**ORN - DEFINITION**
Radiographic lytic or mixed sclerotic lesion of bone and/or visibly exposed bone and/or bone probed through a periodontal probe or fistula
**AND**
Occurring at an anatomical site previously exposed to radiotherapy (RTx)
Osteoradionecrosis (ORN) is characterized by the following clinical and radiographic criteria:
- Radiographic evidence of a lytic or mixed sclerotic lesion of the bone.
- Visibly exposed bone or bone that can be probed through a periodontal probe or fistula.
- The condition must occur at an anatomical site previously exposed to radiotherapy (RTx).
<img src="figure_description.jpg" alt="Abstract header image with orange, white, and blue abstract shapes">
# **Prevention and Management of Osteoradionecrosis in Patients With Head and Neck Cancer Treated With Radiation Therapy: ISOO-MASCC-ASCO Guideline**
Douglas E. Peterson, DMD, PhD, FDS RCSEd, FASCO$^{1}$ $\text{ID}$; Shlomo A. Koyfman, MD$^{2}$; Noam Yarom, DMD, MPH$^{3,4}$ $\text{ID}$;
Charlotte Duch Lynggaard, MD, PhD$^{5}$ $\text{ID}$; Nofisat Ismaıla, MD, MSc$^{6}$ $\text{ID}$; Lone E. Forner, DDS, PhD$^{7}$; Clifton David Fuller, MD, PhD$^{8}$ $\text{ID}$;
Yvonne M. Mowery, MD, PhD$^{9,10}$ $\text{ID}$; Barbara A. Murphy, MD$^{11}$ $\text{ID}$; Erin Watson, DMD, MHSc$^{12}$ $\text{ID}$; David H. Yang, DDS, FRCD(C)$^{13}$ $\text{ID}$;
Ivan Alajbeg, DMD, MSc, PhD$^{14}$ $\text{ID}$; Paolo Bossi, MD$^{15,16}$ $\text{ID}$; Michael Fritz, MD$^{2}$; Neal D. Futran, MD, DMD$^{17}$; Daphna Y. Gelblum, MD$^{18}$;
Edward King, JD$^{19}$; Salvatore Ruggiero, DMD, MD, FACS$^{20}$; Derek K. Smith, DDS, PhD, MPH$^{21}$; Alessandro Villa, DDS, MPH, PhD$^{22}$ $\text{ID}$;
Jonn S. Wu, BMSc, MD, FRCPC$^{13}$; and Deborah Saunders, DMD$^{23}$
DOI https://doi.org/10.1200/JCO.23.02750
#### Guideline Authors
- **Douglas E. Peterson, DMD, PhD, FDS RCSEd, FASCO** (University of Connecticut Health)
- **Shlomo A. Koyfman, MD** (Cleveland Clinic)
- **Noam Yarom, DMD, MPH** (Tel-Aviv University; Sheba Medical Center)
- **Charlotte Duch Lynggaard, MD, PhD** (Rigshospitalet, Copenhagen University Hospital)
- **Nofisat Ismaıla, MD, MSc** (American Society of Clinical Oncology)
- **Lone E. Forner, DDS, PhD** (Rigshospitalet, Copenhagen University Hospital)
- **Clifton David Fuller, MD, PhD** (The University of Texas MD Anderson Cancer Center)
- **Yvonne M. Mowery, MD, PhD** (Duke University Medical Center; Durham VA Health Care System)
- **Barbara A. Murphy, MD** (Vanderbilt University Medical Center)
- **Erin Watson, DMD, MHSc** (Princess Margaret Cancer Centre)
- **David H. Yang, DDS, FRCD(C)** (BC Cancer)
- **Ivan Alajbeg, DMD, MSc, PhD** (University of Zagreb)
- **Paolo Bossi, MD** (University of Brescia; ASST Spedali Civili di Brescia)
- **Michael Fritz, MD** (Cleveland Clinic)
- **Neal D. Futran, MD, DMD** (University of Washington)
- **Daphna Y. Gelblum, MD** (Memorial Sloan Kettering Cancer Center)
- **Edward King, JD** (Patient Representative)
- **Salvatore Ruggiero, DMD, MD, FACS** (New York Center for Orthognathic and Maxillofacial Surgery)
- **Derek K. Smith, DDS, PhD, MPH** (Vanderbilt University Medical Center)
- **Alessandro Villa, DDS, MPH, PhD** (University of California San Francisco)
- **Jonn S. Wu, BMSc, MD, FRCPC** (BC Cancer)
- **Deborah Saunders, DMD** (Health Sciences North)
**DOI:** https://doi.org/10.1200/JCO.23.02750
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Abstract header image with orange, white, and blue abstract shapes, serving as a decorative element at the top of the document.
**TABLE 1. Characteristics of Studies Identified in the Literature Search**
| Topics | RCT | Prospective (non-RCT) | Retrospective | Total |
|---|---|---|---|---|
| Grading | 0 | 0 | 2 | 2 |
| **Grading** | 0 | 0 | 2 | 2 |
| **Prevention** | | | | |
| Before RT | 0 | 3 | 15 | 18 |
| After RT | 0 | 3 | 5 | 8 |
| Mixed | 0 | 0 | 2 | 2 |
| **Management** | | | | |
| Medication | 0 | 2 | 6 | 8 |
| HBO | 6 | 1 | 4 | 11 |
| Surgery | 0 | 4 | 20 | 24 |
| Combination | 0 | 0 | 6 | 6 |
| Laser (PBM) | 0 | 1 | 0 | 1 |
| Total | 6 | 14 | 60 | 80 |
Abbreviations: RCT, randomized controlled trial; RT, radiation therapy; HBO, hyperbaric Oxygen; PBM, photobiomodulation.
#### Literature Search Summary
| Topics | RCT | Prospective (non-RCT) | Retrospective | Total |
| :--- | :---: | :---: | :---: | :---: |
| **Grading** | 0 | 0 | 2 | 2 |
| **Prevention** | | | | |
| Before RT | 0 | 3 | 15 | 18 |
| After RT | 0 | 3 | 5 | 8 |
| Mixed | 0 | 0 | 2 | 2 |
| **Management** | | | | |
| Medication | 0 | 2 | 6 | 8 |
| HBO | 6 | 1 | 4 | 11 |
| Surgery | 0 | 4 | 20 | 24 |
| Combination | 0 | 0 | 6 | 6 |
| Laser (PBM) | 0 | 1 | 0 | 1 |
| **Total** | **6** | **14** | **60** | **80** |
**Abbreviations:** RCT, randomized controlled trial; RT, radiation therapy; HBO, hyperbaric Oxygen; PBM, photobiomodulation.
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TABLE 1. Characteristics of Studies Identified in the Literature Search, which categorizes studies by topics (Grading, Prevention, Management) and study designs (RCT, Prospective non-RCT, Retrospective), showing the total number of studies for each category. The table includes data on various management methods such as Medication, HBO, Surgery, Combination, and Laser (PBM), with a total of 80 studies identified.
# **KEY STUDY QUESTIONS**
1. How should ORN be characterized, graded, and reported?
2. What are the recommended best practices for the prevention of ORN of the head and neck prior to radiation therapy?
3. What are the recommended best practices for the prevention of ORN after radiation therapy?
4. How should ORN be managed nonsurgically?
5. How should ORN be managed surgically?
6. When, how, and by whom should patients diagnosed with ORN be assessed for adverse events associated with and/or caused by ORN?
1. How should ORN be characterized, graded, and reported?
2. What are the recommended best practices for the prevention of ORN of the head and neck prior to radiation therapy?
3. What are the recommended best practices for the prevention of ORN after radiation therapy?
4. How should ORN be managed nonsurgically?
5. How should ORN be managed surgically?
6. When, how, and by whom should patients diagnosed with ORN be assessed for adverse events associated with and/or caused by ORN?
**GRADING**
Watson EE, Hueniken K, Lee J, et al: Development and standardization of an osteoradionecrosis classification system in head and neck cancer: implementation of a risk-based model. 2024. J Clin Oncol 10.1200/JCO.23.01951
**TABLE 5. ClinRad–A Novel Classification System for ORN**
| Description | Stage | Radiographic Findings | Clinical Findings | Intervention | ClinRad Clinical Trial Grade Proposal |
|---|---|---|---|---|---|
| Distinct from ORN, occurs more often in patients with history of RT | Minor bone spicules | None, aside from superficial sequestra | Superficial mobile spicules/ sequestra within mucosa | None indicated | Grade 0 |
| Radiographic evidence of bone necrosis confined to alveolar bone with no clinical signs of ORN | Stage 0 | Bone necrosis confined to alveolar bone including: Bone lysis/sclerosis Widening periodontal ligament (PDL) space Absence of osseous filling of extraction sockets | Intact mucosa | None indicated | Grade 1 |
| Clinical signs of ORN with or without radiographic evidence of bone necrosis confined to alveolar bone | Stage I | None or as stage 0 | Exposed bone$^a$ | Minor surgical intervention$^b$ and/or medical management$^c$ may be indicated with or without adjunctive conservative management$^d$ | Grade 2 |
| Radiographic evidence involving basilar bone or without clinical signs of ORN | Stage II | Bone necrosis involving the basilar bone or maxillary sinus | Intact mucosa or exposed bone$^a$ | Intermediate surgical intervention may be indicated$^e$, with or without adjunctive conservative and medical management | Grade 3 |
| Advanced ORN | Stage III | One or more of the following: Pathologic fracture Orocútaneous fistula Oral antral communication/oral nasal communication | One or more of the following: Pathologic fracture Orocútaneous fistula Oral antral communication/ oral nasal communication | Reconstructive surgical intervention is indicated$^f$, with or without adjunctive conservative and medical management | Grade 4 |
Abbreviations: **ORN**, **osteoradionecrosis**; **RT**, **radiotherapy**.
$^a$Including pinpoint mucosal breach (intraoral fistula) that probes to bone and/or probing to bone along periodontal tissues.
$^b$Examples include sequestrectomy.
$^c$Examples include pentoxifylline-tocopherol and hyperbaric oxygen.
$^d$Examples include chlorhexidine rinses and antibiotics.
$^e$Examples include transoral surgical intervention and debridement, alveolectomy, and soft tissue closure.
$^f$Examples include segmental maxillectomy/mandibulectomy with vascularized free tissue reconstruction.
#### Overview of the ClinRad Model
The ClinRad system was developed to provide a standardized, risk-based model for the classification of osteoradionecrosis (ORN) in head and neck cancer patients.
| Description | Stage | Radiographic Findings | Clinical Findings | Intervention | ClinRad Grade |
| :--- | :--- | :--- | :--- | :--- | :--- |
| Distinct from ORN; occurs more often in patients with history of RT | Minor bone spicules | None, aside from superficial sequestra | Superficial mobile spicules/sequestra within mucosa | None indicated | Grade 0 |
| Radiographic evidence of bone necrosis confined to alveolar bone; no clinical signs | Stage 0 | Bone necrosis (lysis/sclerosis, widened PDL space, lack of socket filling) | Intact mucosa | None indicated | Grade 1 |
| Clinical signs of ORN with or without alveolar bone necrosis | Stage I | None or as stage 0 | Exposed bone* | Minor surgical intervention** and/or medical management*** | Grade 2 |
| Radiographic evidence involving basilar bone or without clinical signs | Stage II | Bone necrosis involving the basilar bone or maxillary sinus | Intact mucosa or exposed bone* | Intermediate surgical intervention**** | Grade 3 |
| Advanced ORN | Stage III | Pathologic fracture, orocutaneous fistula, or oral antral/nasal communication | Pathologic fracture, orocutaneous fistula, or oral antral/nasal communication | Reconstructive surgical intervention***** | Grade 4 |
**Notes on Findings and Interventions:**
- *Includes pinpoint mucosal breach (intraoral fistula) probing to bone or probing along periodontal tissues.
- **Examples: sequestrectomy.
- ***Examples: pentoxifylline-tocopherol, hyperbaric oxygen, chlorhexidine rinses, and antibiotics.
- ****Examples: transoral surgical intervention, debridement, alveolectomy, and soft tissue closure.
- *****Examples: segmental maxillectomy/mandibulectomy with vascularized free tissue reconstruction.
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The image contains Table 5, titled "ClinRad-A Novel Classification System for ORN," which presents a classification system for osteoradionecrosis (ORN) in head and neck cancer. The table is organized into columns for Description, Stage, Radiographic Findings, Clinical Findings, Intervention, and ClinRad Clinical Trial Grade Proposal, detailing various stages of ORN from Grade 0 to Grade 4 based on clinical and radiographic evidence.
| Clinical Question | Recommendation | Type | Evidence Quality | Strength of Recommendation |
|---|---|---|---|---|
| 1. How should ORN be characterized, graded, and reported?<br>a. Which patients should be considered at high risk for ORN?<br>b. What is the recommended workup to characterize ORN? | 1.1. Osteoradionecrosis of the jaw (mandible, maxilla) should be characterized as a radiographic lytic or mixed sclerotic lesion of bone and/or visibly exposed bone and/or bone probed through a periodontal pocket or fistula, occurring within an anatomical site previously exposed to a therapeutic dose of head and neck radiation therapy | Informal consensus | Low | Strong |
| | 1.2. A patient with radiation dose to the jaw of 50 Gy or higher should be considered at risk for development of ORN. Modifiable risk factors including poor oral hygiene, dentoalveolar surgeries, and/or tobacco use, should be considered as further increasing this lifelong risk | Evidence-based | High | Strong |
| | 1.3. Clinicians evaluating ORN should utilize the ClinRad staging system for ORN, as should clinical trials | Evidence-based | Moderate | Strong |
| | 1.4. ORN assessment should have a defined formal characterization for disease evaluation at each visit which is usable across members of the clinical care or provider specialty spectrum. The panel recommends utilizing the ClinRad Classification system for ORN developed by Watson et al$^{83}$ | Evidence-based | Moderate | Strong |
| | 1.5. ORN case reporting and diagnosis should include formal informatics, ontology, and lexical standards consistent with the characterization noted in Recommendation 1.1 | Informal consensus | Low | Strong |
| | 1.6. Recommended initial evaluation of ORN should include one or more of the following: (1) clinical intraoral examination (including direct visual or endoscopic examination and/or formal periodontal assessment) and/or (2) formal radiographic examination (ie, x-ray orthopanogram, cone-beam or fan-beam computed tomography, magnetic resonance imaging) | Evidence-based | Moderate | Strong |
| | *Qualifying statement: If either clinical or radiographic findings are initially detected, suspected or positive, subsequent confirmatory examination or imaging assessment is recommended* | | | |
| | 1.7. Recommended serial characterization or surveillance of ORN should include clinical intraoral examination (including direct visual, endoscopic examination, and/or comprehensive periodontal assessment) and comprehensive radiographic examination (ie, x-ray orthopanogram, cone-beam or fan-beam computed tomography, magnetic resonance imaging) | Evidence-based | Moderate | Strong |
#### Characterization and Risk Assessment
- **1.1. Definition:** Osteoradionecrosis (ORN) of the jaw should be characterized as a radiographic lytic or mixed sclerotic lesion of bone and/or visibly exposed bone and/or bone probed through a periodontal pocket or fistula, occurring within an anatomical site previously exposed to therapeutic head and neck radiation. (Type: Informal consensus; Quality: Low; Strength: Strong)
- **1.2. Risk Factors:** Patients receiving a radiation dose to the jaw of 50 Gy or higher are at risk. Modifiable factors such as poor oral hygiene, dentoalveolar surgeries, and tobacco use further increase this lifelong risk. (Type: Evidence-based; Quality: High; Strength: Strong)
#### Staging and Reporting Standards
- **1.3. Staging System:** Clinicians and clinical trials should utilize the ClinRad staging system for ORN. (Type: Evidence-based; Quality: Moderate; Strength: Strong)
- **1.4. Formal Characterization:** ORN assessment must have a defined formal characterization usable across all clinical specialties. The panel recommends the ClinRad Classification system. (Type: Evidence-based; Quality: Moderate; Strength: Strong)
- **1.5. Informatics Standards:** Case reporting and diagnosis should include formal informatics, ontology, and lexical standards consistent with Recommendation 1.1. (Type: Informal consensus; Quality: Low; Strength: Strong)
#### Evaluation and Surveillance
- **1.6. Initial Evaluation:** Should include clinical intraoral examination (visual, endoscopic, or periodontal assessment) and/or formal radiographic examination (orthopanogram, CT, or MRI). (Type: Evidence-based; Quality: Moderate; Strength: Strong)
- *Qualifying statement: If findings are suspected or positive, subsequent confirmatory examination or imaging is recommended.*
- **1.7. Serial Surveillance:** Recommended monitoring includes clinical intraoral examination and comprehensive radiographic examination (orthopanogram, CT, or MRI). (Type: Evidence-based; Quality: Moderate; Strength: Strong)
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A structured table presenting clinical recommendations for osteoradionecrosis (ORN) of the jaw, categorized by clinical question, recommendation, evidence quality, and strength of recommendation. The table includes seven recommendations (1.1-1.7) related to characterization, risk assessment, workup, staging, reporting, and surveillance of ORN, with details on diagnostic methods such as clinical examination and radiographic imaging. The table also includes a qualifying statement regarding confirmatory assessments.
**PREVENTING ORN PRE-RADIOTHERAPY**
1. IMRT to reduce dose to bone to less than 50Gy
2. Comprehensive dental or hospital dentists review prior to RTx
3. Extraction of teeth with poor prognosis, moderate to severe periodontal disease within the field.
4. Consider extraction of teeth with periapical disease, caries, and partially erupted $3^{\text{rd}}$ molars – depending on individual and time for healing
5. Ideally at least 2 weeks of healing prior to Rtx but not at the cost of delaying Rtx
6. Aim exo's prior to mask fabrication if it will alter VD
7. High fluoride toothpaste
#### Clinical Protocols Before Radiation Therapy
1. Use IMRT to reduce the radiation dose to the bone to less than 50 Gy.
2. Conduct a comprehensive dental or hospital dentist review prior to radiotherapy.
3. Extract teeth with poor prognosis or moderate-to-severe periodontal disease within the radiation field.
4. Consider extraction of teeth with periapical disease, caries, and partially erupted third molars, depending on individual patient factors and time available for healing.
5. Ideally, allow at least 2 weeks of healing prior to radiotherapy, provided it does not delay the start of cancer treatment.
6. Aim to complete extractions prior to mask fabrication if the procedure will alter the vertical dimension (VD).
7. Prescribe high-fluoride toothpaste.
PREVENTING ORN POST RTX - SURGICAL
1. Review radiation fields prior to as part of treatment planning
2. Teeth at high risk of ORN – avoid exo’s if possible unless patient has recurrent infection, pain or
other sx that cannot be alleviated by extractions
3. Avoid implants in high risk zones
4. Oral antibiotics 1 day before and 7 days after dentoalveolar procedures + CHX mouthwash
5. If delayed healing post extractions occurs commence CHX mouthwash and observe with
specialist input
6. Pentoxifylline 400mg BD and tocopherol 1000IU 1 week prior and 4 week post exo or
preferably until socket is healed in cancer free patients (up to 3 months)
7. Preventive HBOT no longer supported for routine use
#### Surgical Protocols After Radiation Therapy
1. Review radiation fields as part of treatment planning prior to any surgical procedure.
2. For teeth at high risk of ORN, avoid extractions if possible unless the patient has recurrent infection, pain, or other symptoms that cannot be otherwise alleviated.
3. Avoid dental implants in high-risk radiation zones.
4. Administer oral antibiotics 1 day before and 7 days after dentoalveolar procedures, supplemented with chlorhexidine (CHX) mouthwash.
5. If delayed healing occurs post-extraction, commence CHX mouthwash and observe with specialist input.
6. Administer Pentoxifylline (400mg BD) and Tocopherol (1000IU) starting 1 week prior and continuing 4 weeks post-extraction, or preferably until the socket is healed in cancer-free patients (up to 3 months).
7. Preventive hyperbaric oxygen therapy (HBOT) is no longer supported for routine use.
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The image contains a numbered list of seven preventive measures for osteoradionecrosis (ORN) after radiation therapy, presented under the heading "PREVENTING ORN POST RTX - SURGICAL." The list includes recommendations such as reviewing radiation fields, avoiding extractions in high-risk teeth, avoiding implants in high-risk zones, using oral antibiotics and CHX mouthwash, monitoring delayed healing, administering pentoxifylline and tocopherol, and noting that preventive hyperbaric oxygen therapy (HBOT) is no longer supported for routine use. The content is text-based and formatted as a clinical guideline.
**TREATING ORN– NON-SURGICAL**
1. Pentoxyfylline may be used in cancer free patients. Potential to be beneficial esp combined with tocopherol, antibiotics and prednisolone
Pentoxifylline used in prevention of ORN
- Vasodilation, improves RBC deformation, antifibrotic (by inhibiting $\text{TNF}\alpha$)
- 3 months pre-exo until healed - 400mg BD
Tocopherol: Vitamin E - scavenges free radicals
1. HBOT in conjunction with surgical management may be used in cancer free patients. Most potential benefit in mild cases
#### Pharmacological Management
- **Pentoxifylline:** May be used in cancer-free patients. It is potentially beneficial when combined with tocopherol, antibiotics, and prednisolone.
- Mechanism: Promotes vasodilation, improves RBC deformation, and acts as an antifibrotic by inhibiting TNF-alpha.
- Dosage: 400mg BD from 3 months pre-extraction until healed.
- **Tocopherol (Vitamin E):** Used to scavenge free radicals.
#### Adjunctive Therapy
- **Hyperbaric Oxygen Therapy (HBOT):** May be used in conjunction with surgical management in cancer-free patients. It shows the most potential benefit in mild cases.
**TREATING ORN – SURGICAL**
1. ClinRad stage 1 or 2 – start with transoral minor intervention – debridement, sequestrectomy, alveolectomy, soft tissue flap closure
2. ClinRad stage 2, 3 or 4 – segmental resection and free flap reconstruction is recommended (esp if greater that 2.5cm in length)
3. Removal of superficial bony sequestra should be performed if viewed as low disk by the clinic. Reduction and disease burden and biofilm environment can be synergistic with the ongoing systemic therapy.
#### Surgical Intervention Strategies
1. **Early Stage (ClinRad Stage 1 or 2):** Initiate treatment with transoral minor interventions, including debridement, sequestrectomy, alveolectomy, and soft tissue flap closure.
2. **Advanced Stage (ClinRad Stage 2, 3, or 4):** Segmental resection and free flap reconstruction are recommended, especially if the lesion is greater than 2.5 cm in length.
3. **Sequestra Management:** Removal of superficial bony sequestra should be performed if assessed as low risk by the clinic. Reducing the disease burden and biofilm environment can act synergistically with ongoing systemic therapy.
#### Conservative Surgical Interventions
Conservative surgical approaches are typically employed for early-stage osteoradionecrosis (ORN) or as a preliminary measure to control infection and stabilize the affected area. These interventions include:
- **Sequestrectomy and Debridement**: Removal of necrotic bone fragments (sequestra) and infected soft tissue to promote healing of the surrounding healthy structures.
- **Clinical Outcomes**: While conservative surgery may provide symptomatic relief, the success rates vary depending on the extent of the disease and the vascularity of the remaining tissue.
#### Radical Surgical Resection and Reconstruction
For advanced or refractory ORN (Stages II and III), more extensive surgical procedures are often required to restore function and aesthetics.
- **Segmental Mandiburectomy**: Complete removal of the involved segment of the mandible when the bone is fractured or extensively necrotic.
- **Microvascular Free Tissue Transfer**: This is considered the gold standard for reconstructing large defects. Common donor sites include:
- Fibula free flap (preferred for long bony defects).
- Radial forearm osteocutaneous flap.
- Scapular flap.
- **Benefits of Vascularized Bone Grafts**: Unlike non-vascularized grafts, free flaps bring a new blood supply to the irradiated field, which is critical for successful healing and integration in a hypoxic environment.
#### Surgical Adjuncts and Considerations
- **Antibiotic Prophylaxis**: Perioperative antibiotics are standard practice to manage secondary infections, although they do not treat the underlying radiation-induced bone damage.
- **Pathologic Fractures**: The presence of an orocutaneous fistula or a pathologic fracture generally necessitates radical resection rather than conservative management.
- **Timing of Intervention**: Early identification and surgical referral are crucial for patients who do not respond to conservative medical management to prevent further bone loss and soft tissue complications.
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Close-up photo of the inside of a mouth showing a lesion on the tongue, with visible teeth and oral cavity structures.
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Close-up photo of the inside of a mouth showing a large, raised lesion on the lower lip, with visible teeth and oral cavity structures.
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Close-up photo of the inside of a mouth showing a large, irregular mass on the lower jaw near the teeth, with visible oral tissues and teeth.
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Close-up photo of the inside of a mouth showing a white, patchy lesion on the tongue, with visible teeth and oral cavity structures.
[^1]: Original PDF page 1: [[W2.2 ORN.pdf#page=1|W2.2 ORN, p.1]]
[^2]: Original PDF page 2: [[W2.2 ORN.pdf#page=2|W2.2 ORN, p.2]]
[^3]: Original PDF page 3: [[W2.2 ORN.pdf#page=3|W2.2 ORN, p.3]]
[^4]: Original PDF page 4: [[W2.2 ORN.pdf#page=4|W2.2 ORN, p.4]]
[^5]: Original PDF page 5: [[W2.2 ORN.pdf#page=5|W2.2 ORN, p.5]]
[^6]: Original PDF page 6: [[W2.2 ORN.pdf#page=6|W2.2 ORN, p.6]]
[^7]: Original PDF page 7: [[W2.2 ORN.pdf#page=7|W2.2 ORN, p.7]]
[^8]: Original PDF page 8: [[W2.2 ORN.pdf#page=8|W2.2 ORN, p.8]]
[^9]: Original PDF page 9: [[W2.2 ORN.pdf#page=9|W2.2 ORN, p.9]]
[^10]: Original PDF page 10: [[W2.2 ORN.pdf#page=10|W2.2 ORN, p.10]]
[^11]: Original PDF page 11: [[W2.2 ORN.pdf#page=11|W2.2 ORN, p.11]]