Hyperbaric Oxygen in ORL-HNS: Facts, Fictions, and Evidence

1
Hyperbaric Oxygen in ORL-HNSFacts, Fictions,
and Evidence

• Evan R. Ransom, MD
• University of Pennsylvania
• Otorhinolaryngology, Head Neck Surgery
• Faculty Discussant
• Kevin Hardy, MD
• Emergency Medicine, Hyperbaric Medicine

2
Overview

• Why HBO2?
• History
• Basics
• Details
• ORL-HNS Applications
• Data
• Discussion

3
History

• Initial discovery
• 1662 ? Henshaw built first hyperbaric chamber
• English physician and clergyman
• Called the chamber the Domicilum
• Hermetically sealed box with organ bellows
  valves
• "In times of good health this domicilium is
  proposed to promote insensible respiration, to
  facilitate breathing and expectoration of
  excellent use for prevention of most affections
  of the lungs."

4
Background

• Elemental Oxygen
• 1775 ? Discovered by Priestly (English)
• Surgical use
• 1870s ? Fontaine Bert (France)
• Prolong anesthesia
• Improved surgical outcomes
• Wound healing
• Infection rates
• Decompression sickness
• 1910-30s ?Drager, then Behnke Shaw
• Reduced morbidity of decompression
• Studies of cardiopulmonary effects initiated

5
Background

• Cardiothoracic Surgery
• 1950s ? Boerema (Dutch)
• Increase tissue oxygen stores prior to
  cross-clamping
• Repair of congenital heart defects
• With Brummelkamp, discovered effects on anaerobes
• Bacteriostatic
• Treat gas gangrene (Clostridium perfringens)
• Carbon monoxide poisoning
• 1962 ? Smith Sharp (English) treated coal
  minors exposed to carbon monoxide
• US Military Research
• 1930s ? determine maximal pressure tolerated
• 1960s ? potentiation of radiation doses

6
Common Current Uses

• Decompression Sickness
• Gas Embolism
• Crush Injuries
• Anaerobic Infections
• Osteomyelitis
• Chronic Wounds
• Necrotizing Infections
• Osteoradionecrosis

7
Theory

• Why did we think HBO2 would work?
• Respiration is good so why not more of it?
• What if we increase tissue oxygen delivery to
  supraphysiologic levels?
• How about generating more reactive oxygen to kill
  pathogens and tumors!?

8
Theory

• Some physics weve all forgotten
• Boyles Law
• Daltons Law
• Henrys Law

9
Physics

• Boyles Law ? at a constant temperature, the
  pressure and volume of a gas are inversely
  proportional.
• Hyperbaric chamber
• Compression of a given volume of gas therefore
  elevates its pressure
• One-way valve to add gas volume to chamber

10
Physics

• Daltons Law ? in a gas admixture, each component
  gas exerts a pressure proportional to its
  fraction of the total volume (i.e., partial
  pressure).
• Increasing the proportion of oxygen in the
  inhaled gas mixture increases its partial
  pressure
• Air at sea level is 21 O2
• HBO2 treatments use FiO2 100

11
Physics

• Henrys Law ? the amount of gas dissolved in a
  liquid is directly proportional to its partial
  pressure at the liquid/gas interface.
• Increasing the partial pressure of oxygen results
  in more oxygen dissolved in the blood
• Blood oxygen carriage therefore increases
• In addition to saturation of available hemoglobin

12
Physiology

• Cardiopulmonary
• Increase in PaO2
• Saturation of available hemoglobin molecules
• Hgb 97 saturated at atmospheric pressure
• Maximization does NOT significantly increase O2
  delivery
• Increase in dissolved O2
• PAO2 is 100mm Hg at atmospheric pressure
• Using 100 FiO2 at 3 atm ? up to 2000mm Hg
• Increase O2 from 3ml/L blood to to 60ml/L
• 20 times more O2 circulating in plasma

13
Physiology

• Cardiopulmonary
• Dissolved O2 diffuses into RBC-impassible areas
• May also deliver O2 in absence of functional Hgb
• 100 O2 at 3.0atm ? effects at capillary beds
• Doubles distance of venous diffusion
• Quadruples distance of arteriolar diffusion

14
Physiology

• Tissue Cellular level
• Tissue PO2 is 55mm Hg at atmospheric pressure
• Using FiO2 100 at 3atm, increase to 500mm Hg
• Almost 10 fold increase in tissue oxygen tension
• Tissue PO2 gt 40mm Hg needed to initiate any
  healing
• Tissue response proportional to O2 delivery
• O2 diffuses down the partial pressure gradient
• Gradient from arterioles ? capillary bed ? venous
  return is increased 37 fold
• Increase activation of fibroblasts osteoblasts
• Promotes angiogenesis neovascularization

15
Mechanism

• Three main effects of HBO2
• 1) Delivery of O2 to hypoperfused tissues
• Limit ischemic damage, cell death, and
  inflammation
• Promotes collagen synthesis and angiogenesis
• Decreases lactate production and tissue acidosis
• 2) Generation of oxygen free radicals
• Aids in oxygen-dependent killing of bacteria
• Facilitates oxygen dependent transport of
  antibiotics
• 3) Vasoconstriction
• Limits leukocyte adhesion and degrannulation
• Decreases tissue edema

16
Dosing and Delivery

• Parameters
• All regimens use 100 O2
• Pressure more variable
• Most use 2.4 atm
• Maximum tolerated is 3 atm
• 4 atm induces seizures

Monoplace Hyperbaric Chamber.
17
Dosing and Delivery

• Common regimens
• Dives between 30 and 120 minutes
• May be daily or BID
• Total number varies by indication
• Most treatments around 30 dives
• Optional addition of 10 or more dives
• Monoplace vs. multiplace chambers

Multiplace Hyperbaric Chamber.
18
Contraindications

• One absolute contraindication
• Pneumothorax
• Pressure converts to tension pneumothorax
• Circulatory disruption and collapse
• All patients get screening CXR
• Relative contraindications
• History of spontaneous pneumothorax
• History of throacic surgery
• Concurrent URI
• Emphysema and COPD
• Seizure disorders

19
Complications

• Barotrauma
• Middle ear
• Eustachian tube dysfunction or obstruction
• Poor pressure equalization
• May cause
• Significant pain
• Hemotympanum
• TM rupture

20
Complications

• Barotrauma
• Lung parenchyma
• Elevated pressures may damage alveoli
• Alveolar hemorrhage
• Hemoptysis
• Pneumonitis
• Alveolar rupture
• Pneumothorax
• Pulmonary interstitial emphysema

Tension Pneumothorax
21
Complications

• Lens deformation causes temporary myopia
• Exacerbation of other processes
• Dental abscess, sinusitis, laryngocele, etc.
• Claustrophobia, anxiety, etc.
• Oxygen toxicity
• Very rare, but may cause seizures
• Potential effects on tumor growth
• Controversial more on this later

22
Fire Risk

• Perfect set up for fire (especially monoplace)
• 100 oxygen
• Highly pressurized
• Enclosed space
• Rare but not rare enough
• 50 deaths due to HBO2-related fires since 1980
• Must remove all flammable materials
• Fire safety protocol is essential
• Risk reduced in multiplace chambers
• Chamber pressurized
• O2 delivered individually via tight-fitting masks
• Attendants may enter in an emergency

23
Costs

• HBO2 is relatively expensive
• Monoplace chamber gt 150,000
• Most facilities have multiplace chambers, which
  can cost millions
• Each 30 min costs 170
• Average full course is 30 dives of 90 min
• Billed for 15,300
• Plus physician fees, hospital stay, meds, etc.
• But
• Medicare reimburses for most accepted indications

24
Costs

• Cost efficacy analyses
• Studies from Europe, Canada, Japan
• Significant cost savings for multiple indications
• E.g., osteoradionecrosis of the mandible
• Reduced surgical costs in ORN patients
• Reduced length of stay
• Overall 17 cost reduction in Europe
• U.S. studies focus on diabetic foot ulcers
• HBO2 cost effective for this indication
• Very limited U.S. data for ORL-HNS indications

25
Applications

• Proposed or Studied for ORL-HNS
• Osteoradionecrosis
• Chondroradionecrosis
• Enhancement of graft flap viability
• Necrotizing infections
• Chronic wounds
• Fistulas
• Malignant otitis externa
• Skull base osteomyelitis
• Sudden SNHL
• Tinnitus
• Idiopathic facial paralysis (Bells palsy)
• Radiation sensitization

26
Applications

• Todays review
• Osteoradionecrosis
• Pharyngocutaneous fistulas
• Enhancement of graft flap viability
• Malignant otitis externa
• Sudden SNHL
• Radiation sensitization

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Osteoradionecrosis

• Damage to osteocytes from XRT
• Weakens bone, predisposing to fracture
• Often painful, broken down mucosal coverage
• Decreases blood flow, difficult to fight
  infection
• Body of the mandible most affected
• Least redundant blood supply muscle coverage
• Incidence decreased significantly in last 30
  years
• Lower radiation doses, more targeted fields
• Currently less than 5 of patients receiving HN
  XRT

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Osteoradionecrosis

• Pathophysiology
• Significant fibrotic changes in bone and marrow
• Reduction in caliber number of feeding vessels
• Periosteal mucosal damage ? bone necrosis

ORN Histology Mandible
ORN X-ray Mandible
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Osteoradionecrosis

• HBO2 used for ORN since 1960s
• Multiple staging systems treatment regimens
• Marx, et al. 1982, 1983, 1990 (retrospective)
• Sequential treatment combining HBO2, debridement,
  surgical resection reconstruction
• Over 90 success rate
• Neovius, et al. 1997
• Cured 12/15 patients with ORN, CRN, or tissue
  necrosis
• Combination HBO2, wound care, debridement,
  antibiotics
• Significant improvement over historical controls
  (7/15)
• Conservative measures alone

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Osteoradionecrosis

• Not all data agree (Annane, et al. 2004)
• Prospective, randomized, controlled trial
• enrollment after 2 months conservative Tx
• 30 dives for 90 min at 2.4 atm vs. placebo
• Placebo Pressurized 90 Nitrogen
• No significant difference between groups!?
• Was there a biologic effect of the placebo?
• Not enough dives?

31
Osteoradionecrosis

• Cochrane review 2005
• Outcome measures
• Primary Survival, resolution of disease
• Secondary Mucosal coverage, bony continuity,
  pain (poor data)
• Identified 6 trials that met evidence standards
• Treatment algorithms differed slightly
• Pooled data for mandible
• 92 resolution with HBO2, 65 in control group
• Improved mucosal coverage (93 v. 67)
• RR 1.4 (95CI 1.2-1.6, plt 0.001) NNT 4
• Improved bony continuity (92 v. 65)
• RR 1.4 (95CI 1.1-1.7 p0.009) NNT 4
• Conclusion HBO2 is safe and likely effective for
  ORN

32
Chronic Wound Data

• Relatively little data from HN
• Cochrane review 2005
• Lower incidence of wound dehiscence with HBO2
• 6 v. 37 post-XRT for HN SCCA
• Significant result only in subset with flaps or
  grafts
• Limited data on speed of healing, major vessel
  bleeding, decannulation, or need for laryngectomy
• Implies that HBO2 would be useful in HN
  reconstruction specifically

33
Chronic Wound Data

• Generalizing from other fields
• Diabetic foot ulcers
• Significant reduction in morbidity
• Significant improvement in functional outcomes
• Significant cost savings
• Mechanism shown in laboratory analyses
• Enhances fibroblast activity
• Collagen synthesis
• Neovascularization
• Improves infection control (especially anaerobes
• Treatment response can be predicted
• Based on measurement of tissue PO2 (TcPO2)
• gt40mm Hg predicts at least some response

34
Pharyngocutaneous Fistula

• Post-laryngectomy
• Significant increases
• Morbidity
• Cost
• Incidence
• Varies widely (3 to gt50)
• Consensus 10-15
• Pathophysiology
• Incomplete healing or breakdown of pharyngeal
  suture line
• Connection develops between mucosa and skin
• First sign is generally post-op fever

Post-laryngectomy Fistula
35
Pharyngocutaneous Fistula

• Complications
• Major vessel bleed
• Aspiration pneumonia, infection, sepsis
• NPO status associated with poor patient QOL
• Treatment
• Most fistulas respond to conservative measures
• NPO enteral nutrition
• Local wound care antibiotics
• Delayed surgical closure
• Non-healing fistulas
• Large fistulas
• Local rotational flaps
• Pectoralis major flap
• Hyperbaric oxygen?
• Prophylactic? Adjuvant?

36
Pharyngocutaneous Fistula

• Davis, et al. 1979
• 15/16 patients with soft tissue necrosis neck
  post-XRT
• Poor patient descriptions, scant wound
  documentation
• Marx, et al. 1993
• Tested prophylactic HBO2 in post-XRT resections
• Prospective with80 patients, 80 controls
• Decreased rate and severity of wound
  complications
• 11 dehiscence in HBO2 vs. 48 without
• 6 infections in HBO2 vs. 24 without
• 11 prolonged hospital stay in HBO2 vs. 55
  without
• Neovius, et al. 1997
• 15 patients with post-XRT wounds
• 4/5 patients with fistulas healed (3/4 with
  pharyngocutaneous)
• Narzony, et al. 2005
• 8 post-XRT patients successfully treated with
  HBO2
• 1 pt had a post-laryngectomy fistula
  polymicrobial infection
• Partially closed with HBO2, infection fully
  treated
• Definitive closure with local muscle flap
  post-HBO2

37
Pharyngocutaneous Fistula

• Limitations
• Small N, patients grouped (i.e., not all
  fistulas)
• Timing and dosing of therapies differ
• Mostly retrospective data
• Penn Study (ORL-HNS, Hyperbaric Medicine)
• Post-radiation laryngectomy
• Effects of HBO2 on wound status outcome
• Prospective data
• Predictive model for wound healing
• Tissue hypoxia
• Angiogenesis

38
Skin Grafts Free Flaps

• Pathophysiology
• Grafted or transplanted tissue may be healthy
• But implantation site may be hypoxic
• Due to tissue bed disease, vasospasm, edema,
  infection
• Oxygen nutrient supply compromised
• Must establish vascular connection for survival
• HBO2 Mechanism
• Improves tissue PO2
• Promotes angiogenesis
• Augments immune response limits inflammation

39
Skin Grafts Free Flaps

• Compromised skin grafts flaps
• Ueda, et al. 1987
• Retrospective HBO2 post-OC composite resection
• 95-100 recovery of compromised flaps grafts
• Waterhouse, et al. 1993
• Retrospective HBO2 for salvage of ischemic free
  flaps
• HBO2 75 salvage vs. 46 without
• Tx within 24hrs ? 100 survival rate
• Tx gt 72hrs ? 0 survival
• Marx, et al. 2002
• Prospective, randomized post-XRT resection
• 11 wound healing delay HBO2 vs. 55 without
• 3.5 major wound dehiscence HBO2 vs. 33 without
• 2.5 major wound infection HBO2 vs. 16 without

40
Malignant Otitis Externa
Design N Results Conclusion
Bath, et al. 1998 Case report 1 Patient cured, CN2 function saved HBO2 Abx is beneficial
Gilain, et al. 1993 Case report 1 Patient cured, CN7 function returned HBO2 Abx is beneficial
Shupak, et al. 1989 Case series 2 Patients cured HBO2 Abx is beneficial
Pilgramm, et al. 1986 Case series 4 Patients cured HBO2 /- Abx is beneficial (one cure with HBO2 alone)
Davis, et al. 1992 Case series 16 Patients cured, 4 year follow-up HBO2 Abx is beneficial used 30 dives
Martel, et al. 2000 Case series 22 (10) Patients cured used HBO2 in 10 cases Surgical debridement HBO2 (15 dives) Abx is beneficial Abx alone cures most cases
Tisch, et al. 2003 Case series 22 Patients cured relapse 27 at 5 year follow-up Surgical debridement HBO2 (20 dives) Abx anti-pseudomonal IG can cure extreme cases, but with some recurrence

• Data is of poor quality
• Mostly case reports
• No prospective data
• But
• Supports use
• Need prospective data
• Need standardization

41
Malignant Otitis Externa

• Cochrane Review 2005
• Data poor quality
• No control groups
• No randomization
• All retrospective
• Suggestion of effect
• Well-characterized and plausible mechanism
• Improved efficacy of immune response
• Enhancement of bacteriacidal antibiotic effects
• Conclusion Need RCTs to truly evaluate this
  indication

42
Sudden SNHL

• Cochrane review 2007
• Data is of poor quality
• Found 6 trials meeting minimum standards
• Conflicting data in hearing recovery
• No difference in improvement of 50 on PTA
• Significant difference of 25 on PTA
• 22 greater chance of this amount of hearing
  improvement
• Clinical significance? (NNT 5)
• Data do not support use in chronic idiopathic
  SNHL
• Summary
• Routine use not recommended due to effect size
  relative to costs
• Need larger trials with randomization to
  determine efficacy

43
Radiation Sensitization

• Among first studied uses of HBO2 (1960s)
• Areas of hypoxia in tumors are resistant to
  therapy
• Increasing oxygen pressure in the tumor can aid
  tumoricidal therapies
• Increase FiO2, increase ambient pressure (i.e.,
  HBO2)
• Administration of radiation sensitizing agents
  (oxygen donors)
• Radiation concurrently (i.e., in HBO2 chamber)
• Technical difficulties (equipment)
• Multiple XRT regimen HBO2 parameters
• Overall suggestion of survival benefit in the
  literature

44
Radiation Sensitization

• Systematic review (Bennett, et al. 2008)
• Found 19 randomized trials of HBO2 with XRT
• HN, cervix, bladder, rectum, esophagus, brain
• HN
• Significant mortality reduction (1 5 yrs)
• Difference seen between fractionization protocols
• gt12 trend to significance
• lt12 RR 0.69 (95CI 0.53-0.89, p0.004), ARR
  20.9
• Significant decrease in recurrence (1 5 yrs)
• Side effects are amplified, too
• Significant increase in radiation morbidity
• ORN, tissue necrosis, xerostomia, etc.

45
Radiation Sensitization

• Data support survival effect
• Need more RCTs to determine
• Timing of XRT (Concurrent? Sequential?)
• Fractionization dosing
• Is it worth the costs?
• XRT side effects are already difficult
• Saving more lives with lower QOL???
• More complications higher treatment costs

46
Tumor Growth!?

• Theoretical historical concern
• HBO2 in malignancy
• Microscopic disease, positive margins, metastasis
• Does HBO2 improve tumor survival? Enhance growth?
• Data are conflicting
• Handful of case reports suggest growth
• GYN malignancies mostly, a couple in HN CA
• Other reports suggest tumor suppression
• Currently, experiments do not show tumor
  progression
• Animal models
• Human SCCA cell cultures
• Systematic reviews have failed to support this
  concern

47
Tumor Growth!?

• Schonmeyr, et al. 2008
• HN SCCA cell culture xenotransplantation
• Measured growth
• In culture in mice (tumor implanted on flank)
• HBO2 90 min/day for 8 days at 2.1 atm, 100 FiO2
• No significant difference in culture or mouse
• No significant difference in
• DNA synthesis
• Angiogenesis
• Trend toward less tumor hypoxia in treatment
  group
• This did not translate to tumor growth
• May actually be helpful for XRT or certain
  chemotherapeutics

48
Summary

• HBO2 derives its clinical benefit via
• Increase in the oxygen delivery to hypoxic tissue
• Promoting native mechanisms of healing
• Decreasing tissue edema reperfusion injury
• Dosing
• Most commonly 30-40 dives of 90 min at 2.4atm
• Costs
• Significant, yet analyses support cost savings in
  proven indications

49
Summary

• Supported ORL-HNS indications
• ORN CRN, radiation soft tissue injury
• Flap graft survival
• Unsupported ORL-HNS indications
• Sudden SNHL, tinnitus, Bells palsy
• Areas of uncertainty
• Likely effect MOE skull base osteo, fistulas
• Poor side effect profile radiation sensitization

50
Summary

• Further research
• Molecular mechanism incompletely understood
• Animal studies
• Human tissue bank studies
• Need ethical randomized control trials
• Variety of indications
• More combination regimens for cancer treatment
  post-XRT reconstruction salvage
• What are the optimal dose delivery shemes?
• Maximize oncologic control quality of life

51
References

• Books
• Handbook on Hyperbaric Medicine. D. Mathieu
  (ed.) Springer (Netherlands), 2006.
• Hyperbaric Medicine Practice. Kindwall P, Whelan
  H (eds) Best Publ. Co. (Arizona), 2002.
• Marx RE. Radiation injury to tissue. Pp. 665-723.
• Cochrane Reviews
• Bennett MH, Feldmeier J, Hampson N, Smee R,
  Milross C. Hyperbaric oxygen for late radiation
  tissue injury. Cochrane Database of Systematic
  Reviews 2005, issue 3.
• Bennett M, Feldmeier J, Smee R, Milross C.
  Hyperbaric oxygen for tumour sensitization to
  radiotherapy. Cochrane Database of Systematic
  Reviews 2005, issue 4.
• Bennett MH, Kertesz T, Yeung P. Hyperbaric oxygen
  for idiopathic sudden sensorineural hearing loss
  and tinnitus. Cochrane Database of Systematic
  Reviews 2007, issue 1.
• Kranke P, Bennett M, Roeckl-Wiedmann I, Debus S.
  Hyperbaric oxygen for chronic wounds. Cochrane
  Database of Systematic Reviews 2004, issue 1.
• Phillips JS, Jones SEM. Hyperbaric Oxygen as an
  adjuvant treatment for malignant otitis externa.
  Cochrane Database of Systematic Reviews 2005,
  issue 2.

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References

• Articles
• Annane D, Depondt J, Aubert P, Villart M, et al.
  Hyperbaric Oxygen Therapy for Radionecrosis of
  the Jaw A Randomized, Placebo-Controlled,
  Double-Blind Trial from the ORN96 Study Group. J
  Clin Onool 2004 22 4893-4900.
• Bennett M, Feldmeier J, Smee R, Milross C.
  Hyperbaric oxygenation for tumour sensitisation
  to radiotherapy A systematic review of
  randomised controlled trials. Cancer Trtmt Rev
  2008 34 577-591.
• DSouza J, Goru J, Goru S, et al. The influence
  of hyperbaric oxygen on the outcomes of patients
  treated for osteoradionecrosis 8 year study.
  Intl J OMFS 2007 36(9) 783-787.
• Daruwalla J, Christophi C. Hyperbaric Oxygen
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• Gal TJ, Yueh B, Futran ND. Influence of prior
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• Gill, AL Bell, CAN. Hyperbaric Oxygen its
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• Hirsch DL, Bell RB, Dierks EJ, Potter JK, Potter
  BE. Analysis of microvascular free flaps for
  reconstruction of advanced mandibular
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• London SD, Park SS, Gampper TJ, Hoard MA.
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• Marx RE, Ames JR. The use of hyperbaric oxygen in
  bony reconstruction of the irradiated and
  tissue-deficient patient. J OMFS 1982 40
  412-420.
• Marx RE. A new concept in the treatment of
  osteoradionecrosis. JOMFS 1983 41 351-357.
• Myers R, Marx RE. Use of hyperbaric oxygen in
  postradiation head and neck surgery. NCI Monogr.
  1990 9 151-157.
• Neovius EB, Lind MG, Lind FG. Hyperbaric oxygen
  therapy for wound complications after surgery in
  the irradiated head and neck a review of the
  literature and a report of 15 consecutive
  patients. HN 1997 19 315-322.
• Shi Y, Lee CS, Wu J, Koch CJ, et al. Effects of
  hyperbaric oxygen exposure on experiemtnal head
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• Schonmeyr BH, Wong AK, Reid VJ, et al. The Effect
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• Wreford-Brown CE, Hampson NB. Hyperbaric oxygen
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Thanks.