Be a Surgical “Multiplier” in MIGS Inspire Brilliance Through Teamwork

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Scientific Program ChairJubilee Brown, MD

Honorary ChairBarbara S. Levy, MD

PresidentMarie Fidela R. Paraiso, MD

SYLLABUSLate Breaking News

Professional Education Information

Target Audience This educational activity is developed to meet the needs of surgical gynecologists in practice and in training, as well as other healthcare professionals in the field of gynecology. Accreditation AAGL is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAGL designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. DISCLOSURE OF RELEVANT FINANCIAL RELATIONSHIPS As a provider accredited by the Accreditation Council for Continuing Medical Education, AAGL must ensure balance, independence, and objectivity in all CME activities to promote improvements in health care and not proprietary interests of a commercial interest. The provider controls all decisions related to identification of CME needs, determination of educational objectives, selection and presentation of content, selection of all persons and organizations that will be in a position to control the content, selection of educational methods, and evaluation of the activity. Course chairs, planning committee members, presenters, authors, moderators, panel members, and others in a position to control the content of this activity are required to disclose relevant financial relationships with commercial interests related to the subject matter of this educational activity. Learners are able to assess the potential for commercial bias in information when complete disclosure, resolution of conflicts of interest, and acknowledgment of commercial support are provided prior to the activity. Informed learners are the final safeguards in assuring that a CME activity is independent from commercial support. We believe this mechanism contributes to the transparency and accountability of CME. ANTI-HARASSMENT STATEMENT AAGL encourages its members to interact with each other for the purposes of professional development and scholarly interchange so that all members may learn, network, and enjoy the company of colleagues in a professional atmosphere. Consequently, it is the policy of the AAGL to provide an environment free from all forms of discrimination, harassment, and retaliation to its members and guests at all regional educational meetings or courses, the annual global congress (i.e. annual meeting), and AAGL-hosted social events (AAGL sponsored activities). Every individual associated with the AAGL has a duty to maintain this environment free of harassment and intimidation. Any individual covered by this policy who believes that he or she has been subjected to such an inappropriate incident has three (3) options for reporting:

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Table of Contents Course Description ........................................................................................................................................ 1 Disclosure ...................................................................................................................................................... 2

A Randomized Controlled Non-Inferiority Trial of Reduced Versus Routine Opioid Prescription after Prolapse Repair E.R.W. Davidson ........................................................................................................................................... 3

How Low Should We Go? Examining Low Quantities of Opioid Tablets After Ambulatory Gynecologic Laparoscopy: A Randomized Controlled Trial K.M. Plewniak................................................................................................................................................ 6

Postoperative Opioid Prescriptions Following Enhanced Recovery After Surgery (ERAS) Implementation in Minimally Invasive Gynecologic Surgery: A Retrospective Cohort Study L.A. Christianson ........................................................................................................................................... 9

UTERUS-11 Study: A Randomized Clinical Trial on Surgical Staging versus CT-Staging Prior to Primary Chemoradiation in Patients with FIGO2009 Stages IIB-IVA Cervical Cancer A.T. Tsunoda ............................................................................................................................................... 11

Laparoscopic Visual Contained In-Bag Morcellation versus Uncontained Conventional Morcellation of Fibroids and Large Uterus with Fibroids – a Research Study P.H. Trivedi ................................................................................................................................................. 14

Outcomes of Women Undergoing Trachelectomy After Supracervical Hysterectomy M.P. McHale ............................................................................................................................................... 16

Abnormal Pathology seen on Appendectomy in Patients with Predominant Right-Sided Pelvic PainK.Sisler ......................................................................................................................................................... 17

Molecular Characterization and Diagnosis of Endometriosis to Aid in Surgical Resection using Ambient Ionization Mass Spectrometry M.T. Breen .................................................................................................................................................. 18

Cultural and Linguistics Competency ......................................................................................................... 23

Late Breaking News

Moderator: Nutan Jain, Eric R. Sokol

Faculty: Michael T. Breen, Lee A. Christianson, Emily R.W. Davidson, Melissa P. McHale, Kari M. Plewniak, Katelin Sisler, Audrey T. Tsunoda, Prakash H. Trivedi

Discussant: Mauricio S. Abrao, Liane M. Belland Sean Dowdy, Stephanie N. Morris, Lois M. Ramondetta, Yukio Sonoda

Course Description The late breaking news session will highlight research that focuses on significant advancements, techniques, complications, new information and important findings as they exist within the field of minimally invasive gynecology and best practice.

Course Objectives At the conclusion of this activity, the participant will be able to: 1) Address late breaking news containing new information and important findings in the field of minimally invasive gynecology.

Course Outline

2:00 E.R.W. Davidson

2:05 K.M. Plewniak

2:10 L.A. Christianson

2:15 2:20 A.T. Tsunoda

2:28 P.H. Trivedi

2:36 M.P. McHale

2:44 K. Sisler

2:52

A Randomized Controlled Non-Inferiority Trial of Reduced Versus Routine Opioid Prescription after Prolapse Repair How Low Should We Go? Examining Low Quantities of Opioid Tablets After Ambulatory Gynecologic Laparoscopy: A Randomized Controlled Trial Postoperative Opioid Prescriptions Following Enhanced Recovery After Surgery (ERAS) Implementation in Minimally Invasive Gynecologic Surgery: A Retrospective Cohort Study Discussant for the first three papers: S. Dowdy UTERUS-11 Study: A Randomized Clinical Trial on Surgical Staging versus CT-Staging Prior to Primary Chemoradiation in Patients with FIGO2009 Stages IIB-IVA Cervical Cancer Discussant: L.M. Ramondetta Laparoscopic Visual Contained In-Bag Morcellation versus Uncontained Conventional Morcellation of Fibroids and Large Uterus with Fibroids – a Research Study Discussant: Yukio Sonoda Outcomes of Women Undergoing Trachelectomy After Supracervical Hysterectomy Discussant: L.M. Belland Abnormal Pathology seen on Appendectomy in Patients with Predominant Right-Sided Pelvic PainDiscussant: S.N. Morris Molecular Characterization and Diagnosis of Endometriosis to Aid in Surgical Resection using Ambient Ionization Mass Spectrometry Discussant: M.S. Abrao

M.T. Breen

Page 1

PLANNER DISCLOSURE The following members of AAGL have been involved in the educational planning of this workshop (listed in alphabetical order by last name). Art Arellano, Professional Education Director, AAGL* Linda D. Bradley, Medical Director, AAGL* Erin T. Carey Consultant: MedIQ Mark W. Dassel Contracted Research: Myovant Sciences Erica Dun* Adi Katz* Linda Michels, Executive Director, AAGL* Erinn M. Myers Speakers Bureau: Laborie Medical Technologies, Teleflex Medical Other: Unrestricted educational grant to support NC FPMRS Fellow Cadaver Lab: Boston Scientific Corp. Inc. Amy Park* Grace Phan, Professional Education Specialist, AAGL* Harold Y. Wu* Linda C. Yang Other: Ownership Interest: KLAAS LLC

SCIENTIFIC PROGRAM COMMITTEE Linda D. Bradley, Medical Director, AAGL* Jubilee Brown* Nichole Mahnert* Shanti Indira Mohling* Fariba Mohtashami Consultant: Hologic Marie Fidela R. Paraiso* Shailesh P. Puntambekar* Matthew T. Siedhoff Consultant: Applied Medical, Caldera Medical, CooperSurgical, Olympus Amanda C. Yunker Consultant: Olympus Linda Michels, Executive Director, AAGL*

FACULTY DISCLOSURE

The following have agreed to provide verbal disclosure of their relationships prior to their presentations. They have also agreed to support their presentations and clinical recommendations with the “best available evidence” from medical literature (in alphabetical order by last name). Mauricio S. Abrao Consultant: AbbVie, Chugai Pharmaceuticals, Johnson & Johnson Contracted Research: Myovant Other: Advisory Board: AbbVie, Applied Medical, Bayer Healthcare Corp. Liane M. Belland* Michael T. Breen* Lee A. Christianson* Emily R.W. Davidson* Sean Dowdy* Nutan Jain* Melissa P. McHale* Stephanie N. Morris* Kari M. Plewniak* Lois M. Ramondetta* Katelin Sisler* Eric R. Sokol Stock Ownership: Pelvalon Other: Grant funding to Stanford University: Acell, Coloplast, Cook MyoSite Other: Travel reimbursement: Contura Yukio Sonoda* Prakash H. Trivedi* Audrey T. Tsunoda Other: Honorarium for educational lectures: AstraZeneca, Roche

Content Reviewer has nothing to disclose.

Asterisk (*) denotes no financial relationships to disclose.

Page 2

A Randomized Controlled Non-Inferiority Trial of Reduced Versus Routine Opioid Prescription After Prolapse Repair

Emily R.W. Davidson, MDMarie Fidela R. Paraiso, MD; Mark Walters, MD; Katie Propst, MD; Beri Ridgeway, MD; Meng Yao, MS; Cecile A. Ferrando, MD MPH

Cleveland Clinic

Disclosures

• I have no financial relationships to disclose.

Objectives

• Recognize the reality of excess postoperativeprescribing

• Compare patient satisfaction after reducingpostoperative opioid quantities

• Evaluate prescribing practices consideringthe principle of opioid stewardship

Background

• Opioid epidemic is deadly - 130 deaths per day1

• Excess opioid prescribed after surgery2-5

- Gynecology patients use 10 of 30+ tabs prescribed2-5

• Risks – diversion, abuse, persistent use6

• …so why are we still overprescribing?

- Patient satisfaction concerns

Study Design• Hypothesis: There will be no difference in patient

satisfaction with postoperative pain control whenreducing postoperative opioid quantity.

• Two-arm, unmasked, single-center RCT of womenundergoing prolapse repair

• Primary outcome: satisfaction at postop visit

118 patients randomized

116 patients with follow-up

Reduced arm: 5 tablets of oxycodone 5mg (n=59)

Routine arm: 28 tablets of oxycodone 5mg (n=59)

All patients received multimodal pain therapy

Page 3

All Subjects (n=118)

Age 62 (±10.4)

Race• White• Black• Hispanic• Other

106 (91.4%)5 (4.3%)1 (0.9%)4 (3.4%)

Post-menopausal 99 (83.9%)

Surgery Type‐ Hyst + Native Tissue Repair‐ Vaginal Colpopexy‐ Hysteropexy‐ SCP

71 (60.2%)18 (15.3%)18 (15.3%)11 (9.3%)

No difference in smoking status, highest level of education, or household income.

Results: Primary Outcome

* = statistical analysis by Farrington-Manning score test for non-inferiority with a 15% margin

All 5 tabs 28 tabs p value

Satisfaction – Yes 108 (93.1%) 53 (93.0%) 55 (93.2%) 0.005*

Satisfaction with pain controlVery Satisfied Somewhat SatisfiedNeutralSomewhat Unsatisfied Very Unsatisfied

96 (82.8%)12 (10.3%)2 (1.7%)1 (0.9%)5 (4.3%)

47 (82.5%)6 (10.5%)1 (1.8%)0 (0%)3 (5.3%)

49 (83.1%)5 (10.2%)1 (1.7%)1(1.7%)2 (3.4%)

0.88

More than originally prescribed?

9 (8.3%) 8 (14.8%) 1 (1.9%) 0.01

Willing to destroy? 101 (95.3%) 50 (94.3%) 51 (96.2) 0.65

# used oxycodone tablets 2 (IQR 0-5.75) 1 (IQR 0-3) 3 (IQR 0-14) 0.03

# unused oxycodone tablets 5 (IQR 3-26) 4 (IQR 2-5) 26 (IQR 15-28) <0.01

Summary of Findings

• Significant opioid excess (1500 vs 230 tabs)

• Prescribing reduced opioids leads to:- Non-inferior satisfaction with pain control

- 15% incidence of needed refills

- Fewer opioid tablets used

- Fewer excess opioid tablets

Conclusions

• Opioid stewardship

• Be aware of the excess

• Surgeons may prescribe fewer opioids afterprolapse surgery without impacting patientsatisfaction- Consider 5-10 tabs for most patients- Recommend multimodal pain treatment

• Systems for disposal of excess opioid

References

1. The opioid epidemic: By the numbers [CDC Website].

2. Swenson CW, Kelley AS, Fenner DE, Berger MB. Outpatient narcotic use after minimally invasiveurogynecologic surgery. Female Pelvic Med Reconstr Surg. 2016;22(5):377-81.

3. Kendall CG, Nisse VC, Department of Gynecology B, et al. Opioid prescription and patient use after gynecologic procedures: A survey of patients and providers. Journal of Minimally Invasive Gynecology. 2018;0(0).

4. Hota LS, Warda HA, Haviland MJ, Searle FM, Hacker MR. Opioid use following gynecologic and pelvicreconstructive surgery. Int Urogynecol J. 2017.

5. Griffith KC, Clark NV, Zuckerman AL, Ferzandi TR, Wright KN. Opioid prescription and patient use after gynecologic procedures: A survey of patients and providers. J Minim Invasive Gynecol. 2017.

6. Bates C, Laciak R, Southwick A, Bishoff J. Overprescription of postoperative narcotics: A look at postoperative pain medication delivery, consumption and disposal in urological practice. J Urol. 2011;185(2):551-5.

Page 4

Patient Eligibility

Inclusion:

• Women 18 years of age or older undergoing a Urogyn procedure with an anticipated overnight hospital admission

- vaginal hysterectomy with vault suspension, sacrospinousligament fixation, hysteropexy, and minimally invasive sacrocolpopexy

Exclusion:

• Chronic pain

• Preoperative opioid use

• Intolerance to study medications

• Score >30 on Pain Catastrophizing Scale

Statistical Power and Analysis

• 59 patients per group, 118 patients- predicted satisfaction of 92%1

- 15% non-inferiority index

- 90% power, 0.05 alpha- 2 additional patients per group due to no-show rate

• Primary outcome: Farrington-Manning-test for non-inferiority; intention-to-treat analysis

• Other outcomes: Student’s t test, chi square, or Mann-Whitney U for nonparametric data

1. Crisp CC, Khan M, Lambers DL, et al. The Effect of Intravenous Acetaminophen on Postoperative Pain and Narcotic Consumption After Vaginal Reconstructive Surgery: A Double-Blind Randomized Placebo-Controlled Trial. Female Pelvic Med Reconstr Surg. 2017;23(2):80-85.

Strengths

• Among the first to study reduction of postoperative opioid use on satisfaction

• Patient population widely applicable to Urogynecology- Potential for extrapolation to other

populations

Limitations

• Inclusion/exclusion criteria- Minor surgeries, chronic pain, NSAIDs

• Protocol deviations- Same day discharge, medication

intolerance

• Patient compliance with surveys- Limits medication counts, daily activities

Acknowledgement

Marie Fidela R. Paraiso, MD; Mark Walters, MD;

Katie Propst, MD; Beri Ridgeway, MD; Meng Yao, MS;

Cecile A. Ferrando, MD MPH

Cleveland Clinic

Page 5

How Low Should We Go? Examining Low Quantities of Opioid Tablets After Ambulatory Gynecologic Laparoscopy: A Randomized Control Trial

Minimally Invasive Gynecologic SurgeryDepartment of Obstetrics & Gynecology and Women’s Health

Montefiore Health System

Kari M Plewniak, MD, FACOG

Disclosure

I have no financial relationships to

disclose.

Objectives

• Examine current practices for

postoperative prescriptions of opioids

• Examine whether prescribing 5 mg 5

tablets of oxycodone with acetaminophen

and ibuprofen adequately treats pain after

minor gynecologic laparoscopy

Background

SOURCE: CDC/NCHS, National Vital Statistics System, Mortality.

Patient comfort

Patient convenience

Excess pills

Avoiding urgent visits

Risks of new persistent use

Safe storage/ disposal

Expectation management

Lacking evidence-

based guidelines

New Persistent Opioid Use

Wright et al 2019

Page 6

Pills Prescribed and Taken After Laparoscopic Cholecystectomy

(Hill et al., 2017)

Study Design• Randomized single-blinded• Objective: to assess if 5 tablets is sufficient for post

operative analgesia

Study Design

• ≥ 18 years old

• Benign minor gynecologic laparoscopy

- (hysterectomy excluded)

• No contraindication to medications

• No chronic opioid use/ treatment for abuse ● Median taken 2.0 tablets and 2.5 tablets (5 vs 10 tab)● 31.8% and 28.3% took no oxycodone● 68.2% and 65.2% took 3 or less tablets

Tablets Used by Day 7

Unscheduled Patient Contact and Treatment Change Within 7 Days

Conclusions

• 5 tablets 5 mg oxycodone is likely sufficient for the

majority of patients

• Decreasing excess pills while still...

○ Keeping pain scores still low

○ Very few refills needed

Page 7

1. Hedegaard H, Miniño AM, Warner M. Drug overdose deaths in the United States, 1999–2017.

NCHS Data Brief, no 329. Hyattsville, MD: National Center for Health Statistics. 2018.

https://www.cdc.gov/nchs/products/databriefs/db329.htm

2. Wright JD, Huang Y, Melamed A, Tergas AI, St Clair CM, Hou JY, Khoury-Collado F, Ananth CV,

Neugut AI, Hershman DL. Use and Misuse of Opioids After Gynecologic Surgical Procedures. Obstet

Gynecol. 2019 Aug;134(2):250-260.

3. Hill MV, McMahon ML, Stucke RS, Barth RJ Jr. Wide Variation and Excessive Dosage of Opioid

Prescriptions for Common General Surgical Procedures. Ann Surg. 2017;265(4):709-714.

4. Eid AI, DePesa C, Nordestgaard AT, et al. Variation of Opioid Prescribing Patterns among Patients

undergoing Similar Surgery on the Same Acute Care Surgery Service of the Same Institution: Time

for Standardization? Surgery. 2018;164(5):926-930.

5. Hota LS, Warda HA, Haviland MJ, Searle FM, Hacker MR. Opioid use following gynecologic and

pelvic reconstructive surgery. Int Urogynecol J. 2018;29(10):1441-1445.

ReferencesEmily Kintzer MD, Ja Hyun Shin MD

Minimally Invasive Gynecologic Surgery

Department of Obstetrics & Gynecology and Women’s Health

Montefiore Health System

Acknowledgment

Page 8

Postoperative Opioid Prescriptions Following Enhanced Recovery After Surgery (ERAS)

Implementation in Minimally Invasive Gynecologic Surgery: A Retrospective Cohort Study

Lee A Christianson MD FACOGMinimally Invasive Gynecologic Surgery

University Medical PartnersStanford OB/GYN Partners for Health

*Research during FMIGS fellowship at Legacy Health, Portland, OR

Disclosure

I have no financial relationships to disclose

Objectives

● Compare surgeon postoperative opioid prescribing practices pre and post Enhanced Recovery After Surgery (ERAS) implementation following minimally invasive gynecologic surgery

● Observe the effect of ERAS implementation on filling additional opioid prescriptions in the 90 days following minimally invasive gynecologic surgery

● Examine persistent postoperative opioid use following minimally invasive gynecologic surgery

Opioid Epidemic

● Deaths from prescription opioids have more than quadrupled since 1999 1

● Opioids frequently prescribed for acute postoperative pain control following minimally invasive hysterectomy despite a lack of prescribing guidelines

● Surgeons prescribe four times the amount of opioids needed for minimally invasive hysterectomy 2

● Estimated 8.8 million oxycodone 5 mg tablets remain in medicine cabinets unused annually from hysterectomy alone 3

Enhanced Recovery After Surgery (ERAS)

● Multimodal, multidisciplinary approach to care of the surgical patient comprised of evidence-based perioperative care measures designed to reduce surgical stress and maintain normal physiologic function postoperatively. 4-6

● Promotes multimodal, non-opioid approach to analgesia 6-8

○ Acetaminophen○ NSAIDs○ Gabapentin

Methods

● Retrospective cohort study in large community-based healthcare system in Portland, OR

● Women undergoing minimally invasive gynecologic surgery in 2015 and 2017 by five high volume subspecialty gynecologic surgeons

● ERAS perioperative care was implemented system wide in April 2016

● Opioid prescription data was collected from the Oregon Prescription Drug Monitoring Program (PDMP) from 90 days preoperatively to 12 months postoperatively.

● Pre and postoperative opioid prescription data was utilized to classified patients as opioid naïve, exposed or tolerant. 9,10

Page 9

Results: Demographics and Surgical Characteristics

Total patients (n = 386) Pre ERAS (n = 177)

Post ERAS (n = 209)

p value

Age (mean) 55.4 59.5 0.08

BMI (mean) 31.1 29.7 0.66

Race, n(%) 0.36

Caucasian 158 (89.3) 186 (89.0)

Hispanic/Latino 5 (2.8) 11 (5.3)

Other 14 (7.9) 12 (5.7)

Smoking, n(%) 20 (11.3) 12 (5.7) 0.14

Insurance, n(%) 0.45

Commercial 95 (53.7) 103 (49.3)

Medicare/Medicaid 82 (46.3) 103 (49.3)

Other 1 (.6) 4 (1.9)

Anxiety, n(%) 19 (10.7) 40 (19.1) 0.03

Depression, n(%) 33 (18.6) 32 (15.3) 0.39

Gynecologic Malignancy, n(%)

61 (34.5) 89 (42.6) 0.13

BMI = Body mass index, ERAS = Enhanced Recovery After Surgery

Total patients (n = 386) Pre ERAS (n = 177)

Post ERAS (n = 209)

p value

Preoperative Opioid Classification, n(%)

0.38

Opioid Naïve 85 (48.0) 124 (59.3)

Opioid Exposed 59 (33.3) 61 (29.2)

Opioid Tolerant 2 (1.1) 4 (1.9)

Opioid History Unknown

31 (17.5) 20 (9.6)

Surgical Procedures, n(%)

Robotic assisted 150 (84.7) 184 (88.0) 0.42

Hysterectomy 114 (64.4) 146 (69.9) 0.30

Operative Time (minutes) 130 150 < 0.01

Length of Stay (days) 1.30 1.16 < 0.01

Postoperative Opioid Prescription OutcomesAll patients

(n=321)Pre ERAS (n = 140)

Post ERAS (n = 181)

p value

Filled surgical prescription*, n(%) 284 (88.5) 122 (87.1) 162 (89.5) 0.63Opioid amount, mean MME (IQ range) 265 (180-338) 296 (225-375) 242 (180-300) <0.001

Filled second prescription**, n(%) 91 (28.4) 39 (27.9) 52 (31.4) 0.96Total additional dispensed opioid amount***, mean MME (IQ range)

214 (0-150) 272 (0-191) 170 (0-150) 0.70

* Prescription dispensed closes to surgery date, corrected for opioid tolerance and unknown opioid history** Dispensed between surgical date and 90 days postoperatively, corrected for opioid tolerance and unknown opioid history*** All additional prescriptions to 90 days postoperatively, surgical prescription excluded, corrected for opioid tolerance and unknown opioid status ERAS = Enhanced Recovery After Surgery, MME = morphine milliequivalents, IQ = inner quartile

Persistent Postoperative Opioid UseAll opioid

naïve patients (n = 209)

Pre ERAS (n = 85)

Post ERAS (n = 124)

P value

Opioid Naïve with Persistent Postoperative Opioid Use, n (%)

8 (3.8%) 2 (2.4%) 6 (4.8%) 0.47

ERAS = Enhanced Recovery After Surgery

• Two large retrospective cohort studies of opioid naïve surgical patients estimated persistent postoperative opioid use ranges from 3.1% to 6.5% 11

• For minimally invasive hysterectomy specifically, one study estimated persistent postoperative opioid use in opioid naïve patients at 1.5% 12

Conclusion

● ERAS implementation reduced the mean opioid initially prescribed for postoperative pain management following minimally invasive gynecologic surgery without an increase in additional opioid filled up to 90 days post surgery.

● Trend towards a reduction in the mean MME for additional opioids prescriptions filled up to 90 days post surgery with ERAS implementation.

● Persistent postoperative opioid use is a potential risk for opioid naïve patients undergoing minimally invasive gynecologic surgery.

References1. Prevention, Center for Disease Control, Annual Surveillance Report of Drug-Related Risks and Outcomes - United States, 2017., U.S. Department for

Health and Human Services, Center for Disease Control and Prevention, Editor. 2017.

2. Wong, M., et al., Opioid use after laparoscopic hysterectomy: prescriptions, patient use, and a predictive calculator. Am J Obstet Gynecol, 2019. 220(3): p. 259 e1-259 e11.

3. Moulder, J.K., et al., Opioid Use in the Postoperative Arena: Global Reduction in Opioids After Surgery Through Enhanced Recovery and Gynecologic Surgery. Clin Obstet Gynecol, 2019. 62(1): p. 67-86.

4. Nelson, G., et al., Guidelines for postoperative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS(R)) Society recommendations--Part II. Gynecol Oncol, 2016. 140(2): p. 323-32.

5. Nelson, G., et al., Guidelines for pre- and intra-operative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS(R)) Society recommendations--Part I. Gynecol Oncol, 2016. 140(2): p. 313-22.

6. Nelson, G., et al., Guidelines for perioperative care in gynecologic/oncology: Enhanced Recovery After Surgery (ERAS) Society recommendations-2019 update. Int J Gynecol Cancer, 2019.

7. Kalogera, E. and S.C. Dowdy, Enhanced Recovery Pathway in Gynecologic Surgery: Improving Outcomes Through Evidence-Based Medicine. ObstetGynecol Clin North Am, 2016. 43(3): p. 551-73.

8. ACOG Committee Opinion No. 750 Summary: Perioperative Pathways: Enhanced Recovery After Surgery. Obstet Gynecol, 2018. 132(3): p. 801-802.

9. Edwards, D.A., et al., American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on Perioperative Management of Patients on Preoperative Opioid Therapy. Anesth Analg, 2019.

10. Kent, M.L., et al., American Society for Enhanced Recovery and Perioperative Quality Initiative-4 Joint Consensus Statement on Persistent Postoperative Opioid Use: Definition, Incidence, Risk Factors, and Health Care System Initiatives. Anesth Analg, 2019.

11. As-Sanie, S., et al., Opioid Prescribing Patterns, Patient Use, and Postoperative Pain After Hysterectomy for Benign Indications. Obstet Gynecol, 2017. 130(6): p. 1261-1268.

12. Clarke, H., et al., Rates and risk factors for prolonged opioid use after major surgery: population based cohort study. BMJ, 2014. 348: p. g1251.

Page 10

UTERUS-11 Study: A Randomized Clinical Trial on Surgical Staging versus CT-Staging

Prior to Primary Chemoradiation in Patients with FIGO2009 Stages IIB-IVA Cervical Cancer

Audrey T Tsunoda, MD, PhDGynecologic Oncology Department - Hospital Erasto Gaertner

Professor at Positivo University

Disclosure

Other: Honorarium for educational lectures: AstraZeneca, Roche

Objectives

● At the conclusion of this presentation, the audience will be able to estimate the results obtained in the first large RCT comparing clinical staging versus surgical staging for locally advanced cervical cancer

Co-authors

Marnitz S, Tsunoda A, Martus P, Vieira M, Affonso RJ,

Nunes JS, Budach V, Schneider A, Hertel H, Mustea A,

Sehouli J, Plaikner A, Ebert A, Köhler C.

simone.marnitz‐schulze@uk‐koeln.de

christhardt.koehler@uk‐koeln.de

atsunoda@gmail.com

Background and Rationale Clinical vs. Surgical Staging

•Considerable limitations of imaging (CT,MRI,PET-CT) with risk of under- and

overstaging (Ramirez P 2011)

•The only randomised trial failed due to imbalanced stages and high radiation

toxicity, and was terminated prematurely after 65 patients (Lai CH 2003)

•Different recommendations in national and international guidelines (NCCN

4.2019, ESGO Guidelines)

•Clear evidence: Surgical staging leads to upstaging in a relevant percentage

of patients with locally advcanced cervical cancer, but oncologic benefit has

been discussed controversially (Gouy S 2013, Marnitz S 2016)

Study Design Patients with histologically proven cervical cancer  FIGO stages IIB‐IVA

Randomisation

Arm A:

Surgical staging (n=125)

Arm B: Clinical staging (n=125) including

CT‐Abdomen (± CT‐guided paraaortic FNAC/Bx)

Positive paraaortic

lymph nodes

Primary pelvic chemo‐radiation including extended field

5 y Follow‐up

Negative paraaortic lymph nodes 

Positive paraaortic 

lymph nodes

Primary pelvic chemoradiation 

5 y Follow‐up

Primary pelvic chemo‐radiation including extended 

field

5 y Follow‐up

Page 11

Endpoints and Study Design

•Prospective randomized, two arms, multicentric study (Charité Berlin, Barretos Cancer Center Brazil, 8 German study centers) 

•Primary Endpoint

•PFS•Secondary Endpoints•OS•Local Control•Acute and Late Toxicity•Quality of Life, Sexuality

Arm A  ‐ Surgical Staging Arm B – Clinical Staging P

Randomised Patients  130 125

Eligible Patients 121 119

Mean Age (years) 47.2 49.6  n.s.

BMI 26.2 26.2 n.s.

FIGO‐ Stage  IIBIIIAIIIBIVA

70%3.5%24%2.5%

67%5%20%8%

n.s.

Removed pelvic nodes (median) 19 ‐‐ ‐‐

Removed paraaortic nodes (median) 17 ‐‐ ‐‐

Pelvic lymph node metastases (mean) 2.4 ‐‐ ‐‐

Paraaortic lymph node metastases (mean)  1.3 ‐‐ ‐‐

Patients´ Characteristics 

Quality of the Surgical Procedure

• Laparoscopic approach 96.7%

•Conversion to open approach: n=1 (0.8%) 

•due to obesity and severe adhesions

•Blood Loss >500 cc: n=2 (1.6%)

•Delay of primary chemo‐radiation:  n=2 

•4 and 5 days, respectively

• Intraoperative Mortality n=0

Köhler C, et al. Perioperative morbidity …Am J Obstet Gynecol 2015; 213;503.e1‐7

Upstaging after Surgical Staging

FIGO Stage IIB IIIA IIIB IVA IVB all Upstaging Arm A

IIB 64 0 0 4 17 85 21/85 (24.7%)

IIIA 0 2 0 0 2 4 2/4 (50%)

IIIB 0 0 14 4 11 29 15/29 (51.7%)

IVA 0 0 0 1 2 3 2/3 (66.6%)

All 64 2 14 9 32 121 40/121 (33%)

Tsunoda AT, Marnitz S, Soares Nunes J, Mattos de Cunha Andrade CE, Scapulatempo Neto C, Blohmer JU, Herrmann J, Kerr LM, Martus P, Schneider A, Favero G, Köhler C. Incidence of histologically proven pelvic and para‐aortic lymph node metastases and rate of upstaging in patients with locally advanced cervical cancer: 

results of a prospective randomized trial. Oncology (Karger) 2017;92:213‐220 

Clinical  Arm (Arm B):patients with positive CT‐guided paraaortic punction:             7/114             (6%)

Chemo‐radiation related Toxicity

•Time Surgery to Chemo‐RT start:  7‐21 days

•Techniques: IMRT: 64% / 3D‐RT: 36% 

•No grade 5 toxicity was observed during CRT

Marnitz S, Martus P, Köhler C, Stromberger C, Asse E, Mallmann P, Schmidberger H, Affonso R, Nunes JS, Sehouli J, Budach V.  Role of surgical versus clinical staging in chemo‐radiated FIGO stage IIB‐IVA cervical cancer patients. Acute toxicity and treatment quality of the Uterus‐11 multicenter phase 

III Intergroup trial of the German Radiation Oncology Group (ARO) and the Gynecologic Cancer Group  (AGO). Int J Radiat Oncol Biol Phys 2016;94:243‐253

0 23 45 68 90

Week 8 GI Tox

Week 6 GI Tox

Week 4 GI Tox

Week 2 GI Tox

GI Toxicity Surgical Arm A 

Grade 4 Grade 3

Grade 2 Grade 1

Grade 0

0 25 50 75 100

Week 8 GI Tox

Week 6 GI Tox

Week 4 GI Tox

Week 2 GI Tox

GI Toxicity Clinical Arm B

Grade 4 Grade 3

Grade 2 Grade 1

Grade 0

0 25 50 75 100

Week 8 GU Tox

Week 6 GU Tox

Week 4 GU Tox

Week 2 GU Tox

GU Toxicity Surgical Arm A

Grade 4

Grade 3

Grade 2

Grade 1

Grade 0

0 25 50 75 100

Week 8 GU Tox

Week 6 GU Tox

Week 4 GU Tox

Week 2 GU Tox

GU Toxicity Clinical Arm B 

Grade 4

Grade 3

Grade 2

Grade 1

Grade 0

Marnitz S, Martus P, Köhler C, Stromberger C, Asse E, Mallmann P, Schmidberger H, Affonso R, Nunes JS, Sehouli J, Budach V.  Role of surgical versus clinical staging in chemo‐radiated FIGO stage IIB‐IVA cervical cancer patients. Acute toxicity and treatment quality of the Uterus‐11 multicenter phase 

III Intergroup trial of the German Radiation Oncology Group (ARO) and the Gynecologic Cancer Group  (AGO). Int J Radiat Oncol Biol Phys 2016;94:243‐253

Chemo‐radiation related Toxicity

Page 12

Oncologic Results

p = 0.088n.s.

p = 0.068n.s.

p = 0.028significant

Median follow‐up 90 months in both arms

Progression‐free survival (PFS)

Overall survival (OS) Cancer‐specific survival (CSS)

Arm A (surgical staging)Arm B(clinical staging)

Arm A (surgical staging)Arm B(clinical staging)

Arm A (surgical staging)Arm B(clinical staging)

•Uterus‐11 is the only completed prospective 

randomised trial on surgical staging

•nearly all surgical staging procedures done by 

minimally invasive approach

•exclusively use of modern radiation techniques

• long‐term median follow‐up (90 months)

•high data completeness  ‐ 6 pts. (2.5%) lost to 

follow up

Strengths and Weaknesses•no PET‐CT included  (no 

recommendation‐no 

reimbursement)

•FIGO stage IB2 (old FIGO) could not 

be included

•Rate of para‐aortic nodes was too 

optimistic

Conclusions

• Laparoscopic surgical staging is a safe procedure and lead to >30% upstaging rate

• Surgical staging does neither delay primary CRT nor increases complication rates

• We demonstrated  a significant cancer‐specific survival benefit in favor for (laparoscopic) 

staging compared to clinical staging

• With regard to survival, distant metastases are the most common cause of death in locally 

advanced cervical cancer patients, there is an urgent need for more effective  systemic 

treatments

Acknowledgements

All patients and families

•Prof. Christhardt Kohler and Prof. Simone Marnitz for the mentorship

•Barretos Cancer Center Colleagues (Gyn Oncol, Medical Oncology, Radiation Oncology, Radiology) for recruiting >30% of the study patients

•Study Nurses Silvia B. (Charité Berlin) and Talita G. (Barretos)

References

• Ramirez PT, Jhingran A, Macapinlac HA, Euscher ED, Munsell MF, Coleman RL, et al: Laparoscopic extraperitoneal para-aortic lymphadenectomy in locally advanced cervical cancer: a prospective correlation of surgical findings with positron emission tomography/computed tomography findings. Cancer 2011; 117: 1928–1934Smits et al. 2014

• Lai CH, Huang KG, Hong JH, Lee CL, Chou HH, Chang TC, et al: Randomized trial of surgical staging (extraperitoneal or laparoscopic) versus clinical staging in locally advanced cervical cancer. Gynecol Oncol 2003; 89: 160–167

• Cervical Cancer NCCN 4.2019

• ESGO Guidelines for Cervical Cancer

• Gouy S, Morice P, Narducci F, Uzan C, Martinez A, Rey A, et al: Prospective multicenter study evaluating the survival of patients with locally advanced cervical cancer

undergoing laparoscopic para-aortic lymphadenectomy before chemoradiotherapy in the era of positron emission tomography imaging. J Clin Oncol 2013; 31: 3026–

3033.

• Kohler C, Mustea A, Marnitz S, Schneider A, Chiantera V, Ulrich U, et al: Perioperative morbidity and rate of upstaging after laparoscopic staging for patients with locally advanced cervical cancer: results of a prospective randomized trial. Am J Obstet Gynecol 2015; 213: 503.e1–e7.

• Tsunoda AT, Marnitz S, Soares Nunes J, Mattos de Cunha Andrade CE, Scapulatempo Neto C, Blohmer JU, Herrmann J, Kerr LM, Martus P, Schneider A, Favero G, Köhler C. Incidence of histologically proven pelvic and para-aortic lymph node metastases and rate of upstaging in patients with locally advanced cervical cancer: results of a prospective randomized trial. Oncology (Karger) 2017;92:213-220

• Marnitz S, Martus P, Köhler C, Stromberger C, Asse E, Mallmann P, Schmidberger H, Affonso R, Nunes JS, Sehouli J, Budach V. Role of surgical versus clinical

staging in chemo-radiated FIGO stage IIB-IVA cervical cancer patients. Acute toxicity and treatment quality of the Uterus-11 multicenter phase III Intergroup trial of the

German Radiation Oncology Group (ARO) and the Gynecologic Cancer Group (AGO). Int J Radiat Oncol Biol Phys 2016;94:243-253

Page 13

Laparoscopic visual contained in-bag morcellation versus uncontained

conventional morcellation of fibroids and large uterus with fibroids –

A Research Study

Dr. Prakash TrivediMD, DNB, FCPS

Director : Trivedi’s Total Health Care Hospital , Mumbai, India

Disclosure

“I have NO financial relationships to disclose”

Objectives

● To evaluate the feasibilility & safety of visual contained laparoscopic power morcellationfor fibroids & large uterus with fibroids.

● To evaluate duration of surgery, blood loss, complications, histopathology & patient parameters during morcellation.

● Study of 426 cases of Laparoscopic visual contained bag morcellation of fibroids & large uterus with fibroid for > 4 years from 14th May, 2015

● Compared to 430 cases of uncontained conventional morcellation of over 4 years from 14th May 2011

● At Trivedi’s Total Health Care Centre- a tertiary referral centre for Fibroids in India

PROBLEMS OF POWER MORCELLATION

● Trauma

● Tissue Disruption

● Dispersion

What is the ONE STEP in myomectomy under our Control??

● Vasopression Infiltration/ Aquadissection● Myometrial Incision● Fibroid Enucleation● Myometrial Closure● Fibroids lying in peritoneal cavity during closure● NONE when spillage is concerned● ONLY STEP WE CAN CONTAIN IS

MORCELLATION

Page 14

Sample under observation

INSERT FILM HERE

Demographic and clinical characteristics of patientsParameters- Conventional Electromechanical morcellation

Parameters - Contained Electro- Mechanical Morcellation

RESULTS

• No case of leiomyosarcoma or mortality in either (856 cases over 8 years).

• No evidence of residual tumor/parasitic spread 6 months post-op on IMAGING MRI & USG

• In both conventional or contained bag morcellation the mean operating time and mean blood loss were comparable,

• For specimen weighing upto2200 grams, with multiple fibroids upto 17 in number and maximum diameter of 20 cms, contained bag morcellationwas feasible.

• Out of 426 cases of Visual Contained Morcellation, 5 Complications

• 2 Conversion to Conventional Morcellation due to uncorrectable Bag Twisting

• 1 Conversion to Open/Mini-Lap retrieval due to Large Calcified fibroid

• 2 Port-Site Wound Infection

Research to Question our Thinking…

● AHRQ-ACOG 1,36,195 cases-160 meta-analysis research reveals very low risk for leiomyosarcoma - 0.02-0.08%.1 Prevalence of leiomyosarcoma was 0.67% out of 10731 uteri morcellated.2

● Vienna Oncology hospitals revealed that out of 71 cases of leiomyosarcoma back traced, none started from fibroid.3

● Pathology text book mentions that leiomyosarcomas are due to a selective gene supressions, but fibroid is due to gene expression. Hence leiomyosarcoma developing from fibroid is a myth & unlikely.4

Scientific Debates & Arguments

● After all steps of Laparoscopic myomectomy are done just putting the specimen in bag, widening the port incision followed by blind cold knife morcellation with 9.2% bag puncture rate is not a safe option.5

● MRI guided FUS and uterine artery embolization are accepted in treatment for fibroid without tissue diagnosis.

● Also laparoscopic radical hysterectomy with lymphadenectomy is accepted, where we deal with proven cancer. Only morcellation becomes the culprit in cases of fibroid.

● Uncontained laparoscopic morcellation has liability of residual fibroids, port site fibroid & leiomyomatosis which can be reduced by contained visual bag morcellation.

Conclusion

Our study of 856 cases over 8 years of laparoscopic removal of fibroids clearly shows visual contained in bag morcellation reduces spillage and improves intraoperative patient’s parameters during morcellation & reduces residual or port site fibroid, becomes a step of extra care to give option of MAS surgery benefits in thousands of women, who deserve it.

References

1. Hartmann KE, Fonnesbeck C, Surawicz T, Krishnaswami S, Andrews JC, Wilson JE, et al. Management of uterine fibroids. Comparative Effectiveness Review No. 195,2017, AHRQ Publication No. 17(18)-EHC028-EF. Rockville (MD): Agency for Healthcare Research and Quality:ES 12

2. Bojahr B, De Wilde RL, Tchartchian G. Malignancy rate of 10,731 uteri morcellated during laparoscopic supracervicalhysterectomy (LASH). Arch Gynecol Obstet 2015;292:665–72.

3. Mayerhofer K, Obermair A, Windbichler G, Petru E, Kaider A, Hefler L, Czerwenka K, Leodolter S, Kainz C. Leiomyosarcoma of the uterus: a clinicopathologic multicenter study of 71 cases.Gynecol Oncol. 1999 Aug;74(2):196-201.

4. Quade BJ, Wang TY, Sornberger K, Dal Cin P, Mutter GL, Morton CC. Molecular pathogenesis of uterine smooth muscle tumors from transcriptional profiling. Genes Chromosomes Cancer. 2004 Jun;40(2):97-108.

5. Cohen SL, Morris SN, Brown DN, et al. Contained tissue extraction using power morcellation: prospective evaluation of leakage parameters. Am J Obstet Gynecol 2016;214:257.e1-6.

Page 15

Title: Outcomes of Women Undergoing Trachelectomy After Supracervical Hysterectomy Authors: McHale MP, Smith AJB, Wethington SL, Fader AN, Objective: Gynecologic surgical subspecialists are frequently consulted for trachelectomy after supracervical hysterectomy. We aimed to characterize the indications and complication rates of women who underwent trachelectomy after supracervical hysterectomy. Design and Subject Selection: We performed a retrospective cohort study of women undergoing trachelectomy after hysterectomy in the 2010-2014 National Inpatient Sample (n=230). ICD-9 codes were utilized to identify indications for trachelectomy and post-procedure pathology. We weighted the hospital-level data to obtain nationwide estimates of patient characteristics, surgical complications, and length of stay. Results: Nationwide, 1,140 women underwent trachelectomy after hysterectomy. The mean age was 49 (95%CI 47-50). The majority of women were white (57%, 95%CI 50-63) and privately-insured (64%, 95%CI 58-70). Fibroids were the most common indication for trachelectomy (35%, 95%CI 29-42) followed by prolapse (14%, 95%CI 9-18). Around 6% (95%CI 3-9) were performed for uterine cancer, 4% (95%CI 2-7) for cervical cancer, 4% (95%CI 1-6) for ovarian cancer, and 1% (95%CI 0-2) for other gynecologic cancers. Only 2% (95%CI 0-4) of trachelectomies were performed laparoscopically; the remainder were performed via an abdominal or vaginal approach. Five percent (95%CI 2-8) of women experienced a urogenital complication, most commonly a urinary tract infection (3%, 95%CI 1-6) or bladder injury (1%, 95%CI 0-2). The median length of stay was 3.7 days (95%CI 3.2-4.3). Conclusions: Women undergoing trachelectomy had high rates of complications and findings of cancer. Supracervical hysterectomy subjects patients to a second surgery for which a minimally invasive approach is often not performed and which carries an increased risk of urologic injury and prolonged hospital admission when compared to that reported for a total hysterectomy. Strong consideration should be given to removal of the cervix at the time of hysterectomy except under exceptional circumstances.

Page 16

Abnormal Pathology seen on Appendectomy in Patients with Predominant Right-Sided Pelvic Pain

Katelin Sisler, PGY4 Saint Louis University Ob/Gyn Study Objective: To determine the prevalence of abnormal pathology within the appendix in women with predominantly right-sided chronic pelvic pain (CPP) compared to generalized chronic pelvic pain. Design: A retrospective case-control study. Setting: Tertiary care center in St. Louis, MO. Patients: 220 women who underwent diagnostic laparoscopy and planned or incidental appendectomy for CPP and suspected endometriosis between January 2015 and December 2018. Interventions: None Results: No significant difference in abnormal appendix pathology was found between women with predominantly right-sided CPP (cases) and women without predominantly right-sided CPP (controls) (30.9% versus 34.5%, p=0.74, odds ratio = 0.85, 95% CI: (0.44, 1.62)). Regardless of where the patient had chronic pain, the incidence of abnormal pathology was found to be 30.6% in macroscopically normal appearing appendices and 37.5% in appendices with gross abnormalities. Conclusion: In this study, the presence of abnormal pathology within the appendix did not correlate with right-sided CPP or abnormal appearance of the appendix. However, performing routine appendectomy may be reasonable for any woman with CPP given the significant rates of abnormal pathology of the appendix found when removed. This study supports the practice of routine appendectomy for patients with CPP by general surgeons and gynecologists.

Page 17

Ambient Ionization Mass Spectrometry for Molecular Characterization of Surgical Diagnosis of Endometriosis

Michael T Breen, MD

AAGL 2019

University of Texas Dell School of Medical SchoolDirector Robotics and Minimally Invasive Surgery

I have no financial relationships to disclose.

2

Disclosure

Explore and evaluate novel technology (Mass Spectrometry) to characterize metabolic and proteomic markers in endometriosis patients using desorption electrospray ionization (DESI) and Mass Spectrometry Pen.

Identify diagnostic markers of endometriosis from ectopic tissue biopsies from endometriosis patients and unaffected patients.

Discuss the potential of Mas Spec Pen as an intraoperative tool for in vivo endometriosis detection in laparoscopic surgeries.

3

Objectives

4

10% of women have endometriosis

176 million women worldwide live with endometriosis – About 10x more people than the total number of people who are diagnosed with cancer each year

In 2017, the NIH allocated 6 million dollars of its 32.3 billion dollar budget to endometriosis research – the same amount allocated to seasonal allergy research

Pediatric and Adolescent gynecology literature focusing awareness toward physical and psychological effects of adenomyosis in adolescent patients.

www.cancer.gov/about-cancer/understanding/statistics

https://report.nih.gov/categorical_spending.aspx

www.mayoclinic.org/diseases-conditions/endometriosis/

Symptoms can include pelvic pain, abdominal distortion, and subfertility.

Currently, causes and pathogenesis of endometriosis is unclear and no proposed biomarkers have proven capable of disease diagnosis.

Diagnosis can take from 5-20 years

Typically, the best treatment option is laparoscopic removal of endometriosis lesions, although ~50% of patients see recurrence of lesions within five years.

Menarche to menopause can be relentless

5

Endometriosis is uncontrolled growth of endometrial tissue outside the uterus Current endometriosis diagnosis procedure

Pelvic Exam

Ultrasound

MRI

6

Challenges:

Non-specific symptoms and comorbidity

Large health care costs and risks

Hesitancy to establish a diagnosis in adolescent population

Page 18

Endometrial Stroma

Endometrial Glands

Hemosiderin

2 histological featured observed

Endometriosis diagnosis

Endometriosis histology

Challenges:

Healthy and endometriosis endometrial

glands/stroma are histologically

identical

Heterogeneity and size of lesions

Permanent pathology does not provide

information about margins or address

atypical lesions in real time.

7

Desorption electrospray ionization (DESI) mass spectrometry for disease characterization

Y

X Moving Stage

VSolvent

N2

Desorbed Ions

%

Rel

. Abu

ndan

ce (

%)

m/z

Rel

. Abu

ndan

ce (

%)

m/z

Rel

. Abu

ndan

ce (

%)

m/z

0 100 0 100 0 100% %

1 mm

5

Scan 1 Scan 2 Scan 3

Scan 1 Scan 2 Scan 3

Desorption electrospray ionization (DESI) mass spectrometry for disease characterization

Y

X Moving Stage

VSolvent

N2

Desorbed Ions

%

Rel

. Abu

ndan

ce (

%)

m/z

Rel

. Abu

ndan

ce (

%)

m/z

Rel

. Abu

ndan

ce (

%)

m/z

0 100 0 100 0 100% %

1 mm

Advantages:

Targeting of specific cellular environments

within heterogeneous samples

Excellent chemical specificity and detection of

relative abundance alterations

Easily translatable into the clinic

5

Perform DESI-MS imaging to analyze healthy endometrium and endometriosis lesions

Develop a tissue classification model to distinguish the endometrial glands and stroma from healthy endometrium and endometriosis lesions

Use mass spectrometry molecular data to evaluate biological differences between healthy endometrium and endometriosis that may give insights into potential pathogenesis and biomarkers of endometriosis.

Can ambient ionization MS help us detect and understand endometriosis?

8

Prospectively collected and sectioned 269 endometrium

and endometriosis samples from

89 patients

DESI-MS analysis in the negative ion

mode at 100 μm spatial

resolution

Pathological evaluation of samples for isolation of endometrial

stroma tissue

Statistical analysis of

molecular data

1) Differentiation between endometrium and

endometriosis stroma

2) Identify molecules showing significant

differences between tissue types

Our DESI-MS imaging workflow

9

2-3 endometriosis surgeries per week

Collection took ~2 years

DESI-MS metabolic profiles of endometrium and endometriosis stroma

Endometrium

1000100 200 300 400 500 600 700 800 900m/z

0

20

40

60

80

100

0

20

40

60

80

100

Re

lativ

e A

bu

nd

an

ce (

%)

PI 38:4885.549

FA 16:0255.233 FA 18:1

281.249 PE 38:4766.539

PS 36:1788.545

FA 20:4303.233

FA 18:1281.249

FA 20:4303.233FA 16:0

255.233

CL 72:8723.478

Endometriosis

Re

lativ

e A

bu

nd

an

ce (

%)

700 720 740 760 780 800 820 840 860 880 900m/z

0

20

40

60

80

100

0

20

40

60

80

100

PE 38:4766.539PE-P 36:4

722.513 PS 36:1788.545

PS 40:4838.560

ST 40:1888.566

PI 38:4885.549

ST 40:1888.566

PI 34:2833.518

Patient #30

PS 36:1788.545

PI 38:4885.549

CL 72:8723.478 PE 38:4

766.539

PS 36:1788.545

PI 38:4885.549

Metabolic profiles of healthy endometrium and endometriosis

Iodine126.905

Endometrium

Endometriosis

8

Page 19

En

do

met

riu

mE

nd

om

etri

osi

s

m/z 766.538PE 38:4

m/z 126.905Iodine

m/z 246.951m/z 788.545

PS 36:1m/z 279.233

FA 16:2m/z 885.549

PI 38:4

Relative A

bundance

0%

100%

1 mm 200 μm

500 μm 100 μm

1 mm 500 μm

1 mm 250 μm

H&E Stained Histology

DESI-MS ion images of healthy endometrium endometriosis

9

Statistical analysis of DESI-MS imaging data

m/z values

pixe

ls

Pathological diagnosis Molecular information

1 mm

%

100

0

~ 30,000 pixels

~ 500 m/z values per pixel

15 million data points!!!

Courtesy of Jonathan Young

12

100%

0%

Ion

inte

nsi

ty

Statistical classification of endometriosis by lasso

73 samples from 36 patients

Training Set

44 endometriosis (3,616 pixels)

15 endometrium (13,329 pixels)

Validation Set

11 endometriosis (1,330 pixels)

3 endometrium (3,886 pixels)

Test Set

21 endometriosis (2,369 pixels)

4 endometrium (4,263 pixels)

Sensitivity: 98.0%Specificity: 88.8%

Overall accuracy: 90.8%

Sensitivity: 99.5%Specificity: 99.3%

Overall accuracy: 99.3%

Sensitivity: 98.0%Specificity: 100.0%

Overall accuracy: 99.3%

14

25 samples from 14 patients

-70 -50 -30 -10 10 30 50 70 90

887.56

255.23

788.54766.54

479.36421.22331.26

307.27303.23

281.25279.23

246.96226.99

215.05201.04

187.04137.03

126.91

Selected m/z features

Ind

icative of E

nd

om

etrium

Ind

icat

ive

of

En

do

met

rio

sis

Lasso weight

Selected lasso features for distinguishing healthy endometrial and endometriosis tissue

m/z Identification

887.558 PI 18:0_20:4†

788.544 PS 18:1_18:0

766.538 PE 18:0_20:4

421.226 Dioctyl sulfosuccinate

331.264 FA 22:4

307.264 FA 20:2

303.233 FA 20:4

281.249 FA 18:1

279.233 FA 18:2

255.233 FA 16:0

226.997 Isocitric acid [M+Cl]

215.033 Hexose [M+Cl]

201.038 Lactate [2M-2H+Na]

137.036 Urocanic acid

126.905 Iodine

*Annotation XX:Y signifies (number of carbons):(level of unsaturation of the FA chains)† Indicates isotopic peak

15

Biological relevance of selected metabolites

m/z Identification

887.558 PI 18:0_20:3

788.544 PS 18:1_18:0

766.538 PE 18:0_20:4

421.226 Dioctyl sulfosuccinate

331.264 FA 22:4

307.264 FA 20:2

303.233 FA 20:4

281.249 FA 18:1

279.233 FA 18:2

255.233 FA 16:0

226.997 Isocitric acid [M+Cl]

215.033 Hexose [M+Cl]

201.038 Lactate [2M-2H+Na]

137.036 Urocanic acid

126.905 Iodine

Glycerophosphoethanolamine (PE) 18:0_20:4

Glycerophosphoserine (PS) 18:0_18:1

16

Chagovets, V. V. et al. Sci. Rep. 2017, 7, 2546.Dutta, M et al. J. Proteome Res. 2016, 15, 2626-2633.Leventis, P. A et al. Annu. Rev. Biophys. 2010, 39, 407-427.

Indicative of Endometriosis

Indicative of Endometrium

Biological relevance of selected metabolites

m/z Identification

887.558 PI 18:0_20:3

788.544 PS 18:1_18:0

766.538 PE 18:0_20:4

421.226 Dioctyl sulfosuccinate

331.264 FA 22:4

307.264 FA 20:2

303.233 FA 20:4

281.249 FA 18:1

279.233 FA 18:2

255.233 FA 16:0

226.997 Isocitric acid [M+Cl]

215.033 Hexose [M+Cl]

201.038 Lactate [2M-2H+Na]

137.036 Urocanic acid

126.905 Iodine

FA 18:1 (Oleic Acid)

FA 18:2 (Linoleic acid)

FA 22:4 (Adrenic Acid)

FA 20:4 (Arachidonic Acid)

Gazvani, M. R., et al. Fertil. Steril., 76, 717-722.Hopeman, M. M, et al. S. Reprod. Sci. 2015, 22, 1083-1087. 17

Indicative of Endometriosis

Indicative of Endometrium

Page 20

-70 -50 -30 -10 10 30 50 70 90

Glycerophosphoinisitol (38:3)

Linoleic acid

Glycerophosphoserine (36:1)

Glycerophosphoethanolamine (38:4)

Dioctyl sulfosuccinate

Palmitic acid

Isocitric acid

Hexose

Lactic acid

Selected m/z features

Ind

icative of E

nd

om

etrium

Ind

icat

ive

of

En

do

met

rio

sis

Lasso weight

15 identified, biologically relevant species that are different between healthy endometrium and endometriosis tissue

20

Adrenic acid

Arachidonic acid

Oleic acid

Eicosadienoic acid

Urocanic acid

Iodine

-70 -50 -30 -10 10 30 50 70 90

Glycerophosphoinisitol (38:3)

Linoleic acid

Glycerophosphoserine (36:1)

Glycerophosphoethanolamine (38:4)

Dioctyl sulfosuccinate

Palmitic acid

Isocitric acid

Hexose

Lactic acid

Selected m/z features

Ind

icative of E

nd

om

etriumIn

dic

ativ

e o

f E

nd

om

etri

osi

s

Lasso weight

15 identified, biologically relevant species that are different between healthy endometrium and endometriosis tissue

20

Adrenic acid

Arachidonic acid

Oleic acid

Eicosadienoic acid

Urocanic acid

Iodine

While healthy endometrium and endometriosis tissue are histologically

identical, our data suggests they are not molecularly identical!

Challenges associated with endometriosis surgery

Endometriosis lesions can have a variety of appearances, some of which can be difficult to identify.

Endometriosis can present as “invisible” microscopic lesions that are difficult for even expert surgeons to remove. Margins of excision can be unclear

Many women undergoing endometriosis surgery are doing so to increase fertility, making conservation of healthy tissue extremely important.

Dinic, S. P.-T. et al. Laparoscopic Surgery in the Treatment of Endometriosis. In Fertility-oriented Female Reproductive Surgery, Darwish, A., Rijeka, 2017; p Ch. 04.

16

The MasSpec Pen: A tool for mass spectral analysis

Biocompatible

Non-destructive

Capable of in vivo tissue analysis

Real-time automated feedback of disease state

17

Zhang, J. et al. Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system. Science Translational Medicine 2017, 9 (406).

Page 21

Use of MS imaging to collect spatial and molecular information from healthy endometrium and endometriosis lesions has been validated.

Ability to distinguish between healthy endometrium and endometriosis glands and stroma with an overall accuracy of 99.3% per pixel on an independent test set of samples.

Identification of 15 species with altered abundances between healthy endometrium and endometriosis glands and stroma, suggesting them as possibly relevant for endometriosis pathogenesis and potential disease biomarkers.

Conclusions

21

Ongoing validation of Mass Spectrometry accuracy and utility in Endometriosis management.

Porcine in vivo studies for evaluation of technology in CO2 laparoscopic environment.

Future IRB submission for human in vivo intraoperative Mass Spectrometry analysis of endometriosis (in preparation).

Identification of adenomyosis unique Mass Spec Signature.

Extrapolation and validation to assist in adolescent endometriosis.

27

Future Applications

28

Acknowledgments

Dr. Livia S. EberlinMacArthur Foundation Fellow

UT Austin Chemistry Department

• Prof. Livia S. Eberlin• Spencer Woody• Dr. Jialing Zhang• Anna Krieger• Eberlin Research Lab• Clara Fielder

Dr. Michael T. Breen Dr. Suzanne LedetKatherine Sebastian

Acknowledgments

Eberlin Group

Clinical collaborators

External funding and resources

22

1. www.cancer.gov/about-cancer/understanding/statistics2. https://report.nih.gov/categorical_spending.aspx3. www.mayoclinic.org/diseases-conditions/endometriosis/4. Chagovets, V. V. et al. Endometriosis foci differentiation by rapid lipid profiling using tissue spray ionization and high resolution mass

spectrometry.Sci. Rep. 2017, 7, 2546.5. Dutta, M et al. Metabolomics Reveals Altered Lipid Metabolism in a Mouse Model of Endometriosis. J. Proteome Res. 2016, 15, 2626-2633.6. Leventis, P. A et al. The distribution and function of phosphatidylserine in cellular membranes. Annu. Rev. Biophys. 2010, 39, 407-4277. Gazvani, M. R., et al. High omega-3:omega-6 fatty acid ratios in culture medium reduce endometrial-cell survival in combined endometrial

gland and stromal cell cultures from women with and without endometriosis. Fertil. Steril., 2001,76, 717-722.8. Hopeman, M. M, et al. Serum Polyunsaturated Fatty Acids and Endometriosis. Reprod. Sci. 2015, 22, 1083-1087.9. Dinic, S. P.-T. et al. Laparoscopic Surgery in the Treatment of Endometriosis. In Fertility-oriented Female Reproductive Surgery, Darwish, A.,

Rijeka, 2017; p Ch. 04.10. Zhang, J. et al. Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system. Science

Translational Medicine 2017, 9 (406).11. Barbar G. et al. When love hurts. A systematic review on the effects of surgical and pharmacological treatments for endometriosis on female

sexual functioning. Acta Obstet Gynecol Scand. 2017, 96:668-687.12. Ianieri, MM. et al. Recurrence in deep infiltrating endometriosis: a systematic review of the literature. J Minim Invasive Gynecol, 2018,

25:786-79313. Eberlin, L. S. et al. Ambient Ionization Mass Spectrometry for Cancer Diagnosis and Surgical Margin Evaluation. Clin. Chem. 2016;62:111-

123.14. Cordeiro, F.B. et al. Metabolomic profiling in follicular fluid of patients with infertility-related deep endometriosis. Metabolomics, 2017,

13(10):120.15. Kyama, C.M. et al. Evaluation of endometrial biomarkers for semi-invasive diagnosis of endometriosis. Fertil. Steril. 2011, 95(4), 1338-U173.16. Adamyan, L. et al. Evidence-Based Medicine: Pandora's Box of Medical and Surgical Treatment of Endometriosis. J. of Minim. Invasive

Gynecol. 2017.

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References

Page 22

CULTURAL AND LINGUISTIC COMPETENCY Governor Arnold Schwarzenegger signed into law AB 1195 (eff. 7/1/06) requiring local CME providers, such as

the AAGL, to assist in enhancing the cultural and linguistic competency of California’s physicians

(researchers and doctors without patient contact are exempt). This mandate follows the federal Civil Rights Act of 1964, Executive Order 13166 (2000) and the Dymally-Alatorre Bilingual Services Act (1973), all of which

recognize, as confirmed by the US Census Bureau, that substantial numbers of patients possess limited English proficiency (LEP).

California Business & Professions Code §2190.1(c)(3) requires a review and explanation of the laws

identified above so as to fulfill AAGL’s obligations pursuant to California law. Additional guidance is provided by the Institute for Medical Quality at http://www.imq.org

Title VI of the Civil Rights Act of 1964 prohibits recipients of federal financial assistance from

discriminating against or otherwise excluding individuals on the basis of race, color, or national origin in any of their activities. In 1974, the US Supreme Court recognized LEP individuals as potential victims of national

origin discrimination. In all situations, federal agencies are required to assess the number or proportion of LEP individuals in the eligible service population, the frequency with which they come into contact with the

program, the importance of the services, and the resources available to the recipient, including the mix of oral

and written language services. Additional details may be found in the Department of Justice Policy Guidance Document: Enforcement of Title VI of the Civil Rights Act of 1964 http://www.usdoj.gov/crt/cor/pubs.htm.

Executive Order 13166,”Improving Access to Services for Persons with Limited English

Proficiency”, signed by the President on August 11, 2000 http://www.usdoj.gov/crt/cor/13166.htm was the genesis of the Guidance Document mentioned above. The Executive Order requires all federal agencies,

including those which provide federal financial assistance, to examine the services they provide, identify any

need for services to LEP individuals, and develop and implement a system to provide those services so LEP persons can have meaningful access.

Dymally-Alatorre Bilingual Services Act (California Government Code §7290 et seq.) requires every

California state agency which either provides information to, or has contact with, the public to provide bilingual

interpreters as well as translated materials explaining those services whenever the local agency serves LEP members of a group whose numbers exceed 5% of the general population.

~

If you add staff to assist with LEP patients, confirm their translation skills, not just their language skills.

A 2007 Northern California study from Sutter Health confirmed that being bilingual does not guarantee competence as a medical interpreter. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2078538.

US Population

Language Spoken at Home

English

Spanish

AsianOther

Indo-Euro

California

Language Spoken at Home

Spanish

English

OtherAsian

Indo-Euro

19.7% of the US Population speaks a language other than English at home In California, this number is 42.5%

Page 23