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Skull Base Neoplasms

Frontal Sinusitis

Communicable Diseases

Respiratory Tract Infections

Paranasal Sinus Diseases

Nose Diseases

Respiratory Tract Diseases

Otorhinolaryngologic Diseases

Chronic Graft Versus Host Disease

Coagulants

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Subjects within the control arm will undergo the Draf III/Endoscopic Modified Lothrop procedure to address their sinus disease. At the end of the procedure, no Cook Biodesign Porcine intestinal submucosal graft will be used to cover the operative site. Light nasal packing will be placed in the nasal cavity for hemostasis. No placebo will be utilized.

Subjects within the experimental group will undergo the Draf III/Endoscopic Modified Lothrop procedure to address their sinus disease. At the end of the procedure, a small piece of Cook Biodesign porcine intestinal submucosal xenograft will be used to cover the exposed bone of the operative site along the frontal beak. It will be bolstered with light nasal packing to keep the graft in place during healing.

Cook Biodesign ENT repair graft will be used in the experimental group to cover exposed bone in the sinonasal cavity as a result of the Draf III/endoscopic modified lothrop procedure.

Porcine Intestinal submucosal xenograft

Jeffrey D Suh, MD

We propose a randomized, single-blinded, prospective trial in order to evaluate the efficacy of the Cook Biodesign ENT Repair graft in improving outcomes after the Draf III or Endoscopic Modified Lothrop procedure. The Cook Biodesign ENT Repair graft is a porcine intestinal submucosal xenograft which has been FDA approved for use as an adjunct to natural healing process in the sinonasal cavity. The Draf III or Endoscopic Modified Lothrop involved creating a large unified drainage pathway for refractory frontal sinusitis. After the procedure is completed, there is exposed bone along the frontal beak region which can become a nidus for inflammation, crusting and eventual scarring, leading to stenosis or even complete blockage of the frontal sinuses. The Cook Biodesign will be used to cover this exposed bone in order to potentially reduce the inflammation, crusting and scarring and possibly improve outcomes.

Chronic rhinosinusitis (CRS) is an inflammatory disorder affecting the sinonasal mucosa. Chronic symptoms include facial pain and pressure, nasal airway obstruction, anosmia and nasal discharge (sometimes purulent), in addition to significant effects on overall quality of life. The cost of CRS is estimated to be approximately $4 billion per year and results in over 20 million physician visits per year. The frontal sinuses are paired paranasal sinuses housed superiorly and anteriorly in the frontal bone on each side, separated by an inter-sinus septum which is contiguous with the nasal septum. The frontal sinuses, like the other paranasal sinuses, can be affected in chronic rhinosinusitis, with inflammation of the frontal sinus outflow tract causing obstruction and subsequent symptoms. First line therapy involves medical therapy often with combination of antibiotics, nasal saline irrigation, topical and/or systemic corticosteroids, with endoscopic sinus surgical therapy reserved for patients with persistent symptoms after medical therapy.

Surgical therapy of the frontal sinus is the most technically demanding aspect of endoscopic sinus surgery, and due to this, surgical dissection of the frontal sinuses has been discouraged in the past. Otolaryngology textbooks also emphasize that chronic frontal sinus disease may be related to unnecessary instrumentation of the frontal recess. With recent advances in endoscopic sinus surgery and the advent of balloon sinusotomy, the rate of frontal sinus surgery has more than doubled from 2000 to 2009.

Primary frontal sinus surgery can be approached with balloon dilation or by endoscopic sinusotomy. Endoscopic sinusotomy of the frontal sinus involves increasing the size of the frontal recess with anterior ethmoidectomy and removal of the agger nasi cell anteriorly, and any frontal cells that may be present. Frontal sinus surgery is effective, as evidenced by a recent study analyzing long-term results after primary frontal sinus surgery showing a patency rate of 92% in a nearly 2-year average follow up period.

Refractory frontal sinusitis can be addressed surgically through external or 'extended' endonasal approaches. Historically, external approaches were first utilized, with introduction of osteoplastic flap techniques by Brieger in the 1890s. Lothrop introduced the Lothrop Procedure in 1914 which required an osteoplastic flap with removal of the frontal sinus floor and intersinus septum along with the upper aspect of the nasal septum to create a unified drainage pathway for the frontal sinuses. In the 1950s, Montgomery popularized the frontal sinus obliteration through osteoplastic flap approach leaving the frontal sinuses permanently non-functional through obliteration with fat or other materials. Though these external approaches often had high success rates, they require extensive dissection and are associated with a high morbidity and complication rate upwards of 20%. These complications included dural exposure, dural laceration with cerebrospinal fluid leak, orbital injury, forehead numbness, osteomyelitis and mucocele formation.

In 1991, Wolfgang Draf described an endoscopic approach to create a common drainage pathway akin to the Lothrop procedure which is now called the Endoscopic Modified Lothrop (EMLP) or Draf III procedure. Currently, the EMLP provides an endoscopic alternative for persistent frontal sinus disease after initial frontal sinusotomy, prior to consideration of frontal sinus obliteration through an osteoplastic flap approach. The EMLP involves drilling out the frontal sinus ostia on both sides and combining them through a superior septectomy, creating a large common drainage pathway for the two frontal sinuses. The EMLP offers reduced morbidity, shorter hospital stay, improved cosmetics, reduced blood loss and preservation of a functional frontal sinus. One meta-analysis study of 18 observational studies showed a restenosis rate of 19% and an overall failure rate of 13.9% (with failure defined as requiring revision surgery), with failure rates ranging from 0-33%. Restenosis of the frontal sinus ostium after EMLP is often attributed to a combination of scarring, adhesions or neo-osteogenesis, which occurs secondary to exposed bone after the surgical procedure. The exposed osteitic bone is believed to act as a source for inflammation and osteoblastic activity. Persistent mucosal disease has also been postulated as a contributor to postoperative stenosis after EMLP. Prevention of restenosis has been attempted with use of stents or medical therapy with topical application of mitomycin C and steroids with variable results.

Recent studies have attempted to address this issue by using mucosal grafts to cover the exposed frontal bone after EMLP. These studies describe using free or pedicled mucosal grafts from various sites in the nasal cavity to cover the bare bone exposed after EMLP drill out procedure. Two studies reported results using free mucosal grafts to cover the exposed bone and showed encouraging results, with patency rates 95% and 100%. Another study using a pedicled flap based off the anterior ethmoidal artery showed no restenosis in 4 patients. These studies utilize mucosa mostly from the nasal septum at the region of the superior septectomy which would otherwise be discarded, but they do also report use of inferior turbinate mucosa harvesting. Though minimal morbidity related to mucosal harvest was reported, any mucosal harvest from sites other than the operative site has the potential for creating additional postoperative morbidity. In addition, use of mucosa from a diseased mucosal cavity may not be optimal. Reducing rates of restenosis and failure in EMLP will allow for improved outcomes following this procedure and may prevent progression to more invasive and extensive surgical procedures.

This study will utilize a proprietary porcine intestinal submucosa graft Cook Biodesign™ ENT Repair graft to cover the exposed bone on the nasofrontal beak region following EMLP in order to evaluate its effects on mucosal healing and reduction of restenosis rates of the surgically augmented frontal sinus ostium after the Endoscopic Modified Lothrop Procedure. The Cook Biodesign™ ENT Repair for nasal mucosal replacement has been in use for sinonasal surgery since its Food and Drug Administration (FDA) approval in 2013. The Cook Biodesign™ ENT Repair graft is FDA approved for prescription use to "separate tissue or structures compromised by surgical trauma, help control minimal bleeding, and act as an adjunct to aid in the natural healing process. The device is indicated for use where an open wound dressing material is required in the nasal and/or sinus cavities following nasal and/or sinus surgery where separation of tissues or structures is desired."

The use of xenograft material in the method proposed in this submission has not been studied extensively. However, using free mucosal grafts or pedicled mucosal flaps after EMLP as previously discussed, have shown promise. The Cook Biodesign™ has been used preliminarily with patients in this proposed setting with good anecdotal results, including reduced crusting and good postoperative outcomes, however, its use has not yet been formally evaluated. The Cook Biodesign™ graft has several advantages over using native mucosal grafts: it is readily available and does not require harvest thus reducing operative times and potential morbidity from mucosa harvest sites, it is thinner than sinus mucosa and handled with ease, and it has tissue characteristics that promote wound healing. With the Cook Biodesign™, our hypothesis is that its use after EMLP surgery will allow for reduction of exposed bone in the sinonasal cavity and thus reduce inflammation, crusting and ultimately reduce restenosis and failure rates. Additionally, we hypothesize that reduction of crusting and inflammation will lead to improved patient reported symptom and quality of life scores on the Sinonasal Outcomes Test-22 (SNOT-22) questionnaire.

Improvement of Outcomes in Draf III/Endoscopic Modified Lothrop Procedure

Prospective Study for Improvement in Outcomes Following Draf III/Endoscopic Modified Lothrop Procedure Using a Porcine Intestinal Submucosal Graft

Evaluate the size of the frontal sinus outflow tract over one year after surgery

Track the number of debridements required in the postoperative period

Track if any further surgical procedures (in office or in operating room) that are required during postoperative period

Track the number of postoperative sinus infections, proven by culture, as well as the number of antibiotic courses required for treatment.

Evaluation of the sinuses using nasal endoscopy and objective measurement using the validated Lund-Kennedy Endoscopy score

Evaluation of patient quality of life using a validated questionnaire called the Sinonasal Outcome Test (SNOT) - 22.

University of California, Los Angeles

Assistant Professor, Department of Head and Neck Surgery

Digestive System Diseases

Mouth and Tooth Diseases

Colorectal Neoplasms

Nasopharyngeal Neoplasms

Chronic Disease

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Pharyngeal Neoplasms

Otorhinolaryngologic Neoplasms

Head and Neck Neoplasms

Nasopharyngeal Diseases

Pharyngeal Diseases

Stomatognathic Diseases

Disease Attributes

Anti-Inflammatory Agents

Respiratory System Agents

Budesonide

Bronchodilator Agents

Anti-Asthmatic Agents

Glucocorticoids

Hormones

Hormone Antagonists

each subject serves as their own control with one nostril being treated with pulmicort and one not

pulmicort

Garrett R Griffin, MD

That high-dose steroid applied to the nasal cavity immediately post-operatively will improve olfaction and healing following endoscopic sinus surgery.

Nasal Packing as a Drug Delivery System Postoperatively in Chronic Sinusitis With Polyposis

will be measured with the University of Pennsylvania Smell Identification Test (UPSIT), whose scores range from 0 to 40, where 0 is the inability to smell anything and 40 is perfect smell identification

will be assessed with the Perioperative Sinus Endoscopy score (POSE), a 20 point scale where 0 is no sinus challenges and 20 represents the greatest blockage.

Scored with the University of Pennsylvania Smell Identification Test, whose scores range from 0 to 40, where 0 is the inability to smell anything and 40 is perfect smell identification

Assessed with Perioperative Sinus Endoscopy (POSE) score

American Rhinologic Society

University of Michigan

Resident/Research Fellow

each subject serves as their own control with one nostril being treated with pulmicort and one not

pulmicort: applied to nasal packing after surgery

Single Arm; Nostrils as Experimental and Comparator

Age, Categorical

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

This was a pilot study with less enrollment than desired and poor rate of completion with only 5 participants completing the full 24 week trial. This study could be done on a larger/similar scale with some additional useful data obtained.

Garrett Griffin, MD

Treated Nostril (Pulmicort)

Untreated Nostril (no Pulmicort)

Of sixteen participants at the three week mark, one participant's data was unable to be unblinded accurately, and one participant had no UPSIT scores taken, leaving an analysis population of 14,

Olfaction

Placebo Treated Nostril (no Pulmicort)

unblinding could not be done on one person accurately, so only 15 rather than 16 people's data could be analyzed

Sinonasal Health

Placebo/Untreated Nostril (no Pulmicort)

Of six participants remaining at 24 weeks, one participant's data could not be accurately unblinded leaving analysis of 5

Of six participants at 24 weeks, one's data was unable to be unblinded accurately, leaving an analysis population of 5 participants

Overall Study

Epistaxis

Paranasal Sinus Neoplasms

Hemorrhage

Signs and Symptoms, Respiratory

Skull Neoplasms

Bone Neoplasms

Bone Diseases

Nose Neoplasms

Respiratory Tract Neoplasms

Those who are undergoing endoscopic sinonasal surgery for benign and malignant tumor removal.

Those who are receiving Endoscopic Skull Base Surgery (ESBS) for minimally-invasive access for removal of skull base tumors, most commonly for ones of pituitary origin.

Individuals with chronic rhinosinusitis (CRS) with or without polyposis that are to have endoscopic sinus surgery, a minimally invasive procedure to open the sinuses.

Those who have severe nose bleeds and requires going into the operating room for management.

During sinus tumor resection, margins will initially be estimated with the naked eye. Then the dye, Indocyanine Green (ICG), will be injected through the intravenous line to identify tumor margins and be compared to estimated margins.

Sinonasal Benign or Malignant Tumor Resection

In this surgery, a piece of individuals septum will be used for the reconstruction. The amount of time for the flap to fluoresce Indocyanine Green (ICG) will be measured. It will be ensured that the it is still lighting up at the end of the surgery, indicating it is still receiving a good supply and ensures longevity of the flap.

Skull Base Surgery (Assessment of Nasoseptal Flap)

During the surgery, the timing of Indocyanine Green (ICG) administration to fluorescence of anterior and posterior ethmoidal artery and of the internal carotid artery will be measured.

Endoscopic Sinus Surgery

During surgery timing of Indocyanin Green (ICG) administration to fluorescence of the sphenopalatine artery will be measured.

Posterior Epistaxis Management (SPA Ligation)

The endoscope is a device placed into the nasal cavity to remove chronic sinus disease or tumor or create access into the skullbase for extensive tumor removal. Indocyanine Green (ICG) is a dye that is injected through an intravenous site and is used to light up vasculature and margins of a tumor during surgery. This helps avoid damage to important vasculature and obtain clear margins during surgery. This study aims to further assess the utility of ICG when operating within the nasal cavity or skullbase.

The investigators aim to evaluate the effectiveness and feasibility of using a fluorescent dye, Indocyanine Green (ICG), in endoscopic sinus, skullbase, sinus tumor resection, or posterior epistaxis surgery.

Adults 19 years or older, seen in the Principal Investigator and Sub investigator's offices presenting with either CRS, benign or malignant sinonasal, skull base tumors, or posterior epistaxis will be identified by the Principal Investigators and invited to participate in this prospective study. Patients will be recruited into the study in a consecutive manner. After providing consent, baseline characteristics will be collected. The investigators aim to recruit 10 patients in each study group respectively given the patients diagnosis.

Sinus tumor resection - Initially margins will be estimated with the naked eye. Then they will be compared to the margins that are fluorescing with the dye.

Skull base tumor resection - The investigators will use a part of the participant's septum for the reconstruction. The investigators will measure the time it takes for the flap to fluoresce and ensure that it is still lighting up at the end of the surgery. This means that it is still receiving a good supply and ensures longevity of the flap.

Sinus Surgery - During the participant's surgery, the investigator will come across important vessels that will be preserved. The investigator will see if the ICG is able to light up those vessels and if it does, then measure the time it takes to light up will be measured.

Posterior epistaxis - If a participant experiences a nose bleed that requires going into the operating room, the investigator will use ICG to locate the vessel that needs to be cauterized. The investigators will measure the time it takes for that vessel to light up.

The investigator will see the participants back on their day of surgery. During surgery, Indocyanine Green (ICG) will be injected through their intravenous line. The investigator will start with the smallest dose and increase to a dose that allows us to see the structures of interest such as vessels or tumor margins. The time it takes for a vessel or margins of a tumor to light up will be measured. Intra-operative data specific to each type of surgery being performed will be collected.

Dose-Escalation Protocol Intravenous injection

* 1.25mg (0.5mL)
* 2.5mg (1mL)
* 3.75mg (1.5mL)
* 5mg (2mL)
* 6.25mg (2.5mL) \[at discretion of surgeon\]
* 7.5mg (3mL) \[at discretion of surgeon\]

Intralesional injection

* 1.25mg (0.5mL)
* 2.5mg (1mL)
* 3.75mg (1.5mL)
* 5mg (2mL)
* 6.25mg (2.5mL) \[at discretion of surgeon\]
* 7.5mg (3mL) \[at discretion of surgeon\]

Descriptive statistics (count, absolute frequency, and 95% confidence interval) will be used to analyze the baseline characteristic data.

Prospective Case-Series and Feasibility Study

Utility of Indocyanine Green Fluorescence in Endoscopic Sinonasal and Skull Base Surgery

The Utility of Indocyanine Green Fluorescence in Endoscopic Sinonasal and Skull Base Surgery - A Prospective Case-Series and Feasibility Study

During surgery, the amount of time it takes for the area of interest to fluoresce will be recorded.

The total amount of ICG administrated to reach fluorescence of distinct structure will be recorded.

The maximum does/interval of ICG administrated to reach fluorescence of distinct structure will be recorded.

Images of the structure of interests origins and margins will be captured. Images estimated by the surgeon and ICG will be collected.

Any adverse events to ICG that are experienced will be collected.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Improvement of Outcomes in Draf III/Endoscopic Modified Lothrop Procedure	NCT02981017	Chronic Sinusit... Frontal Sinusit...	Porcine Intesti...	18 Years -	University of California, Los Angeles
Nasal Packing as a Drug Delivery System Postoperatively in Chronic Sinusitis With Polyposis	NCT01197612	Chronic Sinusit... Polyposis	pulmicort	18 Years - 99 Years	University of Michigan
Utility of Indocyanine Green Fluorescence in Endoscopic Sinonasal and Skull Base Surgery	NCT04374448	Chronic Sinusit... Tumor of Nasal ... Posterior Epist... Skull Base Neop...	Sinonasal Benig... Skull Base Surg... Endoscopic Sinu... Posterior Epist...	19 Years -	St. Paul's Sinus Centre

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