged from 69-151.3 μg/mL for LEV, 11.3-26.7 μg/mL for PHT and 126-223 μg/mL for VPA. Free fraction ranged from 4-19% for PHT and 17-51% for VPA. This is the first report in young children of LEV concentrations with convulsive status epilepticus as well as VPA concentrations after a 40 mg/kg dose. Several challenges limited patient enrollment and blood sampling. Additional studies with a larger sample size are required to evaluate the exposure-response relationships in this emergent condition. This article is protected by copyright. All rights reserved.

BACKGROUND The novel composite metric textbook outcome (TO) has increasingly been used as a quality indicator but has not been reported among patients undergoing surgical resection for retroperitoneal sarcoma (RPS) using multi-institutional collaborative data. METHODS All patients who underwent resection for RPS between 2000 to 2016 from eight academic institutions were included. TO was defined as a patient with R0/R1 resection that discharged to home and was without transfusion, reoperation, grade ≥2 complications, hospital-stay >50th percentile, or 90-day readmission or mortality. Univariate and multivariable analyses were performed. RESULTS Among 627 patients, 56.1% were female and the median age was 59 years. A minority of patients achieved a TO (34.9%). Factors associated with achieving a TO were tumor size

Background The objective of the current study was to define and compare rates of textbook outcomes (TO) among patients undergoing colorectal, lung, esophagus, liver, and pancreatic surgery for cancer at U.S. News & World Report (USNWR) ranked hospitals. Methods Medicare Inpatient Standard Analytic Files 2013-2015 were utilized to examine the relationship of TO and USNWR hospital ratings following surgery for colorectal, lung, esophageal, pancreatic, and liver cancer. TO was defined as no postoperative surgical complications, no prolonged length of hospital stay, no readmission within 90 days after discharge, and no postoperative mortality within 90 days after surgery. Results Among the 35,352 Medicare patients included in the cohort, 16,820 (47.6%) underwent surgery at honor roll hospitals, whereas 18 532 (52.4%) underwent surgery at non-honor roll hospitals. The overall proportion of patients who achieved TO was 50.1%. In examining the clinical outcomes of patients who underwent surgery, there was no difference in the odds of achieving TO at honor roll vs non-honor roll hospitals (colorectal: odds ratio [OR], 0.87; 95% confidence interval [CI], 0.69-1.10; lung: OR, 1.07; 95% CI, 0.87-1.32; esophagus: OR, 1.44; 95% CI, 0.72-2.89; liver: OR, 1.27; 95% CI, 0.87-1.84; pancreas: OR, 1.04; 95% CI, 0.67-1.62). Conclusion and relevance Patients undergoing surgery for lung, esophageal, liver, pancreatic, and colorectal cancer had comparable rates of TO at honor roll vs non-honor roll hospitals. No linear association was observed between hospital position in the rank and postoperative outcomes such as TO indicating that patients should not overly focus on the exact position within USNWR ranked hospitals. These data highlight to patients and physicians that up to one-half of patients undergoing surgery for cancer should anticipate at least one adverse outcome.

BACKGROUND Composite outcomes may more accurately reflect patient and provider expectations around optimal care. We sought to determine the impact of achieving a so-called "textbook oncologic outcome" (TOO) among patients undergoing resection of pancreatic adenocarcinoma (PDAC). METHODS Patients undergoing pancreaticoduodenectomy (PD) for PDAC between 2006 and 2016 were identified in the National Cancer Database (NCDB). TOO was defined by: margin negative resection, compliant lymph node evaluation, no prolonged length-of-stay, no 30-day readmission/mortality, and receipt of adjuvant chemotherapy. Factors associated with TOO and overall survival (OS) were evaluated using multivariable logistic and Cox regression models, respectively. RESULTS Among 18 608 patients who underwent PD at 782 hospitals, many patients successfully achieved certain TOO factors such as R0 margin (77.9%) and no 30-day mortality (96.9%), while other TOO criteria such as receipt of adjuvant therapy (48.2%) were achieved less frequently. Overall, only 3124 (16.8%) patients achieved a TOO. Factors associated with lower odds of TOO included: older age, Black race, Medicaid insurance, Community facility, and low PD facility (

Mitochondrial dysfunction is implicated in the pathogenesis of Parkinson's disease. Preliminary data have shown lower brain adenosine triphosphate (ATP) levels in Parkinson's disease versus age-matched healthy controls. Ursodeoxycholic acid (UDCA) may improve impaired mitochondrial function. Our objective was to evaluate UDCA tolerability, pharmacokinetics, and its effect on brain bioenergetics in individuals with Parkinson's disease. An open-label, prospective, multiple-ascending-dose study of oral UDCA in 5 individuals with Parkinson's disease was completed. A blood safety panel, plasma concentrations of UDCA and UDCA conjugates, and brain ATP levels were measured before and after therapy (week 1: 15 mg/kg/day; week 2: 30 mg/kg/day; and weeks 3-6: 50 mg/kg/day). UDCA and conjugates were measured using liquid chromatography-mass spectrometry. ATP levels and ATPase activity were measured using 7-Tesla 31 P magnetic resonance spectroscopy. Secondary measures included the Unified Parkinson's Disease Rating Scale and Montreal Cognitive Assessment. UDCA was generally well tolerated. The most frequent adverse event was gastrointestinal discomfort, rated by subjects as mild to moderate. Noncompartmental pharmacokinetic analysis resulted in (mean ± standard deviation) a maximum concentration of 8749 ± 2840 ng/mL and half-life of 2.1 ± 0.71 hr. Magnetic resonance spectroscopy data were obtained in 3 individuals with Parkinson's disease and showed modest increases in ATP and decreases in ATPase activity. Changes in Unified Parkinson's Disease Rating Scale (parts I-IV) and Montreal Cognitive Assessment scores (mean ± standard deviation) were -4.6 ± 6.4 and 2 ± 1.7, respectively. This is the first report of UDCA use in individuals with Parkinson's disease. Its pharmacokinetics are variable, and at high doses it appears reasonably well tolerated. Our findings warrant additional studies of its effect on brain bioenergetics.

The novel coronavirus disease 2019 (COVID-19) pandemic presents unique challenges for surgical management of laryngotracheal stenosis. High viral concentrations in the upper aerodigestive tract, the ability of the virus to be transmitted by asymptomatic carriers and through aerosols, and the need for open airway access during laryngotracheal surgery create a high-risk situation for airway surgeons, anesthesiologists, and operating room personnel. While some surgical cases of laryngotracheal stenosis may be deferred, patients with significant airway obstruction or progressing symptoms often require urgent surgical intervention. We present best practices from our institutional experience for surgical management of laryngotracheal stenosis during this pandemic, including preoperative triage, intraoperative airway management, and personal protective measures.

Benzodiazepines, including diazepam (DZP), lorazepam (LZP), and midazolam (MDZ), are considered the initial drugs of choice for status epilepticus (SE) treatment. A number of trials have demonstrated their safety and efficacy; however, the failure rate ranges from 10‐55%.1,2 This may be attributable, in part, to sub‐optimal benzodiazepine dosing and timing of administration.\ud \ud The Neurocritical Care Society (NCS) and American Epilepsy Society (AES) have published evidence‐based guidelines for benzodiazepine use in SE that specify drugs, doses, and routes of administration.

The aim of the current study was to identify the minimum number and the optimal range of lymph nodes (LNs) to be examined among patients with gallbladder cancer (GBC).Between January 1, 2004, and December 31, 2015, patients with a diagnosis of GBC were identified in the National Cancer Database. A machine-based learning approach was used to identify the minimum number and range of LNs to evaluate relative to long-term outcomes.Among 6531 patients with GBC, median number of LNs evaluated was 2 (IQR:1-5); only 21.1% (n = 1376) of patients had 6 or more LNs evaluated. The median number of metastatic LNs was 0 (IQR: 0-1). On multivariable analysis, evaluation of 4 LNs was associated with a higher hazard of death (referent 4-7 LNs: 4 LNs, HR = 1.27, 95% CI, 1.16-1.40; P 0.001), whereas, patients who had 4 to 7 LNs and 7 LNs evaluated had comparable long-term mortality risk (HR = 1.10, 95%CI, 0.98-1.24; P = 0.11). There was no difference in the proportion of patients who had at least one metastatic LN identified per T category based on total number of nodes resected (all P 0.05).The overwhelming majority of patients did not have the American Joint Committee on Cancer (AJCC) recommended 6 total LN count . A machine-based learning approach identified evaluation of 4 to 7 LNs as the LN number associated with optimal staging and survival. While obtaining 6 LNs may be challenging, evaluation of at least 4 LNs may be a more appropriate threshold as this cut-off value was associated with optimal patient outcomes and staging.

Inhibition of the protein phosphatase calcineurin (CN) ameliorates pathophysiologic and cognitive changes in aging rodents and mice with aging‐related Alzheimer's disease (AD)‐like pathology. However, concerns over adverse effects have slowed the transition of common CN‐inhibiting drugs to the clinic for the treatment of AD and AD‐related disorders. Targeting substrates of CN, like the nuclear factor of activated T cells (NFATs), has been suggested as an alternative, safer approach to CN inhibitors. However, small chemical inhibitors of NFATs have only rarely been described. Here, we investigate a newly developed neuroprotective hydroxyquinoline derivative (Q134R) that suppresses NFAT signaling, without inhibiting CN activity. Q134R partially inhibited NFAT activity in primary rat astrocytes, but did not prevent CN‐mediated dephosphorylation of a non‐NFAT target, either in vivo, or in vitro. Acute (≤1 week) oral delivery of Q134R to APP/PS1 (12 months old) or wild‐type mice (3–4 months old) infused with oligomeric Aβ peptides led to improved Y maze performance. Chronic (≥3 months) oral delivery of Q134R appeared to be safe, and, in fact, promoted survival in wild‐type (WT) mice when given for many months beyond middle age. Finally, chronic delivery of Q134R to APP/PS1 mice during the early stages of amyloid pathology (i.e., between 6 and 9 months) tended to reduce signs of glial reactivity, prevented the upregulation of astrocytic NFAT4, and ameliorated deficits in synaptic strength and plasticity, without noticeably altering parenchymal Aβ plaque pathology. The results suggest that Q134R is a promising drug for treating AD and aging‐related disorders., pathophysiology including synapse dysfunction. Small chemical compound, Q134R, inhibits the activity of the downstream calcineurin‐dependent transcription factor NFAT (but does not inhibit calcineurin) and reduces synapse deficits and other AD biomarkers in APP/PS1 mice.

Background Liposomal bupivacaine may be an option for reducing opioid utilization in pediatric scoliosis surgery. The use of liposomal bupivacaine in this patient population has not been previously described. Methods Patients who underwent posterior spinal fusion surgery at our institution from 2011-2016 were identified. We performed a retrospective matched cohort study, matching patients who received intraoperative liposomal bupivacaine by age, gender, and extent of surgery to patients who did not. The primary endpoint was the use of morphine equivalents in the first 72 hours after surgery. Data collection included demographic and surgical data, pain medication utilization, and pain scores. Area under the curve (AUC) for pain scores was calculated. Descriptive statistical methods and univariable analysis were used to compare patients who received liposomal bupivacaine to patients who did not. Results One hundred and forty-one patients met study criteria; 47 patients who received liposomal bupivacaine were matched to 94 control patients who did not receive liposomal bupivacaine. No significant differences were noted in the patient population with the patients requiring a median of 11 segments (range 10-13 segments) fused. Patients received a mean of 56.6 ± 37.4 mg/kg of intravenous acetaminophen, a mean of 3.4 ± 2.1 mg/kg of intravenous ketorolac, and 1.9 ± 0.93 mg/kg of morphine equivalents in the first 72 hours after surgery. On univariable analysis, no differences were noted in intravenous acetaminophen use, pain score AUC, intravenous ketorolac use, or morphine equivalents (2.0 ± 98 vs 1.8 ± 0.82) in patients who did not receive liposomal bupivacaine as compared to those patient who did received liposomal bupivacaine. Conclusion Liposomal bupivacaine was not associated with reductions in postoperative opioid use in pediatric spinal surgery.

A subgroup of patients with drug-resistant epilepsy have seizure clusters, which are a part of the continuum of seizure emergencies that includes prolonged episodes and status epilepticus. When the patient or caregiver can identify the beginning of a cluster, the condition is amenable to certain treatments, an approach known as rescue therapy. Intravenous drug administration offers the fastest onset of action, but this route is usually not an option because most seizure clusters occur outside of a medical facility. Alternate routes of administration have been used or are proposed including rectal, buccal, intrapulmonary, subcutaneous, intramuscular, and intranasal. The objective of this narrative review is to describe the (1) anatomical, physiologic, and drug physicochemical properties that need to be considered when developing therapies for seizure emergencies and (2) products currently in development. New therapies must consider parameters of Fick's law such as absorptive surface area, blood flow, membrane thickness, and lipid solubility, because these factors affect both rate and extend of absorption. For example, the lung has a 50 000-fold greater absorptive surface area than that associated with a subcutaneous injection. Lipid solubility is a physicochemical property that influences the absorption rate of small molecule drugs. Among drugs currently used or under development for rescue therapy, allopregnanolone has the greatest lipid solubility at physiologic pH, followed by propofol, midazolam, diazepam, lorazepam, alprazolam, and brivaracetam. However, greater lipid solubility correlates with lower water solubility, complicating formulation of rescue therapies. One approach to overcoming poor aqueous solubility involves the use of a water-soluble prodrug coadministered with a converting enzyme, which is being explored for the intranasal delivery of diazepam. With advances in seizure prediction technology and the development of drug delivery systems that provide rapid onset of effect, rescue therapies may prevent the occurrence of seizures, thus greatly improving the management of epilepsy.