Camille Apple, Elizabeth Miller, Julie A Stortz, Juan C Mira, - - PowerPoint PPT Presentation

Camille Apple, Elizabeth Miller, Julie A Stortz, Juan C Mira, McKenzie K Hollen, Tyler J Loftus, Maria Cecilia Lopez, Zhongkai Wang, Kolenkode B Kannan, Dina C Nacionales, Christopher R Cogle, Hari K Parvataneni, Kalia K Sadasivan, Matthew Patrick, Jennifer E Hagen, Scott Brakenridge, Frederick A Moore, Henry V Baker, Lyle L Moldawer, Philip A Efron, Alicia M Mohr

 AMM was supported by R01 GM105893‐01A1  I do not have any relevant financial relationships with any

commercial interest that pertains to the content of my presentation

Our patients: PIAA

Acute trauma Hemorrhagic shock Critically ill (ICU) Persistent Anemia (up to 6mo.) Supraphysiologic catecholamine levels Bone marrow (BM) dysfunction

BM suppression of erythroid progenitor colony growth HPC mobilization to peripheral blood Hematopoietic progenitor cell (HPC) sequestration at site of injury Impaired iron homeostasis Myelo‐erythroid reprioritization

 Regulatory RNAs that target mRNA  Significant as a distinct class of biological

regulators in many organisms

 The expression of erythropoiesis‐related miRNAs is altered in

trauma patients

 miRNAs play a role in persistent injury‐associated anemia

 Blood and bone marrow (BM) collected intra‐

• peratively from:
• Severely injured trauma patients who

underwent fracture fixation (n=27)

• Controls ‐ elective hip replacement patients

(n=10)

 Bone marrow to assess GEMM, BFU‐E, CFU‐E

colony growth formation

 Total RNA and miRNA were isolated from HSCs  Genome‐wide gene and miRNA expression was

assayed

 Threshold of significance *p < 0.01  For visualization, expression differences were

clustered using a heat map

CONTROLS (n = 10) TRAUMA (n =27) P‐value Male (n) 4 (40%) 16 (59%) NS Age (years) 66* 43* 0.0004 Admission heart rate (bpm) 72* 99* 0.0005 Admission SBP (mmHg) 128* 110* 0.0318 Admission MAP (mmHg) 86* 73* 0.0199 Admission Lactate (mg/dL) NA 2.9 NA Pre‐operative Hemoglobin (g/dL) 13.7* 9.4* 0.0001 Discharge Hemoglobin (g/dL) 10.3* 8.9* 0.0012

miRNA Trauma/Control Fold Change Function hsa‐miR‐150‐3p 1.7*

Regulates genes whose downstream products encourage megakaryocytic differentiation rather than erythrocytic differentiation

hsa‐miR‐223 1.8*

Promotes granulocytic differentiation and suppresses erythrocytic differentiation

hsa‐miR‐15a 1.2*

Negatively regulates normal erythropoiesis by directly targeting the human activin type I receptors c‐Kit

hsa‐miR‐24‐1 1.2*

Negatively regulates normal erythropoiesis by directly targeting the human activin type I receptors ALK4

hsa‐miR‐23a‐5p 4.5*

Acts as key regulator for erythroid differentiation of CD34+ HPCs by targeting SHP2

* p<0.01

 Following trauma there is decreased growth of bone

marrow erythroid progenitor cells and increased expression

• f five miRNAs that negatively regulate erythropoiesis

 Despite the presence of anemia following hip replacement

and trauma, microRNA regulation within the bone marrow is not similar

Alicia Mohr, MD Elizabeth Miller, MD Kolenkode Kannan, PhD Moldawer Lab Henry Baker, PhD Maria Cecilia Lopez, BS

Acknowledgements

 miRNAs as novel targets for therapeutic intervention

• Microvesicle‐mediated transfer of miRNAs between HSCs and the

bone marrow niche could help us regulate HSCs

• miRNA replacement therapy using miRNA mimics
• Inhibition of miRNA function by anti‐miRNAs

Preterm Neonates Have Persistent Neutrophil Velocity and Transcriptomic Changes that Fail to Resolve Despite Reaching Term Corrected Gestational Age Preterm Neonates Have Persistent Neutrophil Velocity and Transcriptomic Changes that Fail to Resolve Despite Reaching Term Corrected Gestational Age

RB Hawkins, SL Raymond, JC Rincon, R Ungaro, MC Lopez, HV Baker, JL Wynn, LL Moldawer, SD Larson

Disclosures

• Nothing to disclose
• Work Supported by:

–NIH R01 GM097531 (SDL, LLM) –NIH R01 HD089939 (JLW, LLM) –NIH T32 GM008721 (RBH)

Introduction

• Prematurity and its associated complications are leading

causes of death in the neonatal period

• Preterm neonates have quantitative and functional

impairments in immunity that are poorly understood

• To date, assessment of human neonatal immune

function has been limited by high blood volume requirements

Microfluidics

• Microfluidic technologies have emerged, allowing

analysis with only a drop of blood

• Microfluidic assays developed for:

–Neutrophil migration –Phagocytosis –Chemotaxis –Sepsis diagnostics

Hypothesis

Preterm neonates have distinct neutrophil motility and transcriptomic phenotypes at birth that normalize over time

Study Design

• Human preterm and term neonates enrolled
• Inclusion criteria:

–Preterm cohort: <32 weeks gestational age –Term cohort: >36 weeks gestational age –Ability to obtain consent from parent/guardian

• Exclusion criteria:

–Congenital defects, suspected genetic disorders, 32‐36 weeks completed gestation, lack of consent

Study Design

• Term neonates: single 250 µL blood sample DOL1
• Preterm neonates: serial 250 µL blood samples during time

period at highest risk of sepsis/complications

– DOL 4, twice weekly x 3 weeks, weekly until discharge

Microfluidic Analysis

250 µL Whole Blood 50 µL Spontaneous Migration 200 µL Leukocyte Transcriptomics (GeneChip™)

Enrollment

25 Neonates 14 Preterm 11 Term

• Preterm cohort: 50% male, mean gestational age 29.5

weeks, mean birth weight 1254 grams

114 Total Blood Samples Processed

Neutrophil Velocity Increases After Birth for Preterm Neonates, Approaches Term Levels

R2 = 0.36 p = <0.0001

Control: 21 µm/min

Preterm neonates have distinct transcriptomic pattern at birth, does not normalize by 37 corrected gestational age

Preterm neonates have differentially expressed gene pathways at birth and at 2 months of age

• Time ANOVA performed comparing preterm neonatal

samples over time to full term cohort

• 618 genes differentially expressed over time between

preterm and term groups

• Ingenuity Pathway Analysis™ revealed:

–At DOL4, upregulation DNA synthesis and repair, downregulation of apoptosis –At 2 months of age, increased activation of phagocyte degranulation, inhibition of transcription regulation

Conclusions

• Preterm neonates have decreased neutrophil velocity at

birth, which corrects to term levels by ~1 month

• Leukocyte transcriptomic expression follows a distinct

pattern after preterm birth, and does not reach term levels even by hospital discharge

• Transcriptomics suggest ongoing inflammatory response
• These results may partially explain persistent long‐term

immune dysfunction in preterm neonates

Acknowledgements

• University of Florida Department of Surgery

– Dr. Gib Upchurch, Dr. Saleem Islam, Dr. Lyle Moldawer,

• Dr. Shawn Larson

Immune Modulation by Bacterial Endotoxin Suppresses Pancreatic Cancer Progression

Anthony Ferrantella MD, Prateek Sharma MD, Saba Kurtom MD, Vrishketan Sethi MD, Bhuwan Giri MD, Mohammad Tarique PhD, Harrys KC Jacob PhD, Pooja Roy MD, Shweta Lavania MS, Ashok Saluja PhD, Vikas Dudeja MD DeWitt Daughtry Family Department of Surgery Leonard M. Miller School of Medicine University of Miami Miami, FL

Disclosure Statement Anthony Ferrantella, M.D. ‐Nothing to disclose

Background

• Pancreatic ductal adenocarcinoma (PDAC) is an

immunologically “cold” tumor.

• Immunotherapy has not been effective in PDAC.
• Toll‐like receptor 4 (TLR4) signaling promotes

inflammatory pathways.

Sham Surgery Resection + Saline Resection + LPS (5mg/kg twice weekly) Wild‐type (C57BL6) Mice KPC Pancreatic Cancer Cells

Resection model of pancreatic cancer

n = 16-19 per group log-rank p < 0.001 Sham Surgery Resection Only Resection + LPS Median Survival 34 days 41 days not reached

TLR4 activation reduces cancer recurrence

10 20 30 40 50 60 70 80 90 25 50 75 100

Days Following Resection Sham Surgery Resection Only Resection + LPS

Saline LPS (1mg/kg weekly)

Liver metastasis model of pancreatic cancer

Wild‐type (C57BL/6) and Rag1‐/‐ Mice KPC Pancreatic Cancer Cells

n = 8-9 per group ** p < 0.01 n.s. = not significant

Liver metastases weight (g)

Liver metastases weight (g)

n.s.

TLR4 activation suppresses liver metastasis

Wild-type Mice Rag1-/- Mice

n = 5 per group * p < 0.05 ** p < 0.01

TLR4 activation promotes macrophage activation

SALINE LPS

F4/80 MHC-II % MHC-II+ of CD45/F4-80 cells % F4-80+ of CD45 cells

n = 5 per group *** p < 0.001

TLR4 activation reduces pro-tumorigenic MDSCs

SALINE LPS

Ly6G/Ly6C CD11b

% Gr-1/CD11b+ of CD45 cells

n = 10 per group *** p < 0.001

TLR4 activation reduces tumor growth

5 1 1 5 2 2 5

Tumor volume (mm3)

***

5 1 1 5 2 2 5

Tumor volume (mm3)

n = 10 per group *** p < 0.001

TLR4 activation reduces tumor growth

***

n = 10 per group *** p < 0.001

TLR4 activation is effective in other cancers

***

5 1 1 5 2 2 5

Tumor volume (mm3)

5 1 1 5 2 2 5 3

Tumor volume (mm3) ***

n = 10 per group *** p < 0.001

Anti-tumor effects are independent of CD8 T cells

5 1 1 5 2

Tumor volume (mm3)

***

5 1 1 5 2

Tumor volume (mm3) Tumor volume (mm3)

n = 10 per group ** p < 0.01 *** p < 0.001

Adaptive immune system required for anti-tumor effects

***

n = 10 per group * p < 0.05 ** p < 0.01

Activation of TLR4 sensitizes pancreatic cancer to immunotherapy

7 10 14 18 20 24 30 200 400 600 800 1000 1200

Days Saline LPS PD-1 LPS + PD-1 CTLA-4 LPS + CTLA-4 start treatment

KPC Pancreatic Cancer

• 4

• 1

• 4

• 1

Tumor volume (mm3)

Conclusions

• Systemic activation of TLR4 reduces cancer recurrence and suppresses

metastasis in clinically relevant models of pancreatic cancer.

• TLR4‐mediated anti‐tumor response requires both the innate and

adaptive immune systems.

• TLR4 activation renders pancreatic cancer susceptible to immune

checkpoint inhibition in preclinical models.

TRAUMA IN PREGNANCY: Mortality and Delayed Effects

• n the Fetus

Michelle Mulder

Hallie Quiroz, Matthew Sussman, Gabriel Lama, Wendy Yang, Eduardo Perez, Juan Sola, Nicholas Namias, Kenneth Proctor, Chad Thorson

Nothing to Disclose

DISCLOSURE

Introduction

• Trauma is the leading cause of non‐obstetric death in Pregnant females
• Affects 1 in 12
• Significant morbidity
• Protocols to optimize Maternal Management defined
• But what About the Fetus?
• Management?
• Outcomes?
• Mortality
• Complications
• Short‐term
• Long term disabilities
• Prognosis

PURPOSE: To determine the outcomes of the fetus following abdominal trauma in the pregnant mother

Methods

• Retrospective Analysis
• Ryder Trauma Center (Level I Trauma Center)
• 2009-2017
• Females of child bearing age with blunt or penetrating abdominal trauma
• Confirmed pregnancy (-Hcg or Ultrasound)
• Demographics
• Interventions
• Clinical Outcomes

OBJECTIVE:

• Fetal and Maternal

Outcomes

Methods ‐ Complications

• Delivery: decelerations, asphyxia, placenta abruption
• Short Term (Neonatal):
• Intraventricular Hemorrhage (IVH)
• Necrotizing enterocolitis (NEC)
• Hypoxic Ischemic Encephalopathy (HIE)
• Interventions → mechanical ventilation, pressor use, transfusion,
• perations
• Death
• Long Term: developmental delay, death

Results ‐ Maternal

• 5,654 Females Reviewed
• 188 Pregnant
• 84 pregnancies with full records to delivery
• Maternal Demographics
• Age: 27±7 years
• Mechanism of Injury: 81% Blunt
• Gestational Age: 23±11 weeks
• Maternal Mortality 6%

• 38% (n=32) vaginal deliveries
• 48% (n=40) C‐sections
• 29% (n=24) delivery complications*
• EBL: 425 [213‐800]cc

Delivery Data

11 placenta abruptions 9 maternal mortality 8 labor complications 6 repeat C section 4 non‐reassuring fetal heart tones

* decelerations, asphyxia, placenta abruption

• 22% (n= 41) directly affected by trauma
• 11% (n=20) live births
• 7% (n=12) fetal demise
• 5% (n=9) stillborn
• 2 mothers readmitted with stillborn children

Results ‐ Fetal

• 20 live births
• 25% (n=5) fetuses expired during neonatal hospitalization
• Overall infant mortality 14% (n=26)
• 23% (n=43) live births on subsequent admission

Results ‐ Fetal

Subsequent Admission n=43 Born Alive at Maternal Trauma Admission n=20 P Value Emergent Caesariana 5 (12%) 16 (80%) <0.001 Delivery Complicationb 12 (28%) 13 (65%) 0.005 Placental Abruption 1 (2%) 8 (40%) 0.008 Birth Weight (BW) Low BW (< 1500gm) Very Low BW (< 1000gm) 3280±432 gm 2 (5%) 2072±894 gm 13 (65%) 5 (25%) All p<0.001 Gestational Age at Birth Premature (< 37 weeks) 39±2 weeks 6 (14%) 34±5 weeks 13 (65%) Both p<0.001 Neonatal Complicationc 16 (37%) 14 (70%) 0.015 NICU Admission 19 (44%) 16 (80%) <0.001 Hospital LOS 3 [2‐4] days 6 [3‐30] days 0.015 Mortality 5 (25%) <0.001

• 56% NICU admission
• 6 [0‐ 6] days
• 52% suffered newborn complications
• IVH, NEC, HIE, respiratory distress
• 17% experienced long term complications
• Developmental delay, seizure disorders, learning deficits

Neonatal Data (n=63 born alive)

Conclusions

TRAUMA DURING PREGNANCY HAS SIGNIFICANT IMMEDIATE MORTALITY AND DELAYED EFFECTS ON THE UNBORN FETUS

OPTIMAL THRESHOLDS FOR VENOUS DUPLEX ULTRASOUND SCREENING FOR THROMBOEMBOLISM IN TRAUMA OPTIMAL THRESHOLDS FOR VENOUS DUPLEX ULTRASOUND SCREENING FOR THROMBOEMBOLISM IN TRAUMA

Michelle B. Mulder, MD, Charles A. Karcutskie, MD, MA, Matthew S. Sussman, MD, Sarah A. Eidelson, MD, Jonathan P. Meizoso, MD, MSPH, Laura Hudson, MD, Carl I. Schulman, MD, MSPH, PhD, Enrique Ginzburg, MD, Nicholas Namias, MD, MBA, Kenneth G. Proctor, PhD Michelle B. Mulder, MD, Charles A. Karcutskie, MD, MA, Matthew S. Sussman, MD, Sarah A. Eidelson, MD, Jonathan P. Meizoso, MD, MSPH, Laura Hudson, MD, Carl I. Schulman, MD, MSPH, PhD, Enrique Ginzburg, MD, Nicholas Namias, MD, MBA, Kenneth G. Proctor, PhD

Dewitt Daughtry Family Department of Surgery Division of Trauma, Critical Care, and Burn Surgery University of Miami / Jackson Memorial Hospital Ryder Trauma Center Miami, FL Dewitt Daughtry Family Department of Surgery Division of Trauma, Critical Care, and Burn Surgery University of Miami / Jackson Memorial Hospital Ryder Trauma Center Miami, FL

DISCLOSURES: DISCLOSURES:

Nothing Nothing

→ FAILURE to screen= MEDICAL ERROR → SCREENING & TREATMENT most important for patient safety → EFFECTIVE PREVENTION & TREATMENTS

Greenfield’s Risk Assessment Profile (RAP) Greenfield’s Risk Assessment Profile (RAP)

1997 Jan;42(1):100‐3

The Journal of

TRAUMA

Injury, Infection and Critical Care

>20 years since first described No consensus on optimal threshold

The American Surgeon

2011 Jun;77(6):783‐9. 2016 Jan;222(1):65-72.

HYPOTHESIS HYPOTHESIS

A DISCRETE RAP THRESHOLD CAN OPTIMIZE PATIENT SAFETY AS WELL AS HOSPITAL RESOURCES

• DESIGN: Retrospective review
• SETTING: Ryder Trauma Center, 1/ 2010 – 1/2015
• POPULATION: 1168 consecutive TICU admissions
• DESIGN: Retrospective review
• SETTING: Ryder Trauma Center, 1/ 2010 – 1/2015
• POPULATION: 1168 consecutive TICU admissions

METHODS

DVT defined as venous abnormality on bilateral LE VDU at or below inguinal ligament RAP on TICU admission PEs defined by filling defect on CTA after symptoms of hypoxemia, tachycardia, or both

METHODS

• Total Cost of Bilateral VDU (radiology, technician, depreciation)
• $1000
• Cost for treating a PE derived from averaged estimated costs cited in the

literature: $60,000

• 30% of DVT >> PE
• Univariate analysis compared VTE at each RAP score, with sensitivity,

specificity, & AUROC

• Total Cost of Bilateral VDU (radiology, technician, depreciation)
• $1000
• Cost for treating a PE derived from averaged estimated costs cited in the

literature: $60,000

• 30% of DVT >> PE
• Univariate analysis compared VTE at each RAP score, with sensitivity,

specificity, & AUROC

METHODS

DEMOGRAPHICS DEMOGRAPHICS

• 75% MALE
• 43 ± 19 Years
• 69.6% Blunt (n=813), 27.7% Penetrating (n=324), 2.7% Burn (n=31)
• ISS 20 ± 12
• RAP 8 ± 5
• VTE: 9% (n=105)
• DVT: 6.8% (n=80)
• PE: 2.6% (n=30)
• 75% MALE
• 43 ± 19 Years
• 69.6% Blunt (n=813), 27.7% Penetrating (n=324), 2.7% Burn (n=31)
• ISS 20 ± 12
• RAP 8 ± 5
• VTE: 9% (n=105)
• DVT: 6.8% (n=80)
• PE: 2.6% (n=30)

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

VTE Frequency by RAP score

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

VTE Frequency by RAP score

RAP AREA UNDER THE CURVE 4 0.558 5 0.607 6 0.640 7 0.672 8 0.673 9 0.689 10 0.693 11 0.685 12 0.665

RAP AREA UNDER THE CURVE 4 0.558 5 0.607 6 0.640 7 0.672 8 0.673 9 0.689 10 0.693 11 0.685 12 0.665

MISS 36 VTE’s!!!

$720,000

RAP AREA UNDER THE CURVE 4 0.558 5 0.607 6 0.640 7 0.672 8 0.673 9 0.689 10 0.693 11 0.685 12 0.665

BUT.. CATCH 96% VTE

++ $1,114,000

CONCLUSION CONCLUSION

VDU at Higher RAPs upfront costs, but missed $$$$ VDU at Higher RAPs upfront costs, but missed $$$$

RAP‐ driven is the best compromise between patient safety & hospital resources RAP‐ driven is the best compromise between patient safety & hospital resources BOTTOM LINE BOTTOM LINE

The Outcomes of Inhalation Injury in Lesser Burns: Still a Deadly Injury

• S. Ruiz, S. Puyana, F. Amador, S. Hai, R. Lim, M. Askari,
• M. Mckenney, H. Mir.

Kendall Regional Medical Center Department of Surgery Miami, USA

Disclosures

• No Disclosures

• Inhalation injury adds a negative effect on burn patients
• Increases the requirements of fluid resuscitation and the

incidence of pulmonary complications.

• Can be associated with longstanding pulmonary dysfunction.
• It has widely been proposed that inhalation injury worsens
• utcomes, yet no large-scale study has shown the exact

relationship between inhalation injury and burn outcomes.

• Our study proposes inhalation injuries as a risk factor that

worsens burn outcomes.

Background

Methodology

• Retrospective review of the American Burn Association Burn

Registry from 2002-2011.

• Compared the outcomes of all the burn with a TBSA <15
• A total of 93,781 burn patients meet our inclusion criteria and

divided in two groups

• Group 1: Inhalation injury
• Group 2: No inhalation injury
• Demographic characteristics and outcome variables were collected

and compared between each group.

• Outcome measures included: in-hospital mortality rate, hospital

length of stay, ICU length of stay and ventilator days.

• Chi- Squared and t-test analyses were used with significance defined

as p<0.05.

Results

Table 1: Demographic and outcome variables between patient with inhalation injury and patient with no inhalation injury

TBSA Group 1 (Inhalation) Group 2 (Non-Inhalation) p-value Total # of Patients 4204 89577 Mean age (years) 44.8 31.2 <0.0001 Average TBSA 3.50 3.58 0.24 Hospital days 11.48 6.27 <0.0001 ICU- LOS (Days) 8.55 1.89 <0.0001 Average Vent Days 6.07 0.67 <0.0001 In-hospital Mortality (%) 8.54% (359) 1.42% (1278) <0.0001

Results

• Mean TBSA was not significantly different, with 3.5% in group 1

compared to 3.58% in group 2. (p =0.24, t-test)

• Higher ICU length of stay at 8.55 days in group 1 compared to

6.27 in the group 2 (p=0.0001, χ2)

• Higher hospital length of stay at 11.48 days in group 1 compared

to 6.27 in the group 2 (p=0.0001, χ2)

• Higher ventilator support days at 6.01 days in group 1 compared

to 0.67 days in the group 2 (p=0.0001, χ2)

• Higher in-hospital mortality at 8.54% in group 1 compared to

1.42% in the group 2 (p=0.0001, χ2)

Conclusion

• Burn patients with inhalation injuries had an increased ICU length of

stay, in-hospital length of stay, average ventilator days and in-hospital mortality.

• The presence of inhalation injury may be a predictor of increased

mortality and poor long-term pulmonary outcome in patients with similar size burns.

Limitations

• Retrospective study
• Possible confounders
• Tobacco use
• Age

References

• Thompson PB, Herndon DN, Traber DL, Abston S. Effect on mortality of inhalation
• injury. The Journal of trauma. NLM Citation ID:3944839 (PubMed ID)
• E E Tredget, H A Shankowsky, T V Taerum, G L Moysa, and J D Alton. The role of

inhalation injury in burn trauma. A Canadian experience. Ann Surg. 1990 Dec. PMCID:

• PMC1358258. PMID: 2256764
• Perenlei Enkhbaatar, Daniel L. Traber. Pathophysiology of acute lung injury in combined

burn and smoke inhalation injury. Clinical Science. DOI: 10.1042/CS20040135

• Masaru Suzukia, Naoki Aikawaa, Kunio Kobayashib, Ryouhei Higuchib. Prognostic

implications of inhalation injury in burn patients in Tokyo. Burns, Volume 31, Issue 3, May 2005, Pages 331-336. DOI: 10.1016/j.burns.2004.10.016

• Toon, Michael H; Maybauer, Marc O; Greenwood, John E; Maybauer, Dirk M and Fraser,

John F. Management of Acute Smoke Inhalation Injury. Critical Care and Resuscitation,

• Vol. 12, No. 1, Mar 2010: 53-61. ISSN: 1441-2772.
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treatment strategies. Scandinavian Journal of Trauma, Resuscitation and Emergency

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burn mortality. Ann Surg. 1987, 205: 82-87. 10.1097

Thank you

• Kendall Regional Medical Center
• Burn and Reconstructive Centers of America