bluuebunny/crossref_metadata_2025_split huggingface dataset:
From the Broad Phase II Trial to Precision Oncology: A Perspective on the Origins of Basket and Umbrella Clinical Trial Designs in Cancer Drug Development
Authors: Doroshow Deborah B. , Doroshow James H. 
Published: July 2019

Abstract
Oncologic phase II trials that evaluate the activity of new therapeutic agents have evolved dramatically over the past 50 years. The standard approach beginning in the late 1960s focused on individual studies that evaluated new anticancer agents against a wide range of both solid and hematopoietic malignancies often in a single “broad phase II trial” that included hundreds of patients; such studies efficiently established the landscape for subsequent development of a specific drug with respect to likely disease focus, toxicity, dose, and schedule. In the 1980s and 1990s, emphasis on histological context drove an explosion in the number of individual phase II trials conducted; despite this increase in trial activity, investigations based on histology per se failed to improve the success rate of new agents brought to the clinic. Over the past 20 years, evolution toward a molecular drug development paradigm has demonstrably improved our ability to select patients more likely to benefit from systemic treatment; simultaneously, technological advances have permitted initial attempts at the rapid assignment of therapy based on predefined molecular characteristics of tumor or germline in broad-based master protocols that are inclusive of many diseases and molecularly characterized disease subsets, akin to but much more sophisticated scientifically than the broad phase II platforms of the past.
Visit-to-Visit Hemoglobin A1c Variability Is Associated With Later Cancer Development in Patients With Diabetes Mellitus
Authors: Saito Yuki , Noto Hiroshi , Takahashi Osamu , Kobayashi Daiki 
Published: July 2019

Purpose
Recent studies have shown that patients with diabetes mellitus have a higher risk of tumorigenesis. However, the effect of glycemic variability on tumorigenesis among diabetic patients has not been well investigated. Hence, we performed a retrospective cohort study to analyze the effect of visit-to-visit hemoglobin A1c (HbA1c) variability and later onset of malignancies.

Methods
This study included 2640 patients with diabetes mellitus 50 years or older. To analyze visit-to-visit glycemic activity, we calculated intrapersonal SD of all recorded HbA1c and used SD-HbA1c as a measure of glycemic variability. Because the number of individual visits varied, we divided SD-HbA1c by visit times in order to adjust for the potential influence of visit time difference between individuals. Patients were divided into quartiles according to their HbA1c variability, and Cox regression models were used to evaluate the association between glycemic variability and later onset of tumorigenesis.

Results
Three hundred thirty patients (12.5%) developed malignancy during follow-up. The median follow-up period was 1511 days (4.1 years; interquartile range, 2487.5 days). Relative to the group with the lowest glycemic variability (first quartile), the groups with higher glycemic variability showed a dose-dependent association with tumorigenesis. The odds ratios for the second, third, and fourth quartiles were 1.20 (95% confidence interval, 0.88–1.65), 1.43 (1.02–2.00), and 2.19 (1.52–3.17), respectively. The mean HbA1c and diabetes mellitus duration periods were not significantly associated with tumorigenesis. This result was consistent when limiting the number of covariates.

Conclusions
These results demonstrated that visit-to-visit HbA1c variability is a potential risk factor for later tumorigenesis. The association may be mediated by oxidative stress or hormone variability. Routine cancer screening may be suggested for diabetic patients with unstable glycemic control.
National Cancer Institute Basket/Umbrella Clinical Trials
Authors: Chen Alice P. , Eljanne Mariam , Harris Lyndsay , Malik Shakuntala , Seibel Nita L. 
Published: July 2019

Abstract
With advances in genetic testing and its common usage, the field of precision medicine has exploded in the field of oncology. The National Cancer Institute is uniquely positioned to lead in this area of research through its wide network of investigators, partnerships with pharmaceutical companies in drug development, and laboratory capabilities. It has developed a portfolio of trials as part of a Precision Medicine Initiative that uses various basket/umbrella designs to increase the understanding of treatment of cancer through genetic selection and targeted therapies. This article describes these trials, ALCHEMIST, LungMAP, NCI/NRG ALK Trial, MPACT, NCI-MATCH, and pediatric MATCH, and their contributions to the area of precision medicine.
Precision Cancer Trials With Immunomodulatory Agents
Authors: Baretti Marina , Azad Nilofer Saba 
Published: July 2019

Abstract
Advances in high-throughput technologies have yielded impressive insights into the molecular biology behind cancers, resulting in a powerful ally for the development of biomarkers-selected clinical trials, which are critical for translating our genomic knowledge into clinically meaningful outcomes. “Basket studies” or histology-agnostic clinical trials in biomarker-defined populations represent an important research strategy to continue making progress in this field. The recent accelerated US Food and Drug Administration approvals of anti–programmed death 1 pembrolizumab and nivolumab for mismatch repair–deficient cancers, as well as larotrectinib for cancers carrying TRK fusions, support the fundamental premise that some cancers may be best classified based on molecular phenotype and not site of origin. The studies that were conducted showing the efficacy of this approach serve as validation of the basket study paradigm. In the field of immune oncology, the advent of tumor agnostic strategies represents an important step toward discovering biomarkers of response and elucidating mechanisms of treatment efficacy and resistance across a variety of cancer types. We present a review and discussion of the progress in biomarker-defined approaches to drug development in immunology.
Defining, Identifying, and Understanding “Exceptional Responders” in Oncology Using the Tools of Precision Medicine
Authors: Tsimberidou Apostolia M. , Said Rabih , Staudt Louis M. , Conley Barbara A. , Takebe Naoko 
Published: July 2019

Abstract
Widely available molecular profiling technology, including next-generation sequencing has changed the landscape of drug development in cancer. An increasing number of clinical trials in early drug development require patient selection based on molecular alterations. Concurrently, efforts to identify molecular alterations in tumors that exhibited exceptional response after systemic treatment with standard or investigational agents have been published or are in progress. These discoveries may ultimately serve as predictive markers or “actionable mutations” for future therapies. To test the feasibility of collecting the archival tissues from proposed exceptional responder patients and successful subsequent molecular profiling, the National Cancer Institute opened a nationwide exceptional responder initiative protocol in 2014. In addition, an increasing number of exceptional responder cases have been identified and published from academia institutions. The Network of Enigmatic Exceptional Responders study uses crowdsourcing to identify exceptional responders and will molecularly profile tumors to discern molecular correlates with exceptional response. In this review, we discuss the potential role of exceptional responder molecular analysis in new biomarker discovery efforts to further advance precision medicine in oncology therapeutics.
Basket Trials and the MD Anderson Precision Medicine Clinical Trials Platform
Authors: Said Rabih , Tsimberidou Apostolia-Maria 
Published: July 2019

Abstract
Precision medicine incorporates information regarding tumor biology involved in patients' carcinogenesis and individualized treatment of patients using drugs that inhibit the molecular basis of their disease. Implementation of precision medicine accelerated the drug approval process, translating discoveries in basic science and biotechnology into patient care. Clinical trials with innovative or adaptive design including “basket” and “umbrella” trials explore personalized therapies against in selected tumor types and/or across tumor types. In 2007, we started the Initiative for Molecular Profiling and Advanced Cancer Therapy, the first precision medicine program across tumor types. We demonstrated that therapy matched to patients' tumor molecular profiling is associated with improved rates of response, progression-free survival, and overall survival compared with nonmatched targeted therapy. We have now entered a new era of precision medicine that includes comprehensive tumor testing and multiple innovative modalities hoping to overcome the complexity of tumor biology to improve patient outcomes.
Quality Improvement Project in Congenital Cardiothoracic Surgery Patients: Reducing Surgical Site Infections
Authors: Hodge Ashley B. , Thornton Brandis A. , Gajarski Robert , Hersey Diane , Cannon Melissa , Naguib Aymen N. , Joy Brian F. , McConnell Patrick I. 
Published: July 2019

Background:
Healthcare-associated infections are a major focus for quality improvement in hospitals today. Surgical site infections (SSIs), a postoperative complication in cardiac surgery, are associated with increased morbidity, mortality, hospital length of stay, and financial burden.

Methods:
A recent increase in cardiothoracic surgery SSIs (CT-SSIs) at our institution instigated a multidisciplinary team to explore infection prevention, bundle element compliance, and to identify interventions to reduce the CT-SSI rate. Key interventions included preoperative screening and decolonization of methicillin-sensitive Staphylococcus aureus and methicillin-resistant S. aureus with repeated intranasal applications of mupirocin, universal skin prep with chlorhexidine for all patients, and additional antibiotic dosing upon initiating cardiopulmonary bypass.

Results:
In 2014, the CT-SSI rate at our institution was 1.9/100 cases, which increased during the “intervention period” to 3.6 infections/100 cases in 2015 (16 total infections). Postinterventions, the CT-SSI rate decreased to 0.3 infections/100 cases (2 total infections), which was significantly lower than our baseline before the spike in infection rate.

Conclusions:
A comprehensive interdisciplinary approach with multiple interventions was successful in significantly reducing the CT-SSI rate in cardiothoracic surgery at a tertiary care pediatric hospital.
A Quality Initiative Reducing Adverse Outcomes in Pediatric Patients with DKA During Intrafacility Transit
Authors: Stoner Michael J. , Burkey Kelli S. , Cohen Daniel M. 
Published: July 2019

Introduction:
Treatment of diabetic ketoacidosis (DKA) requires close and timely monitoring to prevent serious adverse events. This quality improvement project details how our institution improved blood glucose monitoring around hospital admission. The project aimed to increase the blood glucose assessments for children with DKA receiving insulin in the emergency department (ED) within 30 minutes before transitioning to an inpatient unit.

Methods:
We implemented a series of Plan-Do-Survey-Act (PDSA) cycles established by a multidisciplinary team for this project, with the primary outcome of obtaining the blood glucose level within 30 minutes before leaving the ED and secondarily preventing episodes of hypoglycemia. These PDSAs harnessed the electronic health record, to prompt and direct the medical staff, to improve blood glucose monitoring.

Results:
From March 2015 to November 2017, we saw 640 patients in our ED for DKA. Of these, we admitted 629 to the inpatient unit with treatment that included continuous infusion of insulin. Over this period, we increased blood glucose monitoring for these patients within 30 minutes before the transition from 56% to >90%. Following the final PDSA cycle, we observed no reported episodes of hypoglycemia.

Conclusion:
Using the functionality of the electronic health record, we showed significant, rapid, and sustained increases in compliance with the International Society for Pediatric and Adolescent Diabetes guideline by alerting ED staff caring for patients receiving continuous insulin around the time of care-team transitions. We believe that this program is easily replicable, cost-effective, and safety enhancing.
Early Experience with a Novel Strategy for Assessment of Sepsis Risk: The Shock Huddle
Authors: Stinson Hannah R. , Viteri Shirley , Koetter Paige , Stevens Erica , Remillard Kristin , Parlow Rebecca , Setlik Jennifer , Frizzola Meg 
Published: July 2019

Introduction:
Severe sepsis/septic shock (SS), a leading cause of death in children, is a complex clinical syndrome that can be challenging to diagnose. To assist with the early and accurate diagnosis of this illness, we instituted an electronic scoring tool and developed a novel strategy for the assessment of currently hospitalized children at risk for SS.

Methods:
The Shock Tool was created to alert providers to children at risk for SS. Above a threshold score of 45, patients were evaluated by a team from the pediatric intensive care unit (PICU), led by the Shock Nurse (RN), a specially trained PICU nurse, to assess their need for further therapies. Data related to this evaluation, termed a Shock Huddle, were collected and reviewed with the intensivist fellow on service.

Results:
Over 1 year, 9,241 hospitalized patients were screened using the Shock Score. There were 206 Shock Huddles on 109 unique patients. Nearly 40% of Shock Huddles included a diagnostic or therapeutic intervention at the time of patient assessment, with the most frequent intervention being a fluid bolus. Shock Huddles resulted in a patient transfer to the PICU 10% of the time.

Conclusion:
Implementation of an electronic medical record-based sepsis recognition tool paired with a novel strategy for rapid assessment of at-risk patients by a Shock RN is feasible and offers an alternative strategy to a traditional medical emergency team for the delivery of sepsis-related care. Further study is needed to describe the impact of this process on patient outcomes.
Immediate Breast Reconstruction Allows for the Timely Initiation of Postmastectomy Radiation Therapy
Authors: Shammas Ronnie L. , Ren Yi , Thomas Samantha M. , Hollenbeck Scott T. , Greenup Rachel A. , Blitzblau Rachel C. 
Published: July 2019

Background:Complications from breast reconstruction may delay postmastectomy radiation therapy and impact breast cancer outcomes. The authors hypothesized that immediate breast reconstruction may be associated with delays in the initiation of radiation, but that this delay would not significantly impact overall patient survival.Methods:Using the National Cancer Database, the authors identified women with breast cancer who underwent mastectomy and received postmastectomy radiation therapy. Delayed radiation was defined as treatment initiated 6 months or more after surgery in patients who received adjuvant chemotherapyor12 weeks or more after surgery in patients who received neoadjuvant or no chemotherapy.Results:Women undergoing breast reconstruction had an increased time to postmastectomy radiation therapy, 154 days versus 132 days (p< 0.001), and were more likely to experience a delay in initiating radiation (OR, 1.25; 95 percent CI, 1.188 to 1.314). Other factors associated with delayed radiation included increased Charlson/Deyo scores, neoadjuvant chemotherapy, nonprivate insurance, and black race. Cox proportional hazards models revealed no evidence of a reduced adjusted overall survival in the immediate breast reconstruction group (hazard ratio, 0.836; 95 percent CI, 0.802 to 0.871;p< 0.001). Restricted cubic spline analysis identified the threshold number of days at which the start of radiation began to impact survival at 169 days (95 percent CI, 160 to 190 days), 75 days (95 percent CI, 42 to 90 days), and 71 days (95 percent CI, 41 to 90 days) in patients undergoing adjuvant, neoadjuvant, and no chemotherapy, respectively.Conclusion:Immediate breast reconstruction is associated with a modest delay in initiating postmastectomy radiation therapy but does not impact overall survival.CLINICAL QUESTION/LEVEL OF EVIDENCE:Therapeutic, III.
Local Anesthetic Systemic Toxicity: A Narrative Literature Review and Clinical Update on Prevention, Diagnosis, and Management
Authors: Gitman Marina , Fettiplace Michael R. , Weinberg Guy L. , Neal Joseph M. , Barrington Michael J. 
Published: July 2019

Background:
The objective of this narrative review of local anesthetic systemic toxicity is to provide an update on its prevention, diagnosis, and management.

Methods:
The authors used a MEDLINE search of human studies, animal studies, and case reports and summarize findings following the American Society of Regional Anesthesia and Pain Medicine practice advisories on local anesthetic systemic toxicity.

Results:
Between March of 2014 and November of 2016, there were 47 cases of systemic toxicity described. Twenty-two patients (47 percent) were treated with intravenous lipid emulsion and two patients (4.3 percent) died. Seizures were the most common presentation. The spectrum of presenting neurologic and cardiovascular symptoms and signs are broad and can be obscured by perioperative processes. Local anesthetic type, dosage, and volume; site of injection; and patient comorbidities influence the rate of absorption from the site of injection and biodegradation of local anesthetics. Consider discussing appropriate dosages as a component of the surgical “time-out.” A large-volume depot of dilute local anesthetic can take hours before reaching peak plasma levels. Oxygenation, ventilation, and advanced cardiac life support are the first priorities in treatment. Lipid emulsion therapy should be given at the first sign of serious systemic toxicity with an initial bolus dose of 100 ml for adults weighing greater than 70 kg and 1.5 ml/kg for adults weighing less than 70 kg or for children.

Conclusion:
All physicians who administer local anesthetics should be educated regarding the nature of systemic toxicity and contemporary management algorithms that include lipid emulsion therapy.
Ear Reconstruction after Mohs Cancer Excision: Lessons Learned from 327 Consecutive Cases
Authors: Sanniec Kyle , Harirah Muhammad , Thornton James F. 
Published: July 2019

Background:
The ear serves many functional and aesthetic purposes, and its complex structure presents a notable challenge for reconstruction. A paucity of objective data and analysis on reconstruction of acquired ear defects remains. The goal of this study was to evaluate all ear reconstructions and the lessons learned over the past decades in treating these complicated defects in a large clinical Mohs reconstruction practice.

Methods:
A retrospective analysis of consecutive patients who underwent ear reconstruction after Mohs cancer excision from 2004 to 2018 performed by the senior author (J.F.T) was conducted. Data regarding patient demographics, oncologic type, treatment, defect characteristics, reconstructive modalities, number of stages, and complications were collected and analyzed.

Results:
Three hundred twenty-seven patients underwent ear reconstruction. Defects most commonly involved the superior one-third of the helix and the antihelix. Approximately half of the patients’ defects were reconstructed with full-thickness skin grafts, and approximately one-third of the patients’ defects required flap reconstruction. There were 30 complications (9 percent), ranging from partial flap loss to cancer recurrence. There was no difference in complication rates in elderly patients compared with the younger cohort.

Conclusions:
Optimizing results when reconstructing ear defects is challenging, and there are multiple preoperative variables to consider. Ear reconstruction is safe in an outpatient setting, and age should not preclude patients from undergoing reconstruction of ear defects. The lessons learned from the past decade of ear reconstructions are demonstrated, and an algorithmic approach to treating these defects allows for a safe and reproducible method for reconstructing acquired ear defects.

CLINICAL QUESTION/LEVEL OF EVIDENCE:
Therapeutic, IV.
Personality and Hearing Acuity: Evidence From the Health and Retirement Study and the English Longitudinal Study of Ageing
Authors: Stephan Yannick , Sutin Angelina R. , Caille Pauline , Terracciano Antonio 
Published: July 2019

ABSTRACT

Objective
Several determinants of age-related hearing impairment have been identified, but little is known about the predictive value of psychological factors. The present study examined whether five-factor model personality traits are prospectively associated with hearing acuity in middle-aged and older adults.

Methods
Participants were adults aged 50 to 97 years (N > 10,000) drawn from the Health and Retirement Study (2012–2016) and the English Longitudinal Study of Ageing (2010–2014). In each sample, personality, demographic factors, health-related behaviors, body mass index, and memory function were assessed at baseline, and objective hearing acuity was measured 4 years later.

Results
In both samples, higher conscientiousness and openness were associated with better hearing acuity and lower risk of impairment, whereas neuroticism was associated with a higher risk of hearing impairment. In the Health and Retirement Study and English Longitudinal Study of Ageing, respectively, 1 standard deviation (1-SD) higher conscientiousness, 1-SD higher openness, and 1-SD lower neuroticism were related to 13% to 10%, 8% to 6%, and 10% to 13% lower likelihoods of hearing impairment, respectively. In both samples, additional analyses revealed that physical activity and memory mediated the association between personality and hearing.

Conclusions
The present study provides robust evidence for an association between personality traits and hearing function. The findings broaden knowledge on risk and mitigating factors for age-related hearing impairment, which has implications for the quality of life of middle-aged and older adults.