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Κυριακή 3 Ιανουαρίου 2021

Trauma and Acute Care Surgery

Changes in Traumatic Mechanisms of Injury in Southern California Related to COVID-19: Penetrating Trauma as a Second Pandemic
Background The COVID-19 pandemic resulted in a statewide stay-at-home (SAH) order in California beginning March 19, 2020, forcing large-scale behavioral changes and taking an emotional and economic toll. The effects of SAH orders on the trauma population remains unknown. We hypothesized an increase in rates of penetrating trauma, gunshot wounds, suicide attempts, and domestic violence in the Southern California trauma population after the SAH order. Methods A multicenter retrospective analysis of all trauma patients presenting to 11 American College of Surgeons (ACS) Level I and II trauma centers spanning seven counties in California was performed. Demographic data, injury characteristics, clinical data, and outcomes were collected. Patients were divided into three groups based on injury date: before SAH from 1/1/2020-3/18/2020 (PRE), after SAH from 3/19/2020-6/30/2020 (POST), and a historical control from 3/19/2019-6/30/2019 (CONTROL). POST was compared to both PRE and CONTROL in two separate analyses. Results Across all time periods, 20,448 trauma patients were identified (CONTROL: 7,707, PRE: 6,022, POST: 6,719). POST had a significantly increased rate of penetrating trauma (13.0% vs. 10.3%, p<0.001 and 13.0% vs. 9.9%, p<0.001) and gunshot wounds (4.5% vs. 2.4%, p=0.002 and 4.5% vs. 3.7%, p=0.025) compared to PRE and CONTROL, respectively. POST had a suicide attempt rate of 1.9% and a domestic violence rate of 0.7%, which were similar to PRE (p=0.478, p=0.514) and CONTROL (p=0.160, p=0.618). Conclusions This multicenter Southern California study demonstrated an increased rate of penetrating trauma and gunshot wounds after the COVID-19 SAH orders, but no difference in attempted suicide or domestic violence rates. These findings may provide useful information regarding resource utilization and a target for societal intervention during the current or future pandemic(s). Level of Evidence IV Corresponding Author: Jeffry Nahmias, 333 The City Blvd West, Suite 1600 | Orange, CA, USA 92868-3298 at jnahmias@hs.uci.edu or (714) 456-4553 or Fax: (714) 456-6048 Conflicts of Interest: The authors report that there are no conflicts of interest Meetings: None Disclosures: The authors report that there are no financial disclosures This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections. © 2020 Lippincott Williams & Wilkins, Inc.

"Safer at Home": The effect of the Covid-19 Lockdown on Epidemiology, Resource Utilization and Outcomes at a Large Urban Trauma Center
Background The COVID-19 pandemic has affected the entire global healthcare system. In California, due to a high burden of cases, a lockdown order was announced on March 19th, 2020. This study investigated the impact of the lockdown on the epidemiology and outcomes of trauma admissions at the largest trauma center in Los Angeles. Methods Retrospective study comparing epidemiological and clinical characteristics and outcomes of trauma admissions, during the lockdown period (03/20/2020 to 06/30/2020) to a similar period in the previous year (03/20/2019 to 06/30/2019). Data collection included demographics, mechanism of injury, prehospital transportation, substance use, injury severity, resource utilization, and outcomes. Findings There were 1,202 admissions during the lockdown period in 2020 and 1,143 during the same calendar period in 2019. Following the lockdown, there was a reduction in the automobile versus pedestrian admissions by 42.5%, motorcycle injuries by 38.7%, and bicycle accidents by 28.4%, but no significant effect on the number of motor vehicle accident admissions. There was an increase in ground level falls by 32.5%, especially in the elderly group. The absolute number of gunshot wounds increased by 6.2% and knife injuries by 39.3%. Suicides increased by 38.5%. Positive testing for substance use increased by 20.9%. During the lockdown patients suffered less severe trauma, with ISS<9 (p<0.001), as well as less severe head (p=0.001) and severe chest trauma (p<0.001). Trauma deaths were reduced by 27.9% and the crude overall mortality was significantly lower during the lockdown period (4.1% vs 5.9%, p= 0.046). ICU admission rates, mechanical ventilation, and ICU LOS were all reduced. Conclusions The COVID-19 lockdown in 2020 had a significant effect on the epidemiology, clinical characteristics and critical care resource utilization of trauma admissions in a large academic trauma center. These findings may help in planning and optimization of hospital resources during the pandemic. Level of Evidence Therapeutic, level III study type Retrospective observational Grant support: None Conflicts of interest: None Statement of human rights: The study was approved by the Institutional Review Board of the University of Southern California Address for Correspondance: Demetrios Demetriades MD, PhD, FACS, Professor of Surgery, Department of Surgery, University of Southern California, Los Angeles, demetria@usc.edu This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections. © 2020 Lippincott Williams & Wilkins, Inc.

Advanced age heightens hepatic damage in a murine model of scald burn injury
Background: Elderly burn patients exhibit a lower survival rate compared with younger counterparts. The liver is susceptible to damage after burn injury, which predisposes to poor outcomes. Lipid homeostasis and the antioxidant glutathione system play fundamental roles in preserving liver integrity. Herein, we explored changes in these major pathways associated with liver damage in the aging animals after burn injury. Methods: We compared liver enzymes, histology, lipid-peroxidation, and glutathione-metabolism profiles from young and aged female mice after a 15% total-body-surface-area burn. Mice were euthanized at 24hours after injury, and livers and serum were collected. Results: Aged burn animals exhibited elevated (p< 0.05) Aspartate-aminotransferase (AST), Alanine-aminotransferase (ALT) levels, and increased inflammatory cell infiltration, edema, and necrosis compared to their younger counterparts. The percentage of adipophilin-stained area in livers from young sham, young burn, aged sham, and aged burn groups was 10%, 44%, 16%, and 78% (p< 0.05), respectively. Liver malonaldehyde (DMA) levels were 1.4 ± 0.5, 2.06 ± 0.2, 1.81 ± 0.12, and 3.45 ± 0.2 nmol/mg (p< 0.05) in young sham, young burn, aged sham, and aged burn mice, respectively. Oxidized glutathione (GSSG) content increased 50% in the young burn, and 88% in aged burn animals compared with the young sham group (p< 0.05). The reduced glutathione GSH/GSSG ratio was significantly reduced by 54% in aged burn mice compared to young sham animals (p< 0.05). Furthermore, glutathione peroxidase (GPX) gene expression showed a 96% decrease in the aged burn group compared to young sham mice (p< 0.05). Conclusions: Aged burn animals exhibit severe liver damage from heightened lipid peroxidation and inadequate antioxidative response. The increased peroxidation is associated with abundant lipid deposits in hepatic tissue post-burn and a weak antioxidative response due to hepatic GPX downregulation. Further studies will focus on the functional significance of these findings concerning hepatic homeostasis. Level of evidence This is a basic science paper and, therefore, does not require a level of evidence. Study Type Basic Sciences Conflict of interest: None Disclosures of funding: (Supported by K08GM134185 (J.P.I.) and R01AG018859, R01GM115257, R35GM131831, 1 I01 BX004335 (E.J.K.).) Juan-Pablo Idrovo, M.D., Assistant Professor of Surgery and Critical Care., University of Colorado Denver / Anschutz Medical Campus, 12631 E. 17th Ave, Room 6001, Aurora, CO 80045. Office: 303-724-8366, Fax: 303-724-2733. Email: juan.idrovo@cuanschutz.edu © 2020 Lippincott Williams & Wilkins, Inc.

Letter to the editor, regarding "Timing and volume of crystalloid and blood products in pediatric trauma: An Eastern Association for the Surgery of Trauma multicenter prospective observational study"
No abstract available

TRAUMA PATIENT TRANSPORT TIMES UNCHANGED DESPITE TRAUMA CENTER PROLIFERATION: A 10 YEAR REVIEW
Introduction In certain regions of the U.S. there has been a dramatic proliferation of trauma centers. The goal of our study was to evaluate transport times during this period of trauma center proliferation. Methods Aggregated data summarizing level I trauma center admissions in Arizona between 2009 and 2018 were provided to our institution by the Arizona Department of Health Services. We evaluated patient demographics, transport times and injury severity for both rural and urban injuries. Results Data included statistics summarizing 266,605 level I trauma admissions in the state of Arizona. The number of state-designated trauma centers during this time increased from 14 to 47, with level I centers increasing from 8 to 13. Slight decreases in mean ISS (rural 9.4 vs. 8.4; urban 7.9 vs 7.0) were observed over this period. Median transport time for cases transported from the injury scene directly to a level I center remained stable in urban areas at 0.9 hours in both 2009 and 2018. In rural areas, transport times for these cases were approximately double, but also stable, with median times of 1.8 and 1.9 hours. Transport times for cases requiring inter-facility transfer prior to admission at a level I center increased by 0.3 hours for urban injuries (5.3 hours to 5.6) and 0.9 hours for rural injuries (5.6 to 6.5). Conclusion Despite the 3-fold increase in the number of state-designated trauma centers, transport time has not decreased in urban or rural areas. This finding highlights the need for regulatory oversight regarding the number and geographic placement of state-designated trauma centers. Level of Evidence III The authors declare no conflicts of interest. The study was presented as a Quickshot at the 79th Annual Meeting of AAST & Clinical Congress of Acute Care Surgery held online instead of Waikoloa, Hawaii, September 9-12, 2020. Corresponding Author: Jordan A. Weinberg, MD, Division Chief, Trauma/Acute General Surgery, Trauma Administration, St. Joseph's Hospital and Medical Center, 350 W. Thomas Road, Phoenix, AZ 85013. Tel: (602) 406-3157. Email: JordanWeinberg@Creighton.edu © 2020 Lippincott Williams & Wilkins, Inc.

Transfuse for Hemodynamics Not Hemodilution – Response to Letter to the Editor regarding timing and volume of crystalloid and blood products in pediatric trauma: An Eastern Association for the Surgery of Trauma multicenter prospective observational study
No abstract available

Fast Track Pathway Provides Safe, Value Based Care on Busy Acute Care Surgery Service
Abstract: Background Fast track(FT) pathways have been adopted across a multitude of elective surgeries but have been slow to be adopted into the acute care surgery(ACS) realm. We hypothesized that a FT pathway for acute cholecystitis patients would decrease patient length of stay and resource utilization. Methods All patients at two hospitals, one with a FT pathway and one with a traditional pathway, that underwent an urgent laparoscopic cholecystectomy for acute cholecystitis between May 1, 2019 and October 31, 2019 were queried using CPT codes. Exclusion criteria were conversion to open or partial cholecystectomy. Retrospective chart review was used to gather demographics, operative, hospital course, and outcomes. Time to OR, hospital length of stay, and resource utilization were the primary outcomes. Results There was a total of 479 urgent laparoscopic cholecystectomies performed, four hundred and thirty(89.8%) were performed under the FT pathway. The median[IQR] time to the OR was not different: 14.1 hours[8.3-29.0 hours] for FT and 18.5 hours[11.9-25.9 hours] for traditional(p=0.316). However, the median length of stay was shorter by 15.9 hours in the FT cohort(22.6 hours, [14.2-40.4] vs 38.5 hours,[28.3-56.3];p<0.001). Under the FT pathway, 33.0% of patients were admitted to the hospital and 75.6% were discharged from the PACU, compared to 91.8% and 12.2% on the traditional pathway(both p<0.001). 59.6% of FT patients received a phone call follow up, as opposed to 100% of the traditional patients having clinic follow up(p<0.001). ED bounce back rate, readmission rates, and complication rates were similar(p>0.2 for all). On multivariate analysis, having a fast track pathway was an independent predictor of discharge within 24 hours of surgical consultation(OR 7.65, 95% CI 2.90-20.15, p<0.001). Conclusions Use of a fast track program for patients with acute cholecystitis has a significant positive impact on resource utilization without compromise of clinical outcomes. Level of Evidence Level III, Therapeutic/Care Management Disclosures: All authors have no relevant financial conflicts or personal relationships that could inappropriately influence this work or its conclusions. Sources of funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors Presented at the 79th Annual Meeting of American Association for the Surgery of Trauma, September 8-18th, 2020 as a podium presentation. Address correspondence to: Kali Kuhlenschmidt, MD, University of Texas Southwestern Medical Center, Division of General and Acute Care Surgery, 5323 Harry Hines Blvd., Dallas, Texas 75390-9158. Kali.Kuhlenschmidt@UTSouthwestern.edu. (812) 483-1782 © 2020 Lippincott Williams & Wilkins, Inc.

Efficacy and feasibility of Amniotic membrane for the treatment of burn wounds: a meta-analysis
No abstract available

Roadway Features Associated with Elderly Drivers in Motor Vehicle Crashes
Background As the number of older US drivers has increased over the past decades, so has the number of injuries, hospitalizations, and deaths from motor vehicle crashes (MVCs) involving elderly drivers. We seek to identify personal, environmental, and roadway features associated with increased crashes involving elderly drivers. We hypothesize that elderly drivers are more likely to be involved in MVCs at intersections with more complex signage and traffic flow. Methods This is a retrospective observational study using 2015-2019 police traffic crash reports and a Department of Public Health database of built-environment variables from a single urban center. Demographics and environmental/road features were compared for vehicle-only MVCs involving elderly (≥ 65 years) and younger drivers. Chi-squared and nonparametric tests were used to analyze 36,168 drivers involved in MVCs. Results There were 2,575 (7.1%) elderly drivers involved in MVCs during the study period. Left turns and all-way stop signs were associated with increased crash risk among elderly drivers compared to younger drivers. Elderly-involved MVCs were less likely to occur at intersections with left-turn restrictions, traffic lights, only one-way streets, and bike lanes compared to MVCs with younger drivers. Elderly drivers were more likely to be involved in MVCs on weekdays, less often intoxicated at the time of the crash, and less frequently involved in fatal MVCs compared to younger drivers. However, elderly drivers were more frequently the at-fault party, especially after age 75. Conclusions Updates to roadway features have potential to decrease injury and death from MVCs involving elderly adults. Left turn restrictions or other innovative safety treatments at all-way stops or where left turns are permitted may mitigate road crashes involving older adults. Education may increase awareness of higher-risk driving tasks such as turning left, and driving alternatives including public transportation/paratransit may offer alternate means to maintain activities of daily living. Level of Evidence Level IV Conflict of Interest: The authors have no disclosures Presentation: Presented at the 79th Annual Meeting of the American Association for the Surgery of Trauma and Clinical Congress of Acute Care Surgery, September 9-12, 2020 in Waikoloa, Hawaii (Virtual) Disclosures of Funding: None © 2020 Lippincott Williams & Wilkins, Inc.

The expression of repulsive guidance molecule a (RGMa) after traumatic brain injury: Time-course changes in gene expression in a murine model of controlled cortical impact
INTRODUCTION Repulsive guidance molecule a (RGMa) is a key protein that negatively regulates neuronal regeneration as its inhibition enhances axonal growth and promotes functional recovery in animal models of spinal cord injury. However, the role of RGMa in traumatic brain injury (TBI) remains elusive. This study aimed to clarify TBI-responsive RGMa expression in a murine model. METHODS Adult male C57Bl/6J mice were subjected to controlled cortical impact. Brains were extracted 6 hours and 1, 3, 7, 14 and 21 days after injury (n=6 in each group). Changes in the mRNA expression of RGMa and its receptor, neogenin, were evaluated by quantitative polymerase chain reaction in the damaged area of the cortex and contralateral cortex, along with expression measurement of inflammation-related molecules. Neurological deficit was also assessed by the cylinder test. RESULTS Neurological score was consistently lower in the TBI group compared to the sham group throughout the experimental period. mRNA expressions of representative inflammatory cytokine TNF-alpha and chemokine CCR2 were remarkably increased in the injured cortex on day 1 and gradually decreased over time, although remaining at higher values at least until day 14. mRNA expressions of RGMa and neogenin were significantly suppressed in the damaged cortex until day 3. Interestingly, RGMa expression was suppressed most on day 1 and recovered over time. CONCLUSION In the acute phase of TBI, gene expression of inflammatory cytokines significantly increased, and gene expressions of RGMa and neogenin significantly decreased in the inflammatory milieu of the damaged area. Despite the subsequent remission of inflammation, RGMa gene expression recovered to the normal level one week after TBI. Intrinsic regenerative response to acute brain injury might be hampered by the following recovery of RGMa expression, hinting at the possibility of functional RGMa inhibition as a new, effective maneuver against TBI. Corresponding author: Goro Tajima, MD, PhD, Assistant Professor, Nagasaki University Hospital, Emergency and Critical Care Center, 1-7-1 Sakamoto, Nagasaki city 852-8501, Japan, Tel: +81(095) 819-7765, Fax: +81(095) 819-7978 E-mail: gtajima@nagasaki-u.ac.jp This study was presented at the 79th AAST annual meeting, Sept. 8-18, 2020, Virtual AAST Annual Meeting Conflicts of Interest and Source of Funding: All authors declare no conflicts of interest. This work was supported by the Japan Society for the Promotion of Science Grant-in-Aid Scientific Research (B) (No. 18H02903), and a research funding from Mitsubishi Tanabe Pharma Corporation. © 2020 Lippincott Williams & Wilkins, Inc.


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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,
Telephone consultation 11855 int 1193,

Current Oncology

Androgen receptor: A new player in triple negative breast cancer management
Anurag Mehta, Atika Dogra

Journal of Current Oncology 2020 3(2):51-54



Can a low-energy photon beam be suitable for the treatment of cervical malignancies? A dosimetric analysis
Manindra Bhushan, Deepak Tripathi, Lalit Kumar, Rahul Lal Chowdhary, Anjali Kakria, Pawan Kumar, Swarupa Mitra, Munish Gairola

Journal of Current Oncology 2020 3(2):55-61

Background: Radiotherapy to a patient with cervical cancer can be delivered by four-field &#8220;box technique&#8221; with a benefit of much less dose to intervening tissues along with a better and homogenous dose distribution at the target location. An important ingredient for a good radiotherapy planning is the choice of beam energy. The present study aims to investigate the feasibility of a 4 MV photon beam for the treatment of cervical cancers. Materials and Methods: A population of 20 patients, with carcinoma cervix, was included in the study. All the patients were planned for a prescribed dose of 45 Gy in 25 fractions. Results: Plans were evaluated for planning target volume and found better in terms of coverage and hot spots using 6 MV. The homogeneity index (HI) was 1.1 for both the energies. Similarly, conformity index (CI) was 2.0 depending on the method used for 4 MV and 6 MV photons. Although the HI and CI were comparable for both the plans, yet it seems significantly better for 6 MV. This indicates that spillage in 6 MV plans is lesser as compare to 4 MV. The present study reveals that there is a significant reduction in total monitor units in the plans with 6 MV photon beams, leading to fewer chances of secondary malignancies. Conclusion: A 6 MV photon beam has some proven mileage over 4 MV in terms of target coverage, dose homogeneity, and conformity and remains the best suitable photon energy for the treatment of cervical malignancies.


Indeterminate pulmonary nodules among patients with new diagnosis of colorectal cancer: Prevalence and significance assessment
Nidal H Bokhary, Abdulrahman A Alghamdi, Faisal A Alfaidi, Khaled A Alfaidi, Naif H Aljohani, Fahad K Alshammari, Omar Iskandrani, Hanaa Tashkandi, Atlal Abusanad

Journal of Current Oncology 2020 3(2):62-65

Background: In Saudi Arabia, colorectal cancer (CRC) accounts for 11.5% of cancer incidence, where nearly one-third is metastatic. Global guidelines recommend accurate pretreatment staging to determine resectability and stage-directed treatment. Computed tomography (CT) scan is among the widely used imaging for staging. However, at times, the characterization of abnormalities detected by CT scan is perplexing. Indeterminate pulmonary nodules (IPNs) are nodules that are neither benign nor malignant, which are incidentally detected on baseline staging chest CT. We aimed to estimate the prevalence of IPN that were identified among CRC patients. Materials and Methods: We conducted a retrospective record review of all newly diagnosed CRC patients between June 2013 and June 2018 from an academic hospital in Jeddah, Kingdom of Saudi Arabia (KSA). Demographics and certain prespecified variables were collected. The presence of IPN on staging chest CT as per consultant radiologist report was documented, and the ability of other modalities to identify the nature of IPN was compared. Data were analyzed using SPSS and a P value &#0060; 0.05 was considered significant. Results: Of 283 CRC patients, 208 (73.5%) underwent chest CT, and the mean age was 57.4 years (&#177;SD 13.1). The prevalence of IPN among CRC patients is 17.7%. Thirty IPN patients had a follow-up chest CT for IPN, which identified IPN nature in 18(60%) of them. The likelihood of IPN to be CRC-related metastasis was significantly associated with the presence of synchronous liver metastasis (P = 0.0005), younger age (P = 0.022), and colon cancer (P = 0.011). Conclusion: The prevalence of IPN was 17.7%, which is different in comparison to other studies from different countries. There is a vital need for unified guidelines describing IPN to accurately stage CRC patients, decrease unnecessary follow-ups, and acquire the exact prevalence of IPN.


Biomarkers in colon cancer and its clinical implications
Vijay Kumar Srinivasalu, Keechilat Pavithran

Journal of Current Oncology 2020 3(2):66-71

Colorectal cancers have been a major burden in our society, with nearly 20,000 deaths in a year. Most of the patients are diagnosed with metastatic disease at presentation and have shorter survival despite the best effective treatment. The detection of novel targets and predictive biomarkers has changed the treatment paradigm, resulting in improved quality of life and prolonged survival in these patients. However, the identification of an ideal biomarker has been a major challenge and a quest for better biomarkers to detect premalignant lesions, early-stage cancers; to identify high-risk subsets who derive maximum benefit from adjuvant chemotherapy and minimize unnecessary chemo-toxicity; to identify newer targeted therapies in advanced stage to improve clinical responses; and to provide personalized treatments that would significantly help in improving survival outcomes. In this review article, we provide an overview of the biomarkers with clinical importance and an update on newer noninvasive, sensitive, and clinically reliable biomarkers in development.


Multiple myeloma: an update
Lalit Kumar, Sukesh Nair, Surya Prakash Vadlamani, Priyanshu Chaudhary

Journal of Current Oncology 2020 3(2):72-80

Survival of patients with multiple myeloma has increased significantly during the past two decades. This has been attributed to a better understanding of biology, the introduction of novel agents (immunomodulators, proteasome inhibitors), autologous stem cell transplantation, and maintenance therapy. Supportive care is an important component of overall care for these patients. Most patients have a high burden of symptoms at initial presentation in form of bone pains, fatigue, anemia, renal impairment, and infections, etc. Almost 10&#8211;20% of patients may have serious complications in the first 4&#8211;6 weeks. A high index of suspicion and timely intervention is important to reduce morbidity and mortality. Therapy-related complications, e.g., neuropathy, thromboembolism, cytopenias, GI symptoms (constipation/diarrhea), and relapse of disease, pose therapeutic challenges. Protocol-based approach, systematic assessment with respect to the quality of life and functioning and coordination with a palliative care team from the beginning may improve overall functioning and outcome.


A twisted tale of a family with multiple malignancies: Mystery solved
Anurag Mehta, Shrinidhi Nathany

Journal of Current Oncology 2020 3(2):81-83



Utilization of hydro-dissection: A novel technique during ongoing COVID pandemic
Abhishek Bansal, Arvind K Chaturvedi, Rajiv Kapur, Sunil Pasricha, Ankush Jajodia

Journal of Current Oncology 2020 3(2):84-85



Epithelioid hemangioma of clavicle: A case report and review of literature
Thomas Sumi, Surendran Divya, Augustine Joy

Journal of Current Oncology 2020 3(2):86-89

Epithelioid hemangioma (EH) of the bone is classified within benign vascular tumors. They are uncommon locally aggressive neoplasms. Tumors usually involve long tubular bones. We report a case of EH of clavicle in a 12-year-old girl treated with tumor resection and fibular grafting.


Breast cancer with orbital metastasis: An uncommon entity
Sneha Bothra, Chaturbhuj Agrawal, Pankaj Goyal, Kahitij Domadia, Abhishek Bansal, Dinesh Chandra Doval

Journal of Current Oncology 2020 3(2):90-92

Orbital metastasis is rare in breast cancer. We present a case of a 45-year-old premenopausal lady with hormone positive locally advanced breast cancer managed with surgery, chemotherapy, radiation therapy and adjuvant hormone therapy, had systemic failure after 6 years of completion of definitive therapy, in the form of orbital and vertebral metastases. Patient was investigated for other causes, however was found to have 2.6 x 2.0 x 2.9 cm mass encasing the optic nerve, causing early vision loss in one eye, with minimal proptosis. She was not under any adjuvant hormone therapy during the relapse. She was treated with external beam radiotherapy followed by tamoxifen, which showed good partial response radiologically and gradual improvement in her vision and regression of the tumor.


Renal cell carcinoma arising in an open pyelolithotomy scar: A perplexing scenario!
Sandeep Bhoriwal, Kunal Dhall, Adarsh Barwad, Ashutosh Mishra

Journal of Current Oncology 2020 3(2):93-96

Renal cell carcinoma (RCC) arising in a renal tissue away from the normal kidney is quite rare with only a few cases reported in the literature. The management of such cases is challenging and requires an individualized treatment approach. We report a case of a young male with a prior history of pyelolithotomy who presented with a right paravertebral mass. CECT chest and abdomen revealed a soft-tissue mass near the right kidney with obvious infiltration into posterior abdominal wall muscles and 12th rib erosion. Image-guided biopsy of the mass demonstrated features of metastatic RCC. The patient underwent surgery with en bloc removal of the tumor with 12th rib, infiltrated paraspinal muscles, a small part of the densely adhered right kidney, and overlying skin. Histopathology with recommended IHC panels showed papillary RCC. Because of the above, the multidisciplinary tumor board considered this as a malignancy arising from a pyelolithotomy scar. The patient was planned for follow-up only without any adjuvant treatment. This case highlights the importance of a multidisciplinary team approach and comprehensive planning in such rare and perplexing cases.



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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,
Telephone consultation 11855 int 1193,

Clinical outcomes in patients with atrial fibrillation and frailty

Research article
Open Access
Published: 24 December 2020

Clinical outcomes in patients with atrial fibrillation and frailty: insights from the ENGAGE AF-TIMI 48 trial

Chris Wilkinson, Jianhua Wu, Samuel D. Searle, Oliver Todd, Marlous Hall, Vijay Kunadian, Andrew Clegg, Kenneth Rockwood & Chris P. Gale

BMC Medicine volume 18, Article number: 401 (2020) Cite this article

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Abstract

Background

Atrial fibrillation (AF) is common in older people with frailty and is associated with an increased risk of stroke and systemic embolism. Whilst oral anticoagulation is associated with a reduction in this risk, there is a lack of data on the safety and efficacy of direct oral anticoagulants (DOACs) in people with frailty. This study aims to report clinical outcomes of patients with AF in the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial by frailty status.

Methods

Post hoc analysis of 20,867 participants in the ENGAGE AF-TIMI 48 trial, representing 98.8% of those randomised. This double-blinded double-dummy trial compared two once-daily regimens of edoxaban (a DOAC) with warfarin. Participants were categorised as fit, living with pre-frailty, mild-moderate, or severe frailty according to a standardised index, based upon the cumulative deficit model. The primary efficacy endpoint was stroke or systemic embolism and the safety endpoint was major bleeding.

Results

A fifth (19.6%) of the study population had frailty (fit: n = 4459, pre-frailty: n = 12,326, mild-moderate frailty: n = 3722, severe frailty: n = 360). On average over the follow-up period, the risk of stroke or systemic embolism increased by 37% (adjusted HR 1.37, 95% CI 1.19–1.58) and major bleeding by 42% (adjusted HR 1.42, 1.27–1.59) for each 0.1 increase in the frailty index (four additional health deficits). Edoxaban was associated with similar efficacy to warfarin in every frailty category, and a lower risk of bleeding than warfarin in all but those living with severe frailty.

Conclusions

Edoxaban was similarly efficacious to warfarin across the frailty spectrum and was associated with lower rates of bleeding except in those with severe frailty. Overall, with increasing frailty, there was an increase in stroke and bleeding risk. There is a need for high-quality, frailty-specific population randomised control trials to guide therapy in this vulnerable population.

Trial registration

ClinicalTrials.gov NCT00781391. First registered on 28 October 2008

Peer Review reports

Background

Atrial fibrillation (AF) affects at least 10 million people in Europe [1]. The incidence and prevalence of AF increases with age [2] and is more common in patients with frailty [3, 4], a condition characterised by a decline in a person's biological reserves and deterioration in physiological mechanisms that render them vulnerable to a range of adverse outcomes [5,6,7,8,9]. Frailty provides an insight into biological age and is more useful than chronological age in predicting adverse events and guiding clinical care [10,11,12,13,14]. Frailty is commonly identified using either a frailty index or a frailty phenotype. The frailty index expresses the proportion of health deficits that a person has accumulated divided by all deficits measured, whereas the phenotype defines frailty as poor performance in three of five criteria (weight loss, exhaustion, weakness, slowness, lack of activity) [7]. There is overlap between the two approaches [15].

Whilst AF is associated with an increased risk of stroke and mortality, an appropriate prescription of oral anticoagulation can reduce the risk of stroke by 64% [16, 17]. Therefore, anticoagulation is recommended for men with AF and a CHA2DS2-VASc score of 2 or greater and in women with a score of 3 or greater [18, 19]. Large randomised controlled trials have established the efficacy and safety of direct oral anticoagulant medications (DOACs) in comparison to warfarin for stroke prevention in non-valvular AF [20,21,22,23], including in people aged over 75 years [24], and they are associated with a per patient cost saving [25]. However, we lack data on the efficacy and safety of DOAC in older people with AF who are also frail [3].

Our three objectives for this study were to estimate the prevalence of frailty in people with AF; describe the association between AF, frailty, and clinical outcomes; and compare the efficacy and safety of edoxaban (a DOAC) to warfarin by frailty category.

Methods

We constructed a frailty index using data from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial [26]. The use of a frailty index is an established and validated technique for quantifying frailty using the cumulative deficit model and results in substantially better prediction of mortality and other adverse events than age alone [11, 27, 28].

Study cohort

The design and baseline characteristics of the ENGAGE AF-TIMI 48 study are described elsewhere (NCT00781391) [21, 26]. In brief, this was a randomised, double-blinded, double-dummy trial, in which two once-daily regimens of edoxaban were compared with warfarin in 21,105 patients with AF and a moderate or high risk of stroke. The trial was conducted at 1393 centres across 46 countries. Patients were enrolled from 19 November 2008 to 22 November 2010, and the median follow-up duration was 2.8 years [21]. The protocol and amendments were approved by ethics committees at each participating centre, and all participants provided written informed consent. The dataset supporting the conclusions of this article is available (subject to approval) via application at https://vivli.org. This post hoc analysis was approved by an independent review panel. Data were de-identified at source by the trial team, and patients that were deemed by the study team to be at high risk of identification (for example due to a rare medical history) were excluded from the supplied data set. This left 98.8% (n = 20,867) of the randomised participants for this analysis (Fig. 1).

Fig. 1

Consort diagram

Full size image

Participants

Patients with AF were eligible for inclusion in the ENGAGE AF-TIMI 48 study if they had documented AF of any duration within the 12 months preceding randomisation and had a CHADS2 score of 2 or higher. In this score, 1 point is allocated for each of congestive heart failure, hypertension, diabetes, and an age of 75 years or older. A prior stroke or transient ischaemic attack (TIA) is assigned 2 points. The possible range is 0 to 6, with higher scores associated with an increased stroke risk. Exclusion criteria included AF due to a reversible disorder, an estimated creatinine clearance of less than 30 ml/min, a high risk of bleeding, use of dual antiplatelet therapy, moderate-to-severe mitral stenosis, other indications for anticoagulation therapy; acute coronary syndromes, coronary revascularization, or stroke within 30 days before randomisation; and an inability to adhere to study procedures [21, 26].

Interventions

The study drugs were warfarin (dose-adjusted to achieve an international normalised ratio [INR] of 2 to 3), edoxaban 30 mg daily, or edoxaban 60 mg daily. Patients were randomised in a 1:1:1 ratio. The allocated dose of edoxaban was halved if the patient had or developed a creatinine clearance of 30–50 ml/min, a body weight of 60 kg or less, or the concomitant use of verapamil or quinidine (or dronedarone, after a protocol amendment on 22 December 2010). Standard dosing was resumed if there was no other indication for dose reduction and the verapamil, quinidine, or dronedarone was stopped.

Outcomes

The primary efficacy endpoint was the time to the first adjudicated stroke (ischaemic or haemorrhagic) or systemic embolic event. The primary safety endpoint was adjudicated major bleeding during treatment, as defined by the International Society on Thrombosis and Haemostasis [29]. The composite net clinical endpoints were stroke, systemic embolic event, major bleeding, or death; disabling stroke, life-threatening bleeding, or death; and stroke, systemic embolic event, life-threatening bleeding, or death. Given the established association between frailty and mortality [5], we report death as a separate outcome. For composite endpoints involving deaths, individuals were right censored at death in the analysis. An independent clinical endpoint committee, who were blinded to study assignment, adjudicated all deaths and suspected cerebrovascular events, systemic embolic events, myocardial infarctions, bleeding events, and hepatic events [21]. The definitions used by the clinical endpoint committee are provided in the original study protocol [26].

Blinding

To maintain blinding, each patient received two sets of study drugs—with a placebo matching warfarin for patients in the edoxaban arms or edoxaban for the patients in the warfarin arms. The INR was measured at least monthly, with sham results generated in the edoxaban groups.

Frailty

We defined frailty using the cumulative deficit model, which identifies deficits in health (such as symptoms, signs, diseases, disabilities, or abnormalities in clinical investigations) on the basis that the more deficits a person has, the more likely that the person is frail [30]. The cumulative deficit model enables calculation of a frailty index as an equally weighted proportion of the number of deficits present in an individual to the total possible. For this study, we constructed a frailty index using the available trial data, calculated at the time of study entry. In line with the established guidance for constructing a frailty index, candidate health deficit variables for inclusion were identified on the basis that they were associated with health status, their prevalence generally increases with age, they do not reach saturation too early (over 80% prevalence before the age of 80), and they cover a range of body systems [31]. Data needed to be available for at least 70% of items for inclusion [32]. The 40 items included in the construction of the frailty index are detailed in Additional file 1: Table S1. The presence or absence of each variable was ascertained from data collected by the trial investigators as part of their protocol-specified assessment, which took place within 30 days of study randomisation [33]. Participants were categorised based upon the frailty index into fit (0 to < 0.12), living with pre-frailty (≥ 0.12 to < 0.24), mild-moderate (≥ 0.24 to < 0.36), and severe frailty (≥ 0.36 to 1.0), based upon thresholds that are commonly used in the literature [11, 34].

Statistical methods

Baseline characteristics are reported for the frailty groups and by treatment allocation. Continuous variables are presented as medians with interquartile range, and categorical variables as counts and proportions. Event rates for each of the primary and secondary (composite) outcomes were calculated as the number of events per 100 person-years and reported by frailty category and treatment arm.

Cox proportional hazard models were used to (1) test whether each regimen of edoxaban was non-inferior to warfarin for each primary and secondary (composite) outcomes, stratified by frailty category, and (2) quantify the association between frailty category and the primary and secondary (composite) outcomes, with the treatment arm included as an interaction term. The proportional hazards assumption was assessed using Schoenfeld residuals tests. Hazard ratios with 95% confidence intervals (CIs) were reported for each. As the trial participants were randomised by treatment allocation, but not frailty, comparisons by frailty were adjusted for age, sex, race, and region. These limited adjustments were made to preserve the association between frailty and outcomes. Finally, the impact of an increase of 0.1 in frailty index on each clinical outcome for the complete analytical cohort was calculated. Hazard ratios were adjusted for the treatment group and reported alongside estimates further adjusted for age, sex, race, and region, in the whole cohort. A sensitivity analysis was completed for the association between frailty and the clinical outcomes, where frailty index items were removed if they were related to bleeding (history of non-intracranial bleeding and peptic ulcer). Data were analysed in Stata 15.1 and R version 3.4.1.

Results

Participants

We include 20,867 participants in the analysis (38.1% women [n = 7940]; 86.8% 60 years or older [n = 18,119]; 25.5% with paroxysmal AF [n = 5311]; Fig. 1, Table 1). Overall, 21.4% (n = 4459) of participants were categorised as fit; 59.1% (n = 12,326) were pre-frail; 17.8% (n = 3722) had mild-moderate frailty; and 1.7% (n = 360) had severe frailty (Additional file 1: Fig. S1). The predicted stroke risk was higher with increased frailty (mean CHADS2 score: fit 2.39, pre-frail 2.80, mild-moderate frailty 3.37, severe 4.03).

Table 1 Baseline characteristics of participants by frailty category
Full size table

There was a similar number of participants in each treatment arm (warfarin 33.3% [n = 6957]; edoxaban 30 mg 33.3% [n = 6956]; edoxaban 60 mg 33.3% [n = 6954]), and the distribution of frailty category was comparable between treatment arms (Fig. 1). The characteristics of patients in each treatment group, stratified by frailty, are reported in Additional file 1: Table S2.

Primary outcomes

Across the three treatment arms, 997 patients experienced stroke or systemic embolism (rate per 100 person-years: warfarin 1.73 [95% CI 1.54–1.92]; edoxaban 30 mg 1.95 [1.76–2.15]; edoxaban 60 mg 1.47 [1.30–1.64]; Table 2). There was no difference in stroke or systemic embolism between the treatment arms (Additional file 1: Table S3), including when stratified by frailty category (Table 3). Across the treatment arms, in comparison to the fit group, the average adjusted risk of stroke or systemic embolism over the follow-up period was 84% higher in the group living with mild-moderate frailty and more than double in those living with severe frailty (Table 4). On average over the follow-up period, for each increase of 0.1 in the frailty index (four additional health deficits), the risk of stroke or systemic embolism increased by 37% (adjusted HR 1.37, 1.19–1.58).

Table 2 Numbers and rates of outcome events
Full size table
Table 3 The association between oral anticoagulation and outcomes, stratified by frailty category
Full size table
Table 4 The association between frailty category and clinical outcomes
Full size table

Overall, 1185 participants experienced major bleeding during treatment (rate per 100 person-years: warfarin 2.76, 95% CI 2.52–3.00; edoxaban 30 mg 1.28, 1.12–1.44; edoxaban 60 mg 2.17, 1.96–2.38; Table 2). On average over the follow-up period, bleeding events were 53% lower in patients taking edoxaban 30 mg compared to warfarin (HR 0.47, 95% CI 0.40–0.54) and 21% lower in those taking edoxaban 60 mg (HR 0.79, 0.69–0.89, Additional file 1: Table S3). When stratified by frailty category, edoxaban 30 mg was associated with a reduction in major bleeding compared with warfarin in all but those with severe frailty, and edoxaban 60 mg with a reduction in major bleeding in the pre-frail and mild-moderate frailty groups only (Table 3). Across the treatment arms, the adjusted risk of major bleeding increased with the frailty category, such that for each increase of 0.1 in the frailty index (four additional health deficits), the risk of major bleeding increased by 42% on average over the follow-up period (adjusted HR 1.42, 1.27–1.59).

Composite net clinical endpoints

Overall, 4030 participants experienced stroke, systemic embolic event, major bleeding, or death (rate per 100 person-years: warfarin 7.90, 95% CI 7.50–8.31; edoxaban 30 mg 6.58, 6.22–6.95; edoxaban 60 mg 7.06, 6.68–7.44; Table 2). Disabling stroke, life-threatening bleeding, or death affected 2699 participants (rates: warfarin 5.07, 4.75–5.39; edoxaban 30 mg 4.26, 3.97–4.55; edoxaban 60 mg 4.52, 4.22–4.81; Table 2). Stroke, systemic embolic event, life-threatening bleeding, or death affected 3098 participants (rates: warfarin 5.80, 5.45–6.14; edoxaban 30 mg 5.16, 4.84–5.48; edoxaban 60 mg 5.12, 4.80–5.43; Table 2).

Compared with warfarin, there was a significant reduction for each of the three composite outcomes associated with the use of edoxaban at both 30-mg and 60-mg dosages (Additional file 1: Table S3). When stratified by frailty category, there was no difference in each of the three composite outcomes according to the treatment arm for those in the fit category (Table 3). In those living with pre-frailty, a reduction in all three composite outcomes was associated with edoxaban 60 mg compared with warfarin. For edoxaban 30 mg, the risk was reduced in composite outcome (1) stroke, systemic embolic event, major bleeding, or death and (2) disabling stroke, life-threatening bleeding, or death—but not for the composite outcome (3) stroke, systemic embolic event, life-threatening bleeding, or death. For those living with mild-moderate frailty, there was a reduction in (1) and (2) with the 30-mg dose, and no difference in the composite outcomes between the use of edoxaban 60 mg and warfarin. Finally, in those with severe frailty, there was a reduction in (2) with edoxaban 60 mg compared to warfarin, and no difference in the composite outcomes between edoxaban 30 mg and warfarin, and for the other composite outcomes for the 60-mg dosage (Table 2).

When modelling frailty index on a continuous scale, there was a significantly increased risk of all three composite outcomes with increasing frailty across all three treatment arms. For each increase of 0.1 in the frailty index (four additional health deficits), the adjusted risks on average over the follow-up period of (1) stroke, systemic embolic event, major bleeding, or death increased by 59% (HR 1.59, 1.48–1.69); (2) disabling stroke, life-threatening bleeding, or death by 72% (1.72, 1.59–1.87); and (3) stroke, systemic embolic event, life-threatening bleeding, or death by 67% (1.67, 1.55–1.80). The overall findings were robust to a sensitivity analysis in which the frailty index was modified to remove factors specifically associated with bleeding risk (Additional file 1: Table S4).

Mortality

There was a stepwise association between frailty category and mortality, whereby patients with severe frailty had a hazard ratio for mortality of 4.97 (3.42–7.23) compared to the fit group (Table 4). Mortality accounted for a greater proportion of the composite endpoints with increasing frailty category (Table 2).

Discussion

In this analysis of a large international clinical trial, we have shown that edoxaban is non-inferior to warfarin across the frailty spectrum in stroke prevention. Bleeding events were reduced in patients who received edoxaban except in those living with severe frailty—where standardised bleeding event rates were not statistically significantly different from warfarin. We found that just one in five trial participants had frailty and that frailty was associated with worse clinical outcomes, regardless of treatment arm allocation.

The key finding of the ENGAGE AF-TIMI 48 trial was that edoxaban was associated with lower rates of bleeding and death from cardiovascular causes compared with warfarin, with similar efficacy in stroke and systemic embolism prophylaxis. In our stratified analyses, however, these findings were not upheld for every frailty category. Instead, it appeared that the effect was driven by the pre-frail group, which was the most prevalent frailty category in the trial population. This may relate to a lack of statistical power, particularly as the trend in every subgroup is consistent with the overall trial finding. Even so, we cannot conclude with certainty from this analysis that the overall trial findings are applicable to patients living with severe frailty. Here, those patients were under-represented, even though they are a group at high risk of stroke, and in whom AF is common [3, 4].

The distribution of the frailty scores in this trial is striking. One in five participants was frail, and just one in 50 had severe frailty. This is in contrast with the primary care population of older people with AF, in which over half live with moderate or severe frailty [4]. It is known that health problems tend to accumulate with age and therefore frailty is generally progressive [35], with an average rate of deficit accumulation in community-dwelling older people of 3% per year [36]. With population ageing, the burden of frailty is likely to grow substantially [37], amplifying the need for robust trial data that is specific to people with frailty who are at particular risk of treatment-related harm. The perception of a gap between the representation of people with frailty in trials and the clinical population may explain, at least in part, the relatively low 'real-world' prescription rates of oral anticoagulation for eligible patients [38,39,40] and may reflect clinicians' fear of causing iatrogenic harm, particularly in people with frailty [3]. This must be considered alongside our finding that death is more common in patients with AF and also frailty—which is well known in a general population [10,11,12,13,14].

We have demonstrated that frailty is associated with worse clinical outcomes regardless of treatment arm allocation. The risk of every trial endpoint was at least doubled for patients with severe frailty compared to the fit group, with the appearance of a 'dose-response relationship' despite therapy. This is a population with a high baseline risk of cardiovascular events and death, and a high residual risk remains, despite therapy. This risk is likely to be multifactorial, including non-embolic stroke and death from non-cardiovascular causes that may not be modifiable in the context of advancing multi-organ disease. That the risk of major bleeding on treatment was substantially higher with increasing frailty category may represent a target for improvement. Modifiable bleeding risk factors should be optimised—including a review of concomitant antiplatelet and non-steroidal anti-inflammatory medications [19], as well as a renewed focus on DOAC dosing, which may be complex and is commonly incorrect [41].

A recent randomised controlled trial found that in older Japanese patients, a daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism, without a significantly higher incidence of major bleeding than placebo [42]. These findings are important, but we know that there is a graded degree of risk amongst older people of the same age [4, 7, 10, 30], and there remains a notable lack of generalisable data concerning the outcomes associated with anticoagulation for patients with more advanced frailty [3]. There are many reasons why older people are historically under-represented in clinical trials, including the presence of co-morbidities, communication issues, and physical immobility that limit opportunities for participation [43]. Yet, in view of a high baseline risk of both stroke and iatrogenic harm, there is a strong argument for frailty-specific population randomised trials in this area. In lieu of specific randomised evidence to quantify efficacy and safety in older people with severe frailty, future work modelling outcomes using a combination of epidemiological and trial data may yield interesting insights [44, 45].

This study has strengths, which include the ENGAGE AF-TIMI 48 dataset, in which there were few missing data, a large sample size, and a long follow-up duration [21, 26]. To our knowledge, this study is the first to report the outcomes of such a trial by frailty [3]. As the recruitment of patients with frailty into clinical trials is challenging, these analyses are necessary and important in order to guide clinicians and individualise therapy [46]. Frailty was identified using a conceptually robust and reproducible measure [31], that is increasingly used in understanding the relationship between age and outcomes in clinical trials [10], and allows the risk of adverse outcomes to be defined more precisely than a phenotypic approach [15]. We adjusted the associations between frailty and outcomes for potential confounders. However, we recognise the limitations of our work. In particular, the trial exclusion criteria mean that patients with more severe frailty were excluded, for example patients with a life expectancy of less than 12 months or who were unable to attend for trial visits [26]. This means that the results are not generalisable to the whole population of older people with frailty. Secondly, whilst we did not have access to the complete dataset, the rates of the outcomes were similar to those in the original trial [26]. Thirdly, as the trial was not designed for the analyses that we have undertaken, the analyses stratified by frailty category are likely to be underpowered. Fourthly, data were not available to evaluate phenotypically defined frailty in this dataset. Finally, the study was conducted in the era before specific reversal agents, which may impact upon bleeding severity and associated mortality in future clinical practice.

Conclusion

Patients with AF taking anticoagulation with warfarin or edoxaban are at substantially higher risk of stroke or systemic embolism, major bleeding during treatment, and death if they also have frailty. We showed important differences in the overall risk of adverse outcomes increasing with frailty, and efficacy was similar between warfarin and edoxaban. Whilst a reduction in bleeding was associated with edoxaban overall, this was not substantiated across all frailty categories, and people with more advanced frailty made up a small proportion of the overall trial population. This highlights the need for high-quality, frailty-specific population randomised controlled trials to guide therapy in this vulnerable population.

Availability of data and materials

The dataset supporting the conclusions of this article is available (subject to approval) via application at https://vivli.org.

Abbreviations

AF:

Atrial fibrillation

CHADS2 score:

One point for the history of congestive heart failure, hypertension, age ≥ 75 years, and diabetes; two points for stroke or TIA

CHA2DS2-VASc score:

One point for the history of congestive heart failure, hypertension, diabetes, vascular disease history (prior MI, peripheral artery disease, or aortic plaque), age 65–74 years, and female sex; two points for age ≥ 75, history of stroke, or TIA

CI:

Confidence interval

Cr:

Creatinine

DOAC:

Direct oral anticoagulant

ENGAGE AF-TIMI 48 :

Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48

INR:

International normalised ratio

SD:

Standard deviation

TIA:

Transient ischaemic attack

VKA:

Vitamin K antagonist

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Unusual onset of thyroid associated orbitopathy during pregnancy

Case report
Open Access
Published: 15 December 2020
Unusual onset of thyroid associated orbitopathy during pregnancy: case report and review of literature
Janos K. Aranyosi, Tamas Deli, Annamaria Erdei, Geza Toth, Attila Jakab, Mariann Fodor, Endre V. Nagy & Bernadett Ujhelyi
BMC Endocrine Disorders volume 20, Article number: 183 (2020) Cite this article

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Abstract
Background
Thyroid associated orbitopathy (TAO) is the most common extrathyroidal complication of Graves' disease. The disease course ranges from mild, where symptomatic therapy is sufficient, to severe, where high dose steroid administration or orbital decompression surgery is required. Women of their reproductive age are more likely to be affected. Although pregnancy is a state of enhanced immune tolerance, TAO may develop or worsen in 0.2–0.4% of pregnant women.

Case presentation
We present the case of a 19-year-old woman who has developed hyperthyroidism and progressive TAO during the second trimester of her third pregnancy, which has improved postpartum. The possible mechanisms and the importance of follow up in pregnancy is discussed.

Conclusions
Expectant mothers with Graves' disease require follow up of eye signs throughout pregnancy, preferably in the setting of a thyroid-eye clinic.

Peer Review reports

Background
Graves' disease (GD) and Hashimoto's thyroiditis (HT) are autoimmune disorders, that may affect around 2% of the population [1]. GD occurs more frequently in women, smokers, patients suffering from other autoimmune diseases and those with a positive family history for thyroid autoimmunity [2]. GD is the most common cause of hyperthyroidism in women of reproductive age. It occurs before and during pregnancy in 0.4–1% and 0.2–0.4% of the cases, respectively [3, 4]. According to a recent review by Chin et al. in approximately 40% of the cases GD is accompanied by thyroid associated orbitopathy (TAO) [5]. In 5%, deterioration of visual acuity may occur [6]. In mild cases local therapy such as artificial tears, ointments, sunglasses and higher pillows at night are sufficient. Severe cases require systemic immunosuppressive therapy, usually with high dose corticosteroids [7]. Additional options are retrobulbar irradiation and orbital wall decompression surgery [8]. During pregnancy the therapeutic options are limited.

The majority of autoimmune diseases tend to improve during gestation due to the state of enhanced immune tolerance. Thyroid autoimmune diseases, multiple sclerosis and rheumatoid arthritis show improvement during pregnancy [9, 10]. There are a few exceptions; SLE and type 1 diabetes deteriorate [11].

In GD, humoral immune response predominates. Stimulating antibodies against the TSH receptor (TRAb) result in the clinical manifestations of the disease, including hyperthyroidism, goiter, orbitopathy and dermopathy [12]. The development or exacerbation of GD in pregnancy is rare and spontaneous improvement in the second trimester is typical. This is accompanied by the decrease of stimulating TRAbs [13, 14]. Relapse is often observed between 4 and 8 months after delivery. In this period, the enhanced immune tolerance ceases, resulting in elevated levels of TRAbs [14].

Here we present a case of GD with TAO, which developed in the second trimester of pregnancy.

Case presentation
A 19-year-old pregnant woman has been referred to our department during her 3rd pregnancy for GD and new-onset TAO. Hyperthyroidism was diagnosed by her primary care physician at week 20 of pregnancy. Her laboratory results were: TSH 0.01 mU/L, FT4: 78,4 pmol/L (reference range: 12–22 pmol/L), FT3: 37.4 pmol/L (reference range: 3.1–6.8 pmol/L). For unknown reasons, she showed up three months later, at week 33 of pregnancy, with untreated hyperthyroidism. She did not report any other disease. She has had no history of thyroid disease and no pre-pregnancy TSH values were available. The two previous pregnancies conceived naturally and were completed by cesarean section due to cephalopelvic disproportion. She smoked 20 cigarettes daily during pregnancy and failed to quit smoking in spite of repeated counseling.

On presentation at week 33 her main complaints were proptosis and limited movement of the right eye with accompanying pain. She recalled that her first symptom, the proptosis appeared around week 14 of gestation. On admission TSH and thyroid hormone levels were in the hyperthyroid range (Table 1). Her TRAb level was 2.4 U/L (reference range:< 1 U/L), while the anti-thyroglobulin antibody level was 1324.0 IU/ml (reference range: < 60 IU/ml.). In spite of current recommendations [15] an initial dose of metimazol 50 mg/day has been chosen; severe type T3 hyperthyriodism was considered to carry high risk of preterm delivery, while there was no fetal risk of thiamazole in the 3rd trimester. After 3 days, the dose of thiamazole was reduced to 30 mg per day. Examination showed marked exophthalmos on the right side with restricted and painful eye movement, decreased best corrected visual acuity (20/32) and eyelid edema. Proptosis was 28 and 21 mm at the right and left sides, respectively by Hertel exophthalmometry at 90 mm (regional normal < 20 mm). The disease was graded as severe on the EUGOGO scale [16]. Clinical Activity Score (CAS) was 6/7 and 0/7 on the right and left sides, respectively.

Table 1 Hormone levels and thiamazole doses
Full size table
The fetus showed no signs of intrauterine growth restriction, no tachycardia or goiter and the growth rate was satisfactory on follow up according to the ultrasonography. From week 34, the therapeutic dose of thiamazole was reduced to two times 15 mg daily (Table 1). Eye examination on week 38 showed improvement in visual acuity, CAS and proptosis. (Table 2), although retrobulbar pain, pain on eye movement, eyelid edema and conjunctival redness remained. Because the patient did not develop sight-threatening TAO, the thyroid-eye clinic team decided not to initiate high-dose corticosteroid therapy.

Table 2 Ophthalmologic examinations
Full size table
A healthy female baby was delivered through cesarean section on week 39. Both TAO and cephalopelvic disproportion were contraindications of vaginal delivery. The newborn did not show clinical signs of thyroid dysfunction, and day 3 TSH was in the reference newborn range. The mother's thyroid hormone levels started to rise after delivery; thiamazole dose was modified accordingly, supplemented with bisoprolol. Her eye complaints substantially improved the next day after the cesarean section, CAS declined, and visual acuity returned to normal (Table 2). Proptosis, eyelid and conjunctival redness and swelling of the eyelid and caruncula were still present on day 3 postpartum (Fig. 1). MRI examination was to be performed, however, the patient declined it. For the relapsing Graves' disease and orbital involvement, total thyroidectomy was scheduled; later she declined and she and her baby were lost for follow up.

Fig. 1
figure1
The patient's eyes on day 3 postpartum. Exophthalmos on the right side was still present. Visual acuity returned to 20/20

Full size image
Discussion and conclusions
Graves' disease is caused by autoantibodies, which bind to the thyrotropin receptor on thyroid follicular cells and orbital fibroblasts, causing the overproduction of thyroid hormones [17] and in 40% of these patients TAO, respectively [6]. The autoimmune inflammation of the retrobulbar connective tissue is characterized by the presence of lymphocytes and macrophages and the overproduction of connective tissue matrix by fibroblasts [18, 19].

During normal pregnancy, several physiological changes occur [20]. Both red blood cell mass and plasma volume increase in pregnancy; as the latter increase is more marked, physiological haemodilution is present. Heart rate and stroke volume increase while vascular resistance falls. Glucose tolerance decreases, as does biliary excretion. Estrogen and progesterone levels rise dramatically, estrogen levels being 100-times higher than in the menstrual cycle [20]. The number of natural killer cells (NK) might be normal; however their cytolytic activity is decreased [21]. The number of circulating plasma cells and B-cells remains normal, as do antibody response and antibody production [22]. Although there is no significant change in the number of circulating T-lymphocytes during pregnancy, a slight decline may occur in the proportion of CD4+ cells resulting in suppressed immune activity [23]. Regulatory CD4+ CD25 + T cells, or Treg cells are responsible for regulating Th1-type and Th2-type activities. Th1-type and Th2-type immune processes are involved in cellular and humoral immunity, respectively [24]. In early pregnancy the number of Treg cells increases rapidly, reaching the peak in the second trimester [25]. They can suppress both Th1-type and Th2-type reactivity against fetal alloantigens. Th1 clones are more sensitive to the Treg effect, which leads to the predominance of Th2 clones over Th1 cellular immune response; the cytokine balance is driven away from the adverse effects of Th1 cell activity which could lead to abortion [26]. Therefore, the proper balance of Th1/Th2 cell activities has an important role in maintaining pregnancy. A clear decline in the number of Treg cells is observed in the weeks before delivery. This restoration of the non-pregnant or pre-pregnancy state may facilitate the exacerbation of autoimmune diseases after delivery [27, 28].

Pregnancy has a complex effect on the course of autoimmune disorders. The majority of autoimmune diseases tend to improve during pregnancy, except for SLE and type 1 diabetes, which usually worsen [9, 11]. Stable Graves' disease on thiamazole may transiently worsen in the first trimester due to the thyroid stimulating effect of the hCG rise [29]. There is an improvement due to physiological immune tolerance in the second trimester. A relapse in the postpartum period, when the immune function returns to a normal, is common [30]. Therefore, improvement in the disease activity of both GD and TAO can be anticipated during pregnancy. While this is true for GD, unfortunately, less is known about the course of TAO [19, 31]; GD and TAO might follow separate courses during pregnancy. In one study, 5 out of 9 women with mild to moderate eye symptoms developed proptosis during pregnancy; on the other hand, 70% of patients with pre-existing disease had either improvement or no change in their eye signs and 30% experienced worsening in the postpartum period [32].

In the present case, a relapse of Graves' disease was diagnosed during gestation. TAO appeared around the 14th week of pregnancy whereas she had no similar complaints during her two previous pregnancies. Her orbital condition was severe on presentation. It was not known if the reduced visual acuity was a new complaint. For this reason, both visual acuity and critical fusion frequency were tested on alternate days. We considered the orbitopathy moderate to severe [7], definitely not sight threatening; VA was 20/32. According to the EUGOGO guidelines [7], we decided to restore euthyroidism first and urged the patient to quit smoking. The latter measure is known to be nearly as effective as corticosteroids. As VA improved and signs reduced, there was no need to initiate immunosuppressive treatment.

We believe that the major contributors to TAO development and worsening during pregnancy have been the hypervolemia-related physiological changes and their reflections in the orbital tissue. A minor increase of orbital tissue volume can result in the worsening of TAO, as any volume excess in the orbital cone will lead to elevated cone pressure, further stretching of the rectus muscles, and decreased venous drainage into the cavernous sinus [33]. The usual rapid volume redistribution after delivery may explain the immediate improvement of TAO. It is not entirely clear why some of the TAO patients develop asymmetric disease; at presentation, other causes of unilateral exophthalmos have to be ruled out [34]. We [35] and others found that the orbital process is unequivocally two-sided by imaging, even in those cases where one side appears completely spared. MRI was planned but was postponed until after delivery in accordance with the practice guidelines collaboratively developed by the American College of Radiology (ACR) and the Society for Pediatric Radiology (SPR) for any trimester in pregnancy [36]. The patient failed to show up for imaging.

Further, the pregnant patient smoked 20 cigarettes daily. Although there were no data on the number of cigarettes smoked during her previous two pregnancies, the increasing amount of cigarettes per day throughout the years may account for the appearance of TAO. Furthermore, this case is unusual, because Graves' hyperthyroidism did not limit itself during pregnancy; persisting thyroid dysfunction may have been a contributor to the worsening of TAO.

The limitation of our case report is that we could perform neither the MRI examination nor the follow-up visit due to low compliance of the patient. Her low socioeconomic status may account for both the disappearance from medical care, as well as smoking throughout pregnancy.

Both smoking and hypervolemia may have contributed to the development of TAO. The deterioration in the 3rd trimester may have most probably been volume-related as the eye signs rapidly regressed after delivery, while she maintained the same smoking intensity. Further improvement of the eye signs was confirmed by the patient at the single phone call she returned. Expectant mothers with Graves' disease require follow up of eye signs throughout pregnancy, preferably in the setting of a thyroid-eye clinic.

Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations
TAO:
Thyroid associated orbitopathy

GD:
Graves' disease

HT:
Hashimoto's thyroiditis

TRAb:
TSH receptor autoantibodies

CAS:
Clinical Activity Score

NK:
Natural killer cells

VA:
Visual acuity

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Telephone consultation 11855 int 1193,

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