bluuebunny/crossref_metadata_2025 huggingface dataset:
Nodular Regenerative Hyperplasia: Expression Pattern of Glutamine Synthetase and a Potential Role for Hepatic Progenitor Cells
Authors: Guilbert Marie-Christine , Therrien Amelie , Soucy Geneviève , Trudel Dominique , Nguyen Bich N.
Published: July 2019

Nodular regenerative hyperplasia (NRH) is one of the most frequent causes of noncirrhotic intrahepatic hypertension, but is a difficult histologic diagnosis. The expression of glutamine synthetase (GS) and cytokeratin 7 (CK7) has been reported to be increased in other regenerative/vascular conditions, while CK7 and BerEP4 are also markers of hepatic progenitor cells. The aims of this study were to investigate the use of GS, CK7, and BerEP4 as the potential markers for NRH. This is a retrospective case series of NRH at Centre Hospitalier de l’Universite de Montreal between 1993 and 2013. Normal liver from partial hepatectomies for tumors were used as controls. GS, CK7, CK19, and BerEP4 immunohistochemical stains were performed on all specimens. Immunohistochemical staining patterns were scored from 0 to 3+. NRH was identified in 46 samples obtained from 26 patients. Liver chemistry profile was cholestatic in 45% of the patients. In 93% of the NRH cases, there was abnormal zone 2 expression of GS. Weak panacinar GS staining was seen in all the NRH cases. Aberrant CK7 expression was present in all cases of NRH, but were not associated with cholestasis. BerEP4 was overexpressed in 47% of the NRH cases (P<0.05); all cases with diffuse BerEP4 staining also showed extensive CK7 expression (P<0.01). NRH showed increased immunohistochemical GS staining that may support its morphologic diagnosis. Our findings suggest that there is an activation of hepatic progenitor cells in NRH.
Expression of UTX Indicates Poor Prognosis in Patients With Luminal Breast Cancer and is Associated With MMP-11 Expression
Authors: Kim Gi Jeong , Kim Dong-Hoon , Min Kyueng-Whan , Chae Seoung Wan , Kim Se Hoon , Son Byoung Kwan , Moon Kyoung Min , Kim Young Hwan
Published: July 2019

Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX) is involved in the epigenetic regulation. A previous mouse xenograft study revealed that UTX knockdown is associated with downregulated expression of matrix metalloproteinase-11 (MMP-11). The authors investigated 224 cases of breast cancer from Kangbuk Samsung Medical Center between 2000 and 2005. Nuclear UTX and cytoplasmic MMP-11 expressions were assessed using immunohistochemistry of tumor tissue microarray specimens. The relationships between the expression of UTX, MMP-11, and patients’ outcomes were analyzed. UTX expression was significantly associated with high histologic grade, lymphatic invasion, vascular invasion, and tumoral expression of MMP-11. Survival analysis revealed that patients with UTX expression had a poorer overall survival rate (P=0.010) as well as diminished disease-free survival rate (P=0.001). The prognostic power of UTX expression was significant in patients with luminal-type breast cancer (P=0.027, overall survival; P=0.008, disease-free survival). Validation of UTX can provide further prognostic information beyond traditional indicators and represents a potential therapeutic target for breast cancer.
Comparison of PAX8 Expression in Breast Carcinoma Using MRQ50 and BC12 Monoclonal Antibodies
Authors: Singh Kamaljeet , Hanley Linda C. , Sung C. James , Quddus M. Ruhul
Published: July 2019

PAX8 is a specific marker for kidney, ovarian, and thyroid tissue. Antibody-dependent cross-reactivity for PAX8 has been reported in mesothelial, pancreatic, and B-cell proliferations. We recently described antibody clone-dependent aberrant PAX8 expression in breast cancer. In this study we systematically analyze PAX8 expression in breast cancer on whole tissue sections, using MRQ50 and BC12 PAX8 monoclonal antibodies. Immunohistochemistry was performed on formalin-fixed paraffin-embedded whole tissue sections from 85 invasive mammary carcinomas. Immunostaining was evaluated at ×10 objective; extent (intervals of 10%, 0% to 100%) and intensity (weak, moderate, and strong) of nuclear staining was evaluated in the tumor, benign breast tissue, and lymphocytes. With MRQ50 variable PAX8 nuclear positivity was identified in tumor cells in 35/85 (41%) cases. Of 35 PAX8+ cases, 23 (66%) showed only weak expression in 1% to 10% cells, 8 (23%) were weakly (5/8) or moderately (3/8) PAX8+ in 11% to 50% cells, and 4 (11%) showed weak PAX8 positivity in >50% tumor cells. All 3 (3.5%) cases that showed moderate nuclear PAX8 staining with MRQ50 were histologic grade 3. No PAX8 expression was noted in benign lobules/ducts with either antibody. Breast carcinomas can show nuclear immunostaining with MRQ50 PAX8 antibody with up to 3.5% cases showing moderately intense expression. The BC12 PAX8 antibody does not cross-react with breast carcinoma and lymphocytes. During workup of metastatic carcinoma, weak to moderate PAX8 nuclear expression with MRQ50 clone should be interpreted with caution.
p53, Mismatch Repair Protein, and POLE Abnormalities in Ovarian Clear Cell Carcinoma
Authors: Parra-Herran Carlos , Bassiouny Dina , Lerner-Ellis Jordan , Olkhov-Mitsel Ekaterina , Ismiil Nadia , Hogen Liat , Vicus Danielle , Nofech-Mozes Sharon
Published: July 2019

The PROMISE diagnostic algorithm, which uses p53, mismatch repair (MMR) protein immunohistochemistry, and DNA polymerase ε (POLE) exonuclease domain mutation testing, is a reliable surrogate of the molecular group in endometrial carcinoma. Its prognostic value has been validated in endometrial carcinoma and ovarian endometrioid carcinoma. Moreover, a similar prognostic grouping has been recently documented in endometrial clear cell carcinoma. Thus, we aimed to explore the role of these markers in ovarian clear cell carcinoma, another endometriosis-associated malignancy. A total of 90 cases were identified and confirmed after secondary review. Immunohistochemistry for p53, MLH1, MSH2, MSH6, and PMS2 was performed in formalin-fixed, paraffin-embedded tissue. POLE mutational analysis was performed in 47 cases. Results were correlated with clinicopathologic variables including disease-free survival (DFS), overall survival, and disease-specific survival (DSS). Endometriosis was found in 67 (74%) cases. Six (7%) tumors were p53 abnormal, 82 (91%) were p53 normal, and 2 (2%) tumors had MMR deficiency (1 MSH6 loss and 1 MSH2/6 loss; both were p53 normal). Several POLE variants of unknown significance were detected, but no pathogenic mutations. The mean follow-up period was 43 months (median: 34, range: 1 to 189). Abnormal p53 status was associated with advanced Federation of Gynecology and Obstetrics stage, lymph node metastases, DFS and DSS (P<0.05, Fisher exact test). In univariate analysis, abnormal p53 and positive lymph node status had worse DFS, whereas bilaterality, surface involvement, and advanced stage were associated with worse DFS, overall survival and DSS (P<0.05, Cox regression). On multivariate analysis, only stage retained statistical association with survival. Using a molecular-based approach designed for endometrial carcinoma, most ovarian clear cell carcinomas fall into the copy-number-low molecular subgroup. However, a small but important subset has an abnormal p53 expression (copy-number-high group). This subset is associated with adverse features including extrapelvic disease, nodal metastases, and recurrence similar to endometrial and ovarian endometrioid cancer. Thus, testing for this marker has potential prognostic significance. The role of other markers in the PROMISE algorithm remains to be elucidated, as we found a low frequency of MMR abnormalities and no pathogenic POLE mutations in our series.
Tumor Budding in Intrahepatic Cholangiocarcinoma
Authors: Tanaka Mariko , Yamauchi Naoko , Ushiku Tetsuo , Shibahara Junji , Hayashi Akimasa , Misumi Kento , Yasunaga Yoichi , Morikawa Teppei , Kokudo Takashi , Arita Junichi , Sakamoto Yoshihiro , Hasegawa Kiyoshi , Fukayama Masashi
Published: July 2019

Intrahepatic cholangiocarcinoma (ICC) is an extremely aggressive carcinoma. Useful predictors for the patients’ prognosis after surgery have not been fully established. From the University of Tokyo Hospital pathology archives, we reviewed 107 cases of ICC, 54 cases of perihilar cholangiocarcinoma, and 40 cases of extrahepatic cholangiocarcinoma (ECC); we also investigated the significance of tumor budding in ICC, in comparison with perihilar cholangiocarcinoma and ECC. The tumor-budding frequencies were different by tumor location: 40.2% (43/107) in ICC, 70.4% (38/54) in perihilar cholangiocarcinoma, and 60.0% (24/40) in ECC. Tumor budding in ICC was associated with many pathologic indicators associated with invasion, such as major vascular invasion (P=0.012) and Union for International Cancer Control stage (P=0.007). Univariate and multivariate Cox regression analyses revealed tumor budding as a powerful prognostic factor for both recurrence-free survival (RFS) and overall survival (OS) in ICC by univariate (RFS: hazard ratio [HR]: 2.666; 95% confidence interval [CI]: 1.517-4.683, OS: HR: 4.206; 95% CI: 2.447-7.230) and by multivariate analyses (RFS: HR: 3.038; 95% CI: 1.591-5.973, OS: HR: 4.547, 95% CI: 2.348-8.805). Tumor budding was also a significant prognostic factor of perihilar cholangiocarcinoma, but not of ECC. When ICC was divided into 2 subtypes, type 1 (hilar) and type 2 (peripheral), tumor budding was the strong prognostic factor in type 2 ICC, but not in type 1 ICC, suggesting that some differences in biological behavior exist between type 1 ICC and perihilar cholangiocarcinoma. Tumor budding is prognostically important in ICC, and its pathogenetic role in biliary tract carcinomas might be different by anatomic location.
Adverse Histopathologic Characteristics in Small Clear Cell Renal Cell Carcinomas Have Negative Impact on Prognosis
Authors: Yang Chen , Shuch Brian , Serrano Maria , Kibel Adam S. , Nawaf Cayce , Vollmer Robin , Humphrey Peter A. , Adeniran Adebowale J.
Published: July 2019

Tumor size has been used for decision making in the management of patients with renal masses. Active surveillance in selected patients is now increasingly common in tumors ≤4 cm in size. Clear cell renal cell carcinoma (CCRCC) is the most common type of renal malignancy. Adverse histopathologic characteristics that correlate with worse prognosis have been described in CCRCCs. The aim of our study was to determine the frequency and extent of adverse histopathologic characteristics in CCRCCs ≤4 cm and their association with patient outcome. A search of a single institution for nephrectomies performed for CCRCC identified 631 consecutive cases. Cases were reviewed for the following morphologic features: high nuclear grade, necrosis, lymphovascular invasion, and rhabdoid or sarcomatoid histology. Relationships between the variables were examined by Kruskal-Wallis test, Wilcoxon test, χ2 test, and logistic regression. We found adverse tumor histopathologic characteristics were significantly related to size: In CCRCCs >4 versus ≤4 cm, there were more high nuclear grade (45% vs. 15%, P<0.01), necrosis (46% vs. 21%, P<0.01), and lymphovascular invasion (17% vs. 3%, P<0.01). Although adverse histologic features are less commonly seen in CCRCCs ≤4 cm, their presence was associated with lower disease-free survival (P<0.01). Adverse histopathologic characteristics in CCRCCs ≤4 cm correlated with worse prognosis and identification of these features through needle core biopsy examination may guide clinical management, especially in patients for whom active surveillance is considered.
An Uncommon Diagnosis in a Child Presenting With Double Vision and Imbalance
Authors: Sharp Audrey , Santiago Lucia , Dam Aaron , Pereyra Charles , Mihailos Athena
Published: July 2019

Acute disseminated encephalomyelitis (ADEM) is exceptionally uncommon, with approximately 3 pediatric cases reported in the United States each year. Given the uncommon nature of ADEM, most of the current data rely heavily on case reports. The overwhelming majority of cases have been reported after an acute viral infection or vaccination. Although up to 90% of cases exhibit full remission after intravenous steroids, those in which treatment is delayed can display debilitating sequelae. Here, we present a case of ADEM in a 7-year-old boy who presented with double vision and imbalance with no recent history of acute viral infections or vaccinations.
A Call to Restore Your Calling
Authors: Mull Colette C. , Thompson Amy D. , Rappaport David I. , Gartner J. Carlton , Bowman Wesley R.
Published: July 2019

Physicians suffer from most medical conditions at the same rate as their lay peers. However, physicians' self-care is often sacrificed for patient care. This third article in our series examines physician and trainee illness and impairment. Presenteeism, physician impairment, and substance use disorder (SUD) are defined. We call attention to the potential for harm of dated cultural norms, which often fuel physicians' neglect of their own health and development of ill-advised coping skills.

Although any medical condition may become a functional impairment, the primary cause of physician impairment is SUD. Alcohol and prescription opioids top the list of substances used in excess by physicians. Although SUD is less prevalent in residency, we focus on the rise of marijuana and alcohol use in emergency medicine trainees. A nonpunitive model for the prevention and treatment of SUD in residency is described.

Physicians are ethically and legally mandated to report any concern for impairment to either a state physician health program or a state medical board. However, recognizing physician SUD is challenging. We describe its clinical presentation, voluntary and mandated treatment tracks, provisions for protecting reporters from civil liability, prognosis for return to practice, and prevention efforts. We underscore the need to model healthy coping strategies and assist trainees in adopting them.

In closing, we offer our colleagues and trainees today's to-do list for beginning the journey of reclaiming your health. We also provide resources focused on the practical support of ill and/or impaired physicians.
Implementation of an Innovative, Multiunit, Postevent Debriefing Program in a Children's Hospital
Authors: Zinns Lauren E. , Welch-Horan Thomas B. , Moore Thomas A. , Ades Anne , Wolfe Heather A. , Mullan Paul C.
Published: July 2019

Background

Postevent debriefing has been associated with improved resuscitation outcomes and is recommended by the American Heart Association and the American Academy of Pediatrics to improve clinical performance.

Objective

Despite the benefits of postevent debriefing, published debriefing programs have focused on single areas within a hospital. We are unaware of any hospital-wide debriefing programs implemented in a pediatric setting.

Methods

We established a multidisciplinary, interprofessional debriefing collaborative at the Children's Hospital of Philadelphia to implement postevent debriefings in multiple areas of the hospital. The collaborative created a standardized debriefing form to capture data about the postevent debriefings.

Results

From July 23, 2015 to December 31, 2017, the emergency department performed 153 debriefings (18%) for 850 resuscitations. The neonatal intensive care unit conducted 10 debriefings (9%) for 107 resuscitations, and the pediatric intensive care unit performed 5 debriefings (7%) for 73 resuscitations.

Conclusions

Several departments at the Children's Hospital of Philadelphia have incorporated hot and cold debriefings into their clinical practice as part of their continuous quality improvement programs. By disseminating the tools and lessons learned from the implementation process, the collaborative hopes that other institutions will benefit from their lessons learned to successfully create their own debriefing programs. Widespread adoption of debriefing programs will enable a more scientific approach to studying the outcomes of debriefing.
Clinical, Radiographic, and Ultrasound Findings Between Simple and Complicated Baker’s Cysts
Authors: Park Gi-Young , Kwon Dong Rak , Kwon Dae Gil
Published: July 2019

Purpose

The aim of the study was to compare the clinical, radiographic, and ultrasound findings between simple and complicated Baker’s cysts.

Methods

Forty-seven knees with Baker’s cysts in 45 patients with knee pain were identified from a chart review. Baker’s cysts were classified as simple or complicated according to ultrasound findings. Clinical data, including duration of knee pain, visual analog scale score, Kellgren-Lawrence grade, ultrasound findings, including the size and sonomorphology of the BC, severity of osteophytosis, thickness of joint effusion, meniscal tear, and synovial proliferation of the two types of BC, were compared.

Results

There were 22 knees with a simple cyst and 25 knees with a complicated cyst. The thickness of the suprapatellar effusion in complicated Baker’s cysts (5.7 ± 3.0 mm) was significantly greater than that in simple Baker’s cysts (3.8 ± 3.2 mm), and the presence of synovial proliferation in the suprapatellar recess was significantly higher in complicated Baker’s cysts (22 knees, 88.0%) than in the simple Baker’s cysts (12 knees, 54.5%). However, there were no significant differences in demographic, radiographic, and other ultrasound parameters between the two types of BC.

Conclusions

Synovial proliferation with larger effusion in the suprapatellar recess was more associated with complicated BC than simple BC.
Compensation Strategies in Response to Fatiguing Propulsion in Wheelchair Users
Authors: Bossuyt Fransiska M. , Arnet Ursina , Cools Ann , Rigot Stephanie , de Vries Wiebe , Eriks-Hoogland Inge , Boninger Michael L.
Published: July 2019

Objective

The aims of the study were to examine whether fatigue-inducing wheelchair propulsion changes neuromuscular activation and propulsion biomechanics and to determine predictor variables for susceptibility to fatigue.

Design

This study with a quasi-experimental, one-group, pretest-posttest design investigates a population-based sample of wheelchair users with a spinal cord injury (n = 34, age: 50.8 ± 9.7 yrs, 82% males). Neuromuscular activation and propulsion biomechanics during treadmill propulsion at 25 W and 45 W were assessed before and after a protocol designed to cause fatigue.

Results

With the induced fatigue, wheelchair users propelled with increased neuromuscular activation in the pectoralis major pars sternalis, deltoideus pars acromialis and upper trapezius (45 W, P < 0.05), and a slightly reduced push angle (25 W: 75–74 degrees, P < 0.05, 45 W: 78–76 degrees, P < 0.05). Wheelchair users susceptible to fatigue (47%) were more likely to have a complete lesion, to be injured at an older age, and had less years since injury. This group propelled in general with shorter push angle and greater maximum resultant force, had a greater anaerobic capacity, and had less neuromuscular activation.

Conclusions

Compensation strategies in response to fatiguing propulsion could increase the risk for shoulder injury. Predictor variables for susceptibility to fatigue inform interventions preserving shoulder health and include lesion characteristics, propulsion technique, anaerobic capacity, and neuromuscular activation.

To Claim CME Credits

Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME

CME Objectives

Upon completion of this article, the reader should be able to: (1) Explain a neuromuscular compensation strategy and the corresponding muscles in response to fatiguing wheelchair propulsion; (2) Recommend propulsion biomechanics associated to reduced susceptibly to fatiguing wheelchair propulsion; and (3) List examples of predictor variables of susceptibility to fatigue.

Level

Advanced.

Accreditation

The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Association of Academic Physiatrists designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
Quantitative Evaluation of Interference Patterns on Electromyography in Neuropathy
Authors: Kobayashi Yukiko , Akaboshi Kazuto , Takahashi Osamu , Liu Meigen
Published: July 2019

Objective

The aim of this study was to develop a quantitative evaluation method of interference patterns on needle electromyography that is easy to apply in clinical use and to examine its usefulness. Diagnostic electrophysiological assessments are important for physiatrists, and correct diagnosis and assessment are essential for proper rehabilitation.

Design

A total of 112 maximum interference patterns of upper extremity muscles suspected of being affected by neuropathy were quantitatively evaluated based on the parameters of integration values, mean amplitudes, the number of peaks, and activity. “Activity” was defined as the sum of the time during which myoelectric signals were recorded during 1 sec with maximum voluntary contraction, and it was expressed as a percentage. The relationships of the previous parameters with spontaneous pathological potentials and polyphasic motor unit potentials were examined.

Results

The area under the curve of the receiver operating characteristic curve for the diagnosis of neuropathy was the highest using activity (0.917). The integral value and mean amplitude were useful for the diagnosis of cases with chronic neuropathy showing slightly decreased interference patterns.

Conclusions

The quantitative evaluation of the maximal contraction interference pattern in this study was useful for the diagnosis of neuropathy.
Reduction in Thigh Muscle Strength Occurs Concurrently but Does Not Seem to Precede Incident Knee Pain in Women
Authors: Ruhdorfer Anja , Wirth Wolfgang , Culvenor Adam G. , Eckstein Felix
Published: July 2019

Objective

The aim of the study was to investigate whether muscle strength declines before or concurrent with incident knee pain in subjects with and without radiographic knee osteoarthritis.

Design

Osteoarthritis initiative participants with incident knee pain (occurrence of infrequent/frequent knee pain during the past 12 mos at two consecutive follow-up time points (either years Y3 + Y4 or Y4 + Y5) were compared with controls (no incident knee pain) with 2-yr changes in knee extensor strength during BL➔Y2 (before) and Y2➔Y4 (concurrent).

Results

Two hundred two knees (49% women, 40% radiographic knee osteoarthritis) displayed incident pain, and 439 did not (46% women, 23% radiographic knee osteoarthritis). Women with radiographic knee osteoarthritis displayed a significantly greater (P = 0.04) reduction in knee extensor strength concurrent with incident pain compared with controls (mean = −17.6 N vs. +4.5 N), but men did not. A similar trend was observed in women without radiographic knee osteoarthritis, but this was not statistically significant (P = 0.08). There was no significant relationship with change in extensor strength before incident pain (P ≥ 0.43).

Conclusions

These results suggest that in women, incident knee pain is accompanied by a concurrent reduction in knee extensor strength, whereas loss in strength does not precede incident knee pain. The findings encourage interventional studies that attempt to attenuate a decline in extensor strength once knee symptoms occur.
Future Approaches to Precision Oncology–Based Clinical Trials
Authors: Mittra Arjun , Moscow Jeffrey A.
Published: July 2019

The last 2 decades have seen a rapid advance of the precision oncology paradigm—from its early singular successes to becoming the prevailing model of cancer therapy. As the treatment of cancer moves away from traditional chemotherapy, so too will oncology clinical trials have to move away from the traditional model of phase I to phase III progression of drug development. Achieving this goal of individualized care will involve a concerted effort by the entire cancer care community to fundamentally change the design and implementation of oncology clinical trials. We envision that the next 2 decades will be a period of evolution in precision oncology clinical trials through scientific and technologic advances, transformation of clinical trial infrastructure, and changes in the kind of evidence required for regulatory approval.
Biostatistical and Logistical Considerations in the Development of Basket and Umbrella Clinical Trials
Authors: Yee Laura M. , McShane Lisa M. , Freidlin Boris , Mooney Margaret M. , Korn Edward L.
Published: July 2019

Oncology clinical trials are undergoing transformation to evaluate targeted therapies addressing a wider variety of biologically defined cancer subgroups. Multiarm basket and umbrella trials conducted under master protocols have become more prominent mechanisms for the clinical evaluation of promising new biologically driven anticancer therapies that are integral to precision oncology medicine. These new trial designs permit efficient clinical evaluation of multiple therapies in a variety of histologically and biologically defined cancers. These complex trials require extensive planning and attention to many factors, including choice of biomarker assay platform, mechanism for processing clinicopathologic and biomarker data to assign patients to substudies, and statistical design, monitoring, and analysis of substudies. Trial teams have expanded to include expertise in the interface between biology, clinical oncology, bioinformatics, and statistics. Strategies for the design, conduct, and analysis of these complex trials will continue to evolve to meet new challenges and opportunities in precision oncology medicine.
Clinical Applications of Next-Generation Sequencing in Precision Oncology
Authors: Karlovich Chris A. , Williams P. Mickey
Published: July 2019

The ability of next-generation sequencing (NGS) to comprehensively assess the molecular profile of a tumor specimen has transformed the clinical testing landscape in oncology. Accordingly, recent years have seen broad uptake of clinical NGS to inform cancer patient management. However, significant challenges remain. The annotation and clinical interpretation of variants identified by NGS tests often require rigorous review and may vary between laboratories. While a clearer regulatory path has emerged, reimbursement for NGS tests remains a subject of continuing debate. Basket clinical studies such as the National Cancer Institute Molecular Analysis of Therapy Choice are evaluating the degree to which matching of a targeted therapy to tumor molecular profile by NGS can be applied independently of tissue histology. Newer applications of NGS such as for circulating tumor DNA testing and to identify novel RNA fusion driver events continue to expand its clinical utility.
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

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

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

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

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

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.